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Sample records for tumor tracking delivery

  1. SU-E-T-183: Clinical Quality Assurance Workflow for Dynamic Tumor Tracking Radiation Dose Delivery

    International Nuclear Information System (INIS)

    Mamalui-Hunter, M; Su, Z; Li, Z

    2015-01-01

    Purpose: One of the most important aspects of implementation of new treatment modalities is an ‘end-to-end’ verification of the treatment process. Radiation treatment based on dynamic tracking of a tumor is highly patient-specific, therefore, special attention should be paid to quality assurance of the treatment delivery. Our goal was to design the clinical workflow that ensures accurate delivery of the planned dose using the Dynamic Target Tracking option of VeroTM (BrainLab,MHI) linac. Methods: A patient simulation is designed to include a pre-treatment session to verify whether the system can reliably track the motion of the implanted marker and build the 4D model of the target motion. The external surrogate and target motion patterns are recorded in the ExactracTM log files. In this work, a spectrum of custom marker and external surrogate motion trajectories closely resembling the patient specific motion patterns was used. 1mm thick/11mm long VisicoilTM marker was placed 15 and 20mm from the center of the spherical tissue equivalent target (centroid to centroid distance) in the 4D motion phantom (CIRSTM). 3D conformal (3 mm block margin) SBRT plans were delivered to 2 moving targets in the phantom: 1) 20mm diameter target that allows ion chamber dose measurement and 2) 25mm target that allows using film to measure CAX dose (GafchromicTM EBT3 used). The measured dose was compared to the iPlanTM TPS results using MonteCarlo algorithm (1% variance, Dose-to-water). Results: On average, film shows 98.9% pass using gamma criterion for 2% and 2mm DTA, 94.3% match for 2% and 1 mm DTA, 98% pass for 1% and 2 mm DTA however only 88% points passing for 1% and 1 mm DTA. Ion chamber measurements agreed with the calculation within 1.5%. Conclusion: The clinical QA workflow was designed for SBRT delivery using real-time tumor tracking on VeroTM linac

  2. Motion management during IMAT treatment of mobile lung tumors-A comparison of MLC tracking and gated delivery

    DEFF Research Database (Denmark)

    Falk, Marianne; Pommer, Tobias; Keall, Paul

    2014-01-01

    Purpose:To compare real-time dynamic multileaf collimator (MLC) tracking, respiratory amplitude and phase gating, and no compensation for intrafraction motion management during intensity modulated arc therapy (IMAT). Methods: Motion management with MLC tracking and gating was evaluated for four...... tracking reduced the effects of the target movements, although the gated delivery showed a better dosimetric accuracy and enabled a larger reduction of the margins in some cases. MLC tracking did not prolong the treatment time compared to delivery with no motion compensation while gating had a considerably...... of the dosimetric error contributions showed that the gated delivery mainly had errors in target localization, while MLC tracking also had contributions from MLC leaf fitting and leaf adjustment. The average treatment time was about three times longer with gating compared to delivery with MLC tracking (that did...

  3. Fiber tracking for brain tumor

    International Nuclear Information System (INIS)

    Yamada, Kei; Nakamura, Hisao; Ito, Hirotoshi; Tanaka, Osamu; Kubota, Takao; Yuen, Sachiko; Kizu, Osamu; Nishimura, Tsunehiko

    2003-01-01

    The purpose of this study was to validate an innovative scanning method for patients diagnosed with brain tumors. Using a 1.5 Tesla whole body magnetic resonance (MR) imager, 23 patients with brain tumors were scanned. The recorded data points of the diffusion-tensor imaging (DTI) sequences were 128 x 37 with the parallel imaging technique. The parallel imaging technique was equivalent to a true resolution of 128 x 74. The scan parameters were repetition time (TR)=6000, echo time (TE)=88, 6 averaging with a b-value of 800 s/mm 2 . The total scan time for DTI was 4 minutes and 24 seconds. DTI scans and subsequent fiber tracking were successfully applied in all cases. All fiber tracts on the contralesional side were visualized in the expected locations. Fiber tracts on the lesional side had varying degrees of displacement, disruption, or a combination of displacement and disruption due to the tumor. Tract disruption resulted from direct tumor involvement, compression upon the tract, and vasogenic edema surrounding the tumor. This DTI method using a parallel imaging technique allows for clinically feasible fiber tracking that can be incorporated into a routine MR examination. (author)

  4. Brain tumor-targeted drug delivery strategies

    Directory of Open Access Journals (Sweden)

    Xiaoli Wei

    2014-06-01

    Full Text Available Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.

  5. Lung tumor tracking in fluoroscopic video based on optical flow

    International Nuclear Information System (INIS)

    Xu Qianyi; Hamilton, Russell J.; Schowengerdt, Robert A.; Alexander, Brian; Jiang, Steve B.

    2008-01-01

    Respiratory gating and tumor tracking for dynamic multileaf collimator delivery require accurate and real-time localization of the lung tumor position during treatment. Deriving tumor position from external surrogates such as abdominal surface motion may have large uncertainties due to the intra- and interfraction variations of the correlation between the external surrogates and internal tumor motion. Implanted fiducial markers can be used to track tumors fluoroscopically in real time with sufficient accuracy. However, it may not be a practical procedure when implanting fiducials bronchoscopically. In this work, a method is presented to track the lung tumor mass or relevant anatomic features projected in fluoroscopic images without implanted fiducial markers based on an optical flow algorithm. The algorithm generates the centroid position of the tracked target and ignores shape changes of the tumor mass shadow. The tracking starts with a segmented tumor projection in an initial image frame. Then, the optical flow between this and all incoming frames acquired during treatment delivery is computed as initial estimations of tumor centroid displacements. The tumor contour in the initial frame is transferred to the incoming frames based on the average of the motion vectors, and its positions in the incoming frames are determined by fine-tuning the contour positions using a template matching algorithm with a small search range. The tracking results were validated by comparing with clinician determined contours on each frame. The position difference in 95% of the frames was found to be less than 1.4 pixels (∼0.7 mm) in the best case and 2.8 pixels (∼1.4 mm) in the worst case for the five patients studied.

  6. MRI-guided tumor tracking in lung cancer radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Cervino, Laura I; Jiang, Steve B [Center for Advanced Radiotherapy Technology and Department of Radiation Oncology, University of California San Diego, 3960 Health Sciences Dr., La Jolla, CA 92093-0865 (United States); Du, Jiang, E-mail: lcervino@ucsd.edu [Department of Radiology, University of California San Diego, 200 West Arbor Dr., San Diego, CA 92103-8226 (United States)

    2011-07-07

    Precise tracking of lung tumor motion during treatment delivery still represents a challenge in radiation therapy. Prototypes of MRI-linac hybrid systems are being created which have the potential of ionization-free real-time imaging of the tumor. This study evaluates the performance of lung tumor tracking algorithms in cine-MRI sagittal images from five healthy volunteers. Visible vascular structures were used as targets. Volunteers performed several series of regular and irregular breathing. Two tracking algorithms were implemented and evaluated: a template matching (TM) algorithm in combination with surrogate tracking using the diaphragm (surrogate was used when the maximum correlation between the template and the image in the search window was less than specified), and an artificial neural network (ANN) model based on the principal components of a region of interest that encompasses the target motion. The mean tracking error e and the error at 95% confidence level e{sub 95} were evaluated for each model. The ANN model led to e = 1.5 mm and e{sub 95} = 4.2 mm, while TM led to e = 0.6 mm and e{sub 95} = 1.0 mm. An extra series was considered separately to evaluate the benefit of using surrogate tracking in combination with TM when target out-of-plane motion occurs. For this series, the mean error was 7.2 mm using only TM and 1.7 mm when the surrogate was used in combination with TM. Results show that, as opposed to tracking with other imaging modalities, ANN does not perform well in MR-guided tracking. TM, however, leads to highly accurate tracking. Out-of-plane motion could be addressed by surrogate tracking using the diaphragm, which can be easily identified in the images.

  7. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

    Directory of Open Access Journals (Sweden)

    Bo Zhang

    2017-12-01

    Full Text Available Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents.

  8. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

    Science.gov (United States)

    Zhang, Bo; Hu, Yu; Pang, Zhiqing

    2017-01-01

    Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR) effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents. PMID:29311946

  9. Real-Time Tumor Tracking in the Lung Using an Electromagnetic Tracking System

    Energy Technology Data Exchange (ETDEWEB)

    Shah, Amish P., E-mail: Amish.Shah@orlandohealth.com [Department of Radiation Oncology, MD Anderson Cancer Center Orlando, Orlando, Florida (United States); Kupelian, Patrick A.; Waghorn, Benjamin J.; Willoughby, Twyla R.; Rineer, Justin M.; Mañon, Rafael R.; Vollenweider, Mark A.; Meeks, Sanford L. [Department of Radiation Oncology, MD Anderson Cancer Center Orlando, Orlando, Florida (United States)

    2013-07-01

    Purpose: To describe the first use of the commercially available Calypso 4D Localization System in the lung. Methods and Materials: Under an institutional review board-approved protocol and an investigational device exemption from the US Food and Drug Administration, the Calypso system was used with nonclinical methods to acquire real-time 4-dimensional lung tumor tracks for 7 lung cancer patients. The aims of the study were to investigate (1) the potential for bronchoscopic implantation; (2) the stability of smooth-surface beacon transponders (transponders) after implantation; and (3) the ability to acquire tracking information within the lung. Electromagnetic tracking was not used for any clinical decision making and could only be performed before any radiation delivery in a research setting. All motion tracks for each patient were reviewed, and values of the average displacement, amplitude of motion, period, and associated correlation to a sinusoidal model (R{sup 2}) were tabulated for all 42 tracks. Results: For all 7 patients at least 1 transponder was successfully implanted. To assist in securing the transponder at the tumor site, it was necessary to implant a secondary fiducial for most transponders owing to the transponder's smooth surface. For 3 patients, insertion into the lung proved difficult, with only 1 transponder remaining fixed during implantation. One patient developed a pneumothorax after implantation of the secondary fiducial. Once implanted, 13 of 14 transponders remained stable within the lung and were successfully tracked with the tracking system. Conclusions: Our initial experience with electromagnetic guidance within the lung demonstrates that transponder implantation and tracking is achievable though not clinically available. This research investigation proved that lung tumor motion exhibits large variations from fraction to fraction within a single patient and that improvements to both transponder and tracking system are still

  10. Real-time tumor-tracking radiotherapy for adrenal tumors

    International Nuclear Information System (INIS)

    Katoh, Norio; Onimaru, Rikiya; Sakuhara, Yusuke; Abo, Daisuke; Shimizu, Shinichi; Taguchi, Hiroshi; Watanabe, Yoshiaki; Shinohara, Nobuo; Ishikawa, Masayori; Shirato, Hiroki

    2008-01-01

    Purpose: To investigate the three-dimensional movement of internal fiducial markers near the adrenal tumors using a real-time tumor-tracking radiotherapy (RTRT) system and to examine the feasibility of high-dose hypofractionated radiotherapy for the adrenal tumors. Materials and methods: The subjects considered in this study were 10 markers of the 9 patients treated with RTRT. A total of 72 days in the prone position and 61 treatment days in the supine position for nine of the 10 markers were analyzed. All but one patient were prescribed 48 Gy in eight fractions at the isocenter. Results: The average absolute amplitude of the marker movement in the prone position was 6.1 ± 4.4 mm (range 2.3-14.4), 11.1 ± 7.1 mm (3.5-25.2), and 7.0 ± 3.5 mm (3.9-12.5) in the left-right (LR), craniocaudal (CC), and anterior-posterior (AP) directions, respectively. The average absolute amplitude in the supine position was 3.4 ± 2.9 mm (0.6-9.1), 9.9 ± 9.8 mm (1.1-27.1), and 5.4 ± 5.2 mm (1.7-26.6) in the LR, CC, and AP directions, respectively. Of the eight markers, which were examined in both the prone and supine positions, there was no significant difference in the average absolute amplitude between the two positions. No symptomatic adverse effects were observed within the median follow-up period of 16 months (range 5-21 months). The actuarial freedom-from-local-progression rate was 100% at 12 months. Conclusions: Three-dimensional motion of a fiducial marker near the adrenal tumors was detected. Hypofractionated RTRT for adrenal tumors was feasible for patients with metastatic tumors

  11. Tracking tumor boundary in MV-EPID images without implanted markers: A feasibility study

    International Nuclear Information System (INIS)

    Zhang, Xiaoyong; Homma, Noriyasu; Ichiji, Kei; Takai, Yoshihiro; Yoshizawa, Makoto

    2015-01-01

    tumor boundary in EPID images by using a LSM-based algorithm. Experimental results conducted on phantom and clinical EPID images demonstrated the effectiveness of the tracking algorithm for visible tumor target. Compared with previous tracking methods, the authors’ algorithm has the potential to improve the tracking accuracy in radiation therapy. In addition, real-time tumor boundary information within the irradiation field will be potentially useful for further applications, such as adaptive beam delivery, dose evaluation

  12. A robotic approach to 4D real-time tumor tracking for radiotherapy

    International Nuclear Information System (INIS)

    Buzurovic, I; Yu, Y; Huang, K; Podder, T K

    2011-01-01

    Respiratory and cardiac motions induce displacement and deformation of the tumor volumes in various internal organs. To accommodate this undesired movement and other errors, physicians incorporate a large margin around the tumor to delineate the planning target volume, so that the clinical target volume receives the prescribed radiation dose under any scenario. Consequently, a large volume of healthy tissue is irradiated and sometimes it is difficult to spare critical organs adjacent to the tumor. In this study we have proposed a novel approach to the 4D active tracking and dynamic delivery incorporating the tumor motion prediction technique. This method has been applied to the two commercially available robotic treatment couches. The proposed algorithm can predict the tumor position and the robotic systems are able to continuously track the tumor during radiation dose delivery. Therefore a precise dose is given to a moving target while the dose to the nearby critical organs is reduced to improve the patient treatment outcome. The efficacy of the proposed method has been investigated by extensive computer simulation. The tumor tracking method is simulated for two couches: HexaPOD robotic couch and ELEKTA Precise Table. The comparison results have been presented in this paper. In order to assess the clinical significance, dosimetric effects of the proposed method have been analyzed.

  13. Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery.

    Science.gov (United States)

    Gao, Ning; Bozeman, Erica N; Qian, Weiping; Wang, Liya; Chen, Hongyu; Lipowska, Malgorzata; Staley, Charles A; Wang, Y Andrew; Mao, Hui; Yang, Lily

    2017-01-01

    The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.

  14. Tumor tracking and motion compensation with an adaptive tumor tracking system (ATTS): System description and prototype testing

    International Nuclear Information System (INIS)

    Wilbert, Juergen; Meyer, Juergen; Baier, Kurt; Guckenberger, Matthias; Herrmann, Christian; Hess, Robin; Janka, Christian; Ma Lei; Mersebach, Torben; Richter, Anne; Roth, Michael; Schilling, Klaus; Flentje, Michael

    2008-01-01

    A novel system for real-time tumor tracking and motion compensation with a robotic HexaPOD treatment couch is described. The approach is based on continuous tracking of the tumor motion in portal images without implanted fiducial markers, using the therapeutic megavoltage beam, and tracking of abdominal breathing motion with optical markers. Based on the two independently acquired data sets the table movements for motion compensation are calculated. The principle of operation of the entire prototype system is detailed first. In the second part the performance of the HexaPOD couch was investigated with a robotic four-dimensional-phantom capable of simulating real patient tumor trajectories in three-dimensional space. The performance and limitations of the HexaPOD table and the control system were characterized in terms of its dynamic behavior. The maximum speed and acceleration of the HexaPOD were 8 mm/s and 34.5 mm/s 2 in the lateral direction, and 9.5 mm/s and 29.5 mm/s 2 in longitudinal and anterior-posterior direction, respectively. Base line drifts of the mean tumor position of realistic lung tumor trajectories could be fully compensated. For continuous tumor tracking and motion compensation a reduction of tumor motion up to 68% of the original amplitude was achieved. In conclusion, this study demonstrated that it is technically feasible to compensate breathing induced tumor motion in the lung with the adaptive tumor tracking system

  15. TH-E-17A-10: Markerless Lung Tumor Tracking Based On Beams Eye View EPID Images

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, T; Kearney, V; Liu, H; Jiang, L; Foster, R; Mao, W [UT Southwestern Medical Center, Dallas, Texas (United States); Rozario, T; Bereg, S [University of Texas at Dallas, Richardson, Texas (United States); Klash, S [Premier Cancer Centers, Dallas, TX (United States)

    2014-06-15

    Purpose: Dynamic tumor tracking or motion compensation techniques have proposed to modify beam delivery following lung tumor motion on the flight. Conventional treatment plan QA could be performed in advance since every delivery may be different. Markerless lung tumor tracking using beams eye view EPID images provides a best treatment evaluation mechanism. The purpose of this study is to improve the accuracy of the online markerless lung tumor motion tracking method. Methods: The lung tumor could be located on every frame of MV images during radiation therapy treatment by comparing with corresponding digitally reconstructed radiograph (DRR). A kV-MV CT corresponding curve is applied on planning kV CT to generate MV CT images for patients in order to enhance the similarity between DRRs and MV treatment images. This kV-MV CT corresponding curve was obtained by scanning a same CT electron density phantom by a kV CT scanner and MV scanner (Tomotherapy) or MV CBCT. Two sets of MV DRRs were then generated for tumor and anatomy without tumor as the references to tracking the tumor on beams eye view EPID images. Results: Phantom studies were performed on a Varian TrueBeam linac. MV treatment images were acquired continuously during each treatment beam delivery at 12 gantry angles by iTools. Markerless tumor tracking was applied with DRRs generated from simulated MVCT. Tumors were tracked on every frame of images and compared with expected positions based on programed phantom motion. It was found that the average tracking error were 2.3 mm. Conclusion: This algorithm is capable of detecting lung tumors at complicated environment without implanting markers. It should be noted that the CT data has a slice thickness of 3 mm. This shows the statistical accuracy is better than the spatial accuracy. This project has been supported by a Varian Research Grant.

  16. [The development of novel tumor targeting delivery strategy].

    Science.gov (United States)

    Gao, Hui-le; Jiang, Xin-guo

    2016-02-01

    Tumor is one of the most serious threats for human being. Although many anti-tumor drugs are approved for clinical use, the treatment outcome is still modest because of the poor tumor targeting efficiency and low accumulation in tumor. Therefore, it is important to deliver anti-tumor drug into tumor efficiently, elevate drug concentration in tumor tissues and reduce the drug distribution in normal tissues. And it has been one of the most attractive directions of pharmaceutical academy and industry. Many kinds of strategies, especially various nanoparticulated drug delivery systems, have been developed to address the critical points of complex tumor microenvironment, which are partially or mostly satisfied for tumor treatment. In this paper, we carefully reviewed the novel targeting delivery strategies developed in recent years. The most powerful method is passive targeting delivery based on the enhanced permeability and retention(EPR) effect, and most commercial nanomedicines are based on the EPR effect. However, the high permeability and retention require different particle sizes, thus several kinds of size-changeable nanoparticles are developed, such as size reducible particles and assemble particles, to satisfy the controversial requirement for particle size and enhance both tumor retention and penetration. Surface charge reversible nanoparticles also shows a high efficiency because the anionic charge in blood circulation and normal organs decrease the unintended internalization. The charge can change into positive in tumor microenvironment, facilitating drug uptake by tumor cells. Additionally, tumor microenvironment responsive drug release is important to decrease drug side effect, and many strategies are developed, such as p H sensitive release and enzyme sensitive release. Except the responsive nanoparticles, shaping tumor microenvironment could attenuate the barriers in drug delivery, for example, decreasing tumor collagen intensity and normalizing tumor

  17. Targeted drug delivery and penetration into solid tumors.

    Science.gov (United States)

    Corti, Angelo; Pastorino, Fabio; Curnis, Flavio; Arap, Wadih; Ponzoni, Mirco; Pasqualini, Renata

    2012-09-01

    Delivery and penetration of chemotherapeutic drugs into tumors are limited by a number of factors related to abnormal vasculature and altered stroma composition in neoplastic tissues. Coupling of chemotherapeutic drugs with tumor vasculature-homing peptides or administration of drugs in combination with biological agents that affect the integrity of the endothelial lining of tumor vasculature is an appealing strategy to improve drug delivery to tumor cells. Promising approaches to achieve this goal are based on the use of Asn-Gly-Arg (NGR)-containing peptides as ligands for drug delivery and of NGR-TNF, a peptide-tumor necrosis factor-α fusion protein that selectively alters drug penetration barriers and that is currently tested in a randomized Phase III trial in patients with malignant pleural mesothelioma. © 2011 Wiley Periodicals, Inc.

  18. Vibrations of a delivery car excited by railway track crossing

    International Nuclear Information System (INIS)

    Litak, Grzegorz; Borowiec, Marek; Hunicz, Jacek; Koszalka, Grzegorz; Niewczas, Andrzej

    2009-01-01

    Vertical vibrations of a delivery car passing through railway tracks have been investigated in this paper. The application of recurrence plots allows to examine short time series of acceleration non-stationary courses. Recurrence quantification analysis and square deviations estimated in small windows have been used to monitor car vibrations and transient behaviour. Measuring acceleration on the 'sprung' and 'unsprung' masses of a vehicle has enabled also to test the quality of a car suspension.

  19. T cells enhance gold nanoparticle delivery to tumors in vivo

    Science.gov (United States)

    Kennedy, Laura C.; Bear, Adham S.; Young, Joseph K.; Lewinski, Nastassja A.; Kim, Jean; Foster, Aaron E.; Drezek, Rebekah A.

    2011-12-01

    Gold nanoparticle-mediated photothermal therapy (PTT) has shown great potential for the treatment of cancer in mouse studies and is now being evaluated in clinical trials. For this therapy, gold nanoparticles (AuNPs) are injected intravenously and are allowed to accumulate within the tumor via the enhanced permeability and retention (EPR) effect. The tumor is then irradiated with a near infrared laser, whose energy is absorbed by the AuNPs and translated into heat. While reliance on the EPR effect for tumor targeting has proven adequate for vascularized tumors in small animal models, the efficiency and specificity of tumor delivery in vivo, particularly in tumors with poor blood supply, has proven challenging. In this study, we examine whether human T cells can be used as cellular delivery vehicles for AuNP transport into tumors. We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production). Using a human tumor xenograft mouse model, we next demonstrate that AuNP-loaded T cells retain their capacity to migrate to tumor sites in vivo. In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution. Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation.

  20. Toward the development of intrafraction tumor deformation tracking using a dynamic multi-leaf collimator

    Energy Technology Data Exchange (ETDEWEB)

    Ge, Yuanyuan; O’Brien, Ricky T.; Shieh, Chun-Chien; Keall, Paul J., E-mail: paul.keall@sydney.edu.au [Radiation Physics Laboratory, University of Sydney, NSW 2006 (Australia); Booth, Jeremy T. [Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW 2065 (Australia)

    2014-06-15

    experimental investigation of adapting to tumor deformation has been performed using simple deformable phantoms. For the single tumor deformation, the A{sub u}+A{sub o} was reduced over 56% when deformation was larger than 2 mm. Overall, the total improvement was 82%. For the tumor system deformation, the A{sub u}+A{sub o} reductions were all above 75% and the total A{sub u}+A{sub o} improvement was 86%. Similar coverage improvement was also found in simulating deformation tracking during IMRT delivery. The deformable image registration algorithm was identified as the dominant contributor to the tracking error rather than the finite leaf width. The discrepancy between the warped beam shape and the ideal beam shape due to the deformable registration was observed to be partially compensated during leaf fitting due to the finite leaf width. The clinical proof-of-principle experiment demonstrated the feasibility of intrafraction deformable tracking for clinical scenarios. Conclusions: For the first time, we developed and demonstrated an experimental system that is capable of adapting the MLC aperture to account for tumor deformation. This work provides a potentially widely available management method to effectively account for intrafractional tumor deformation. This proof-of-principle study is the first experimental step toward the development of an image-guided radiotherapy system to treat deforming tumors in real-time.

  1. Captopril improves tumor nanomedicine delivery by increasing tumor blood perfusion and enlarging endothelial gaps in tumor blood vessels.

    Science.gov (United States)

    Zhang, Bo; Jiang, Ting; Tuo, Yanyan; Jin, Kai; Luo, Zimiao; Shi, Wei; Mei, Heng; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2017-12-01

    Poor tumor perfusion and unfavorable vessel permeability compromise nanomedicine drug delivery to tumors. Captopril dilates blood vessels, reducing blood pressure clinically and bradykinin, as the downstream signaling moiety of captopril, is capable of dilating blood vessels and effectively increasing vessel permeability. The hypothesis behind this study was that captopril can dilate tumor blood vessels, improving tumor perfusion and simultaneously enlarge the endothelial gaps of tumor vessels, therefore enhancing nanomedicine drug delivery for tumor therapy. Using the U87 tumor xenograft with abundant blood vessels as the tumor model, tumor perfusion experiments were carried out using laser Doppler imaging and lectin-labeling experiments. A single treatment of captopril at a dose of 100 mg/kg significantly increased the percentage of functional vessels in tumor tissues and improved tumor blood perfusion. Scanning electron microscopy of tumor vessels also indicated that the endothelial gaps of tumor vessels were enlarged after captopril treatment. Immunofluorescence-staining of tumor slices demonstrated that captopril significantly increased bradykinin expression, possibly explaining tumor perfusion improvements and endothelial gap enlargement. Additionally, imaging in vivo, imaging ex vivo and nanoparticle distribution in tumor slices indicated that after a single treatment with captopril, the accumulation of 115-nm nanoparticles in tumors had increased 2.81-fold with a more homogeneous distribution pattern in comparison to non-captopril treated controls. Finally, pharmacodynamics experiments demonstrated that captopril combined with paclitaxel-loaded nanoparticles resulted in the greatest tumor shrinkage and the most extensive necrosis in tumor tissues among all treatment groups. Taken together, the data from the present study suggest a novel strategy for improving tumor perfusion and enlarging blood vessel permeability simultaneously in order to improve

  2. Real-time tumor tracking using implanted positron emission markers: Concept and simulation study

    International Nuclear Information System (INIS)

    Xu Tong; Wong, Jerry T.; Shikhaliev, Polad M.; Ducote, Justin L.; Al-Ghazi, Muthana S.; Molloi, Sabee

    2006-01-01

    The delivery accuracy of radiation therapy for pulmonary and abdominal tumors suffers from tumor motion due to respiration. Respiratory gating should be applied to avoid the use of a large target volume margin that results in a substantial dose to the surrounding normal tissue. Precise respiratory gating requires the exact spatial position of the tumor to be determined in real time during treatment. Usually, fiducial markers are implanted inside or next to the tumor to provide both accurate patient setup and real-time tumor tracking. However, current tumor tracking systems require either substantial x-ray exposure to the patient or large fiducial markers that limit the value of their application for pulmonary tumors. We propose a real-time tumor tracking system using implanted positron emission markers (PeTrack). Each marker will be labeled with low activity positron emitting isotopes, such as 124 I, 74 As, or 84 Rb. These isotopes have half-lives comparable to the duration of radiation therapy (from a few days to a few weeks). The size of the proposed PeTrack marker will be 0.5-0.8 mm, which is approximately one-half the size of markers currently employed in other techniques. By detecting annihilation gammas using position-sensitive detectors, multiple positron emission markers can be tracked in real time. A multimarker localization algorithm was developed using an Expectation-Maximization clustering technique. A Monte Carlo simulation model was developed for the PeTrack system. Patient dose, detector sensitivity, and scatter fraction were evaluated. Depending on the isotope, the lifetime dose from a 3.7 MBq PeTrack marker was determined to be 0.7-5.0 Gy at 10 mm from the marker. At the center of the field of view (FOV), the sensitivity of the PeTrack system was 240-320 counts/s per 1 MBq marker activity within a 30 cm thick patient. The sensitivity was reduced by 45% when the marker was near the edge of the FOV. The scatter fraction ranged from 12% ( 124 I, 74 As

  3. Chemotherapeutic drug delivery by tumoral extracellular matrix targeting

    NARCIS (Netherlands)

    Raavé , R.; Kuppevelt, T.H. van; Daamen, W.F.

    2018-01-01

    Systemic chemotherapy is a primary strategy in the treatment of cancer, but comes with a number of limitations such as toxicity and unfavorable biodistribution. To overcome these issues, numerous targeting systems for specific delivery of chemotherapeutics to tumor cells have been designed and

  4. Tumor Targeting and Drug Delivery by Anthrax Toxin

    Directory of Open Access Journals (Sweden)

    Christopher Bachran

    2016-07-01

    Full Text Available Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery.

  5. Tumor Targeting and Drug Delivery by Anthrax Toxin.

    Science.gov (United States)

    Bachran, Christopher; Leppla, Stephen H

    2016-07-01

    Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery.

  6. Four-dimensional treatment planning and fluoroscopic real-time tumor tracking radiotherapy for moving tumor

    International Nuclear Information System (INIS)

    Shirato, Hiroki; Shimizu, Shinichi; Kitamura, Kei; Nishioka, Takeshi; Kagei, Kenji; Hashimoto, Seiko; Aoyama, Hidefumi; Kunieda, Tatsuya; Shinohara, Nobuo; Dosaka-Akita, Hirotoshi; Miyasaka, Kazuo

    2000-01-01

    Purpose: To achieve precise three-dimensional (3D) conformal radiotherapy for mobile tumors, a new radiotherapy system and its treatment planning system were developed and used for clinical practice. Methods and Materials: We developed a linear accelerator synchronized with a fluoroscopic real-time tumor tracking system by which 3D coordinates of a 2.0-mm gold marker in the tumor can be determined every 0.03 second. The 3D relationships between the marker and the tumor at different respiratory phases are evaluated using CT image at each respiratory phase, whereby the optimum phase can be selected to synchronize with irradiation (4D treatment planning). The linac is triggered to irradiate the tumor only when the marker is located within the region of the planned coordinates relative to the isocenter. Results: The coordinates of the marker were detected with an accuracy of ± 1 mm during radiotherapy in the phantom experiment. The time delay between recognition of the marker position and the start or stop of megavoltage X-ray irradiation was 0.03 second. Fourteen patients with various tumors were treated by conformal radiotherapy with a 'tight' planning target volume (PTV) margin. They were surviving without relapse or complications with a median follow-up of 6 months. Conclusion: Fluoroscopic real-time tumor tracking radiotherapy following 4D treatment planning was developed and shown to be feasible to improve the accuracy of the radiotherapy for mobile tumors

  7. The dosimetric impact of inversely optimized arc radiotherapy plan modulation for real-time dynamic MLC tracking delivery

    DEFF Research Database (Denmark)

    Falk, Marianne; Larsson, Tobias; Keall, P.

    2012-01-01

    Purpose: Real-time dynamic multileaf collimator (MLC) tracking for management of intrafraction tumor motion can be challenging for highly modulated beams, as the leaves need to travel far to adjust for target motion perpendicular to the leaf travel direction. The plan modulation can be reduced......-to-peak displacement of 2 cm and a cycle time of 6 s. The delivery was adjusted to the target motion using MLC tracking, guided in real-time by an infrared optical system. The dosimetric results were evaluated using gamma index evaluation with static target measurements as reference. Results: The plan quality...

  8. Suitability of markerless EPID tracking for tumor position verification in gated radiotherapy

    International Nuclear Information System (INIS)

    Serpa, Marco; Baier, Kurt; Guckenberger, Matthias; Cremers, Florian; Meyer, Juergen

    2014-01-01

    Purpose: To maximize the benefits of respiratory gated radiotherapy (RGRT) of lung tumors real-time verification of the tumor position is required. This work investigates the feasibility of markerless tracking of lung tumors during beam-on time in electronic portal imaging device (EPID) images of the MV therapeutic beam. Methods: EPID movies were acquired at ∼2 fps for seven lung cancer patients with tumor peak-to-peak motion ranges between 7.8 and 17.9 mm (mean: 13.7 mm) undergoing stereotactic body radiotherapy. The external breathing motion of the abdomen was synchronously measured. Both datasets were retrospectively analyzed inPortalTrack, an in-house developed tracking software. The authors define a three-step procedure to run the simulations: (1) gating window definition, (2) gated-beam delivery simulation, and (3) tumor tracking. First, an amplitude threshold level was set on the external signal, defining the onset of beam-on/-off signals. This information was then mapped onto a sequence of EPID images to generate stamps of beam-on/-hold periods throughout the EPID movies in PortalTrack, by obscuring the frames corresponding to beam-off times. Last, tumor motion in the superior-inferior direction was determined on portal images by the tracking algorithm during beam-on time. The residual motion inside the gating window as well as target coverage (TC) and the marginal target displacement (MTD) were used as measures to quantify tumor position variability. Results: Tumor position monitoring and estimation from beam's-eye-view images during RGRT was possible in 67% of the analyzed beams. For a reference gating window of 5 mm, deviations ranging from 2% to 86% (35% on average) were recorded between the reference and measured residual motion. TC (range: 62%–93%; mean: 77%) losses were correlated with false positives incidence rates resulting mostly from intra-/inter-beam baseline drifts, as well as sudden cycle-to-cycle fluctuations in exhale positions. Both

  9. Targeted Delivery of siRNA Therapeutics to Malignant Tumors

    Directory of Open Access Journals (Sweden)

    Qixin Leng

    2017-01-01

    Full Text Available Over the past 20 years, a diverse group of ligands targeting surface biomarkers or receptors has been identified with several investigated to target siRNA to tumors. Many approaches to developing tumor-homing peptides, RNA and DNA aptamers, and single-chain variable fragment antibodies by using phage display, in vitro evolution, and recombinant antibody methods could not have been imagined by researchers in the 1980s. Despite these many scientific advances, there is no reason to expect that the ligand field will not continue to evolve. From development of ligands based on novel or existing biomarkers to linking ligands to drugs and gene and antisense delivery systems, several fields have coalesced to facilitate ligand-directed siRNA therapeutics. In this review, we discuss the major categories of ligand-targeted siRNA therapeutics for tumors, as well as the different strategies to identify new ligands.

  10. Detection of lung tumor movement in real-time tumor-tracking radiotherapy

    International Nuclear Information System (INIS)

    Shimizu, Shinichi; Shirato, Hiroki; Ogura, Shigeaki; Akita-Dosaka, Hirotoshi; Kitamura, Kei; Nishioka, Takeshi; Kagei, Kenji; Nishimura, Masaji; Miyasaka, Kazuo

    2001-01-01

    Purpose: External radiotherapy for lung tumors requires reducing the uncertainty due to setup error and organ motion. We investigated the three-dimensional movement of lung tumors through an inserted internal marker using a real-time tumor-tracking system and evaluated the efficacy of this system at reducing the internal margin. Methods and Materials: Four patients with lung cancer were analyzed. A 2.0-mm gold marker was inserted into the tumor. The real-time tumor-tracking system calculates and stores three-dimensional coordinates of the marker 30 times/s. The system can trigger the linear accelerator to irradiate the tumor only when the marker is located within the predetermined 'permitted dislocation'. The value was set at ±1 to ±3 mm according to the patient's characteristics. We analyzed 10,413-14,893 data sets for each of the 4 patients. The range of marker movement during normal breathing (beam-off period) was compared with that during gated irradiation (beam-on period) by Student's t test. Results: The range of marker movement during the beam-off period was 5.5-10.0 mm in the lateral direction (x), 6.8-15.9 mm in the craniocaudal direction (y) and 8.1-14.6 mm in the ventrodorsal direction (z). The range during the beam-on period was reduced to within 5.3 mm in all directions in all 4 patients. A significant difference was found between the mean of the range during the beam-off period and the mean of the range during the beam-on period in the x (p=0.007), y (p=0.025), and z (p=0.002) coordinates, respectively. Conclusion: The real-time tumor-tracking radiotherapy system was useful to analyze the movement of an internal marker. Treatment with megavoltage X-rays was properly given when the tumor marker moved into the 'permitted dislocation' zone from the planned position

  11. Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery.

    Science.gov (United States)

    Rottmann, Joerg; Keall, Paul; Berbeco, Ross

    2013-09-01

    To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient. 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps. Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time.

  12. Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery

    International Nuclear Information System (INIS)

    Rottmann, Joerg; Berbeco, Ross; Keall, Paul

    2013-01-01

    Purpose: To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient.Methods: 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps.Results: Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error <1.0 mm [root mean square (rms) error of 0.3 mm] was observed. The tracking rms accuracy on BEV images from a lung SBRT patient (≈20 mm tumor motion range) is 1.0 mm.Conclusions: The authors demonstrate for the first time real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time

  13. Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery

    Energy Technology Data Exchange (ETDEWEB)

    Rottmann, Joerg; Berbeco, Ross [Brigham and Women' s Hospital, Dana Farber-Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115 (United States); Keall, Paul [Radiation Physics Laboratory, Sydney Medical School, University of Sydney, Sydney NSW 2006 (Australia)

    2013-09-15

    Purpose: To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient.Methods: 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps.Results: Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error <1.0 mm [root mean square (rms) error of 0.3 mm] was observed. The tracking rms accuracy on BEV images from a lung SBRT patient (≈20 mm tumor motion range) is 1.0 mm.Conclusions: The authors demonstrate for the first time real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time.

  14. The folate receptor as a molecular target for tumor-selective radionuclide delivery

    International Nuclear Information System (INIS)

    Ke, C.-Y.; Mathias, Carla J.; Green, Mark A.

    2003-01-01

    The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including radiolabeled folate-chelate conjugates for diagnostic imaging. We review here some background on the folate receptor as tumor-associated molecular target for drug delivery, and briefly survey the literature on tumor-targeting with radiolabeled folate-chelate conjugates

  15. Eye tracking and gating system for proton therapy of orbital tumors

    International Nuclear Information System (INIS)

    Shin, Dongho; Yoo, Seung Hoon; Moon, Sung Ho; Yoon, Myonggeun; Lee, Se Byeong; Park, Sung Yong

    2012-01-01

    Purpose: A new motion-based gated proton therapy for the treatment of orbital tumors using real-time eye-tracking system was designed and evaluated. Methods: We developed our system by image-pattern matching, using a normalized cross-correlation technique with LabVIEW 8.6 and Vision Assistant 8.6 (National Instruments, Austin, TX). To measure the pixel spacing of an image consistently, four different calibration modes such as the point-detection, the edge-detection, the line-measurement, and the manual measurement mode were suggested and used. After these methods were applied to proton therapy, gating was performed, and radiation dose distributions were evaluated. Results: Moving phantom verification measurements resulted in errors of less than 0.1 mm for given ranges of translation. Dosimetric evaluation of the beam-gating system versus nongated treatment delivery with a moving phantom shows that while there was only 0.83 mm growth in lateral penumbra for gated radiotherapy, there was 4.95 mm growth in lateral penumbra in case of nongated exposure. The analysis from clinical results suggests that the average of eye movements depends distinctively on each patient by showing 0.44 mm, 0.45 mm, and 0.86 mm for three patients, respectively. Conclusions: The developed automatic eye-tracking based beam-gating system enabled us to perform high-precision proton radiotherapy of orbital tumors.

  16. Hyaluronate tethered, "smart" multiwalled carbon nanotubes for tumor-targeted delivery of doxorubicin.

    Science.gov (United States)

    Datir, Satyajit R; Das, Manasmita; Singh, Raman Preet; Jain, Sanyog

    2012-11-21

    The present study reports the optimized synthesis, physicochemical characterization, and biological evaluation of a novel, multiwalled carbon nanotube-hyaluronic acid (MWCNT-HA) conjugate, complexed with an anticancer agent, Doxorubicin (DOX) via π-π stacking interaction. The therapeutic conjugate was concomitantly labeled with a near-infrared fluorescent dye, Alexa-Flour-647 (AF-647), and radiotracer Technetium-99m ((99m)Tc) to track its whereabouts both in vitro and in vivo via optical and scintigraphic imaging techniques. Covalent functionalization of MWCNTs with HA facilitated their internalization into human lung adenocarcinoma, A549 cells via hyaluronan receptors (HR) mediated endocytosis. Internalized nanotubes showed lysosomal trafficking, followed by low pH-triggered DOX release under endolysosomal conditions. Consequently, DOX-loaded HA-MWCNTs exhibited 3.2 times higher cytotoxicity and increased apoptotic activity than free DOX in equivalent concentrations. Organ distribution studies in Ehlrich ascites tumor (EAT) bearing mice model indicated that tumor specific localization of (99m)Tc-MWCNT-HA-DOX is significantly higher than both free drug and nontargeted MWCNTs. Pharmacodynamic studies in chemically breast-cancer-induced rats showed that the tumor-growth inhibitory effect of HA-MWCNT-DOX was 5 times higher than free DOX in equivalent concentration. DOX delivered through HA-MWCNTs was devoid of any detectable cardiotoxity, hepatotoxicity, or nephrotoxicity. All these promising attributes make HA-MWCNTs a "smart" platform for tumor-targeted delivery of anticancer agents.

  17. WE-AB-303-08: Direct Lung Tumor Tracking Using Short Imaging Arcs

    International Nuclear Information System (INIS)

    Shieh, C; Huang, C; Keall, P; Feain, I

    2015-01-01

    Purpose: Most current tumor tracking technologies rely on implanted markers, which suffer from potential toxicity of marker placement and mis-targeting due to marker migration. Several markerless tracking methods have been proposed: these are either indirect methods or have difficulties tracking lung tumors in most clinical cases due to overlapping anatomies in 2D projection images. We propose a direct lung tumor tracking algorithm robust to overlapping anatomies using short imaging arcs. Methods: The proposed algorithm tracks the tumor based on kV projections acquired within the latest six-degree imaging arc. To account for respiratory motion, an external motion surrogate is used to select projections of the same phase within the latest arc. For each arc, the pre-treatment 4D cone-beam CT (CBCT) with tumor contours are used to estimate and remove the contribution to the integral attenuation from surrounding anatomies. The position of the tumor model extracted from 4D CBCT of the same phase is then optimized to match the processed projections using the conjugate gradient method. The algorithm was retrospectively validated on two kV scans of a lung cancer patient with implanted fiducial markers. This patient was selected as the tumor is attached to the mediastinum, representing a challenging case for markerless tracking methods. The tracking results were converted to expected marker positions and compared with marker trajectories obtained via direct marker segmentation (ground truth). Results: The root-mean-squared-errors of tracking were 0.8 mm and 0.9 mm in the superior-inferior direction for the two scans. Tracking error was found to be below 2 and 3 mm for 90% and 98% of the time, respectively. Conclusions: A direct lung tumor tracking algorithm robust to overlapping anatomies was proposed and validated on two scans of a lung cancer patient. Sub-millimeter tracking accuracy was observed, indicating the potential of this algorithm for real-time guidance

  18. Geometric accuracy of a novel gimbals based radiation therapy tumor tracking system.

    Science.gov (United States)

    Depuydt, Tom; Verellen, Dirk; Haas, Olivier; Gevaert, Thierry; Linthout, Nadine; Duchateau, Michael; Tournel, Koen; Reynders, Truus; Leysen, Katrien; Hoogeman, Mischa; Storme, Guy; De Ridder, Mark

    2011-03-01

    VERO is a novel platform for image guided stereotactic body radiotherapy. Orthogonal gimbals hold the linac-MLC assembly allowing real-time moving tumor tracking. This study determines the geometric accuracy of the tracking. To determine the tracking error, an 1D moving phantom produced sinusoidal motion with frequencies up to 30 breaths per minute (bpm). Tumor trajectories of patients were reproduced using a 2D robot and pursued with the gimbals tracking system prototype. Using the moving beam light field and a digital-camera-based detection unit tracking errors, system lag and equivalence of pan/tilt performance were measured. The system lag was 47.7 ms for panning and 47.6 ms for tilting. Applying system lag compensation, sinusoidal motion tracking was accurate, with a tracking error 90% percentile E(90%)tracking errors were below 0.14 mm. The 2D tumor trajectories were tracked with an average E(90%) of 0.54 mm, and tracking error standard deviations of 0.20 mm for pan and 0.22 mm for tilt. In terms of dynamic behavior, the gimbaled linac of the VERO system showed to be an excellent approach for providing accurate real-time tumor tracking in radiation therapy. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    Directory of Open Access Journals (Sweden)

    Li X

    2015-12-01

    Full Text Available Xiaoyu Li, Meiying Wu, Limin Pan, Jianlin Shi State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, People’s Republic of China Abstract: To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4 and a chemotherapeutic drug (doxorubicin and conjugate with targeting molecules (iRGD peptide for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. Keywords: mesoporous silica nanoparticles, drug delivery, tumor vasculatures targeting, antiangiogenic agent

  20. [A review of progress of real-time tumor tracking radiotherapy technology based on dynamic multi-leaf collimator].

    Science.gov (United States)

    Liu, Fubo; Li, Guangjun; Shen, Jiuling; Li, Ligin; Bai, Sen

    2017-02-01

    While radiation treatment to patients with tumors in thorax and abdomen is being performed, further improvement of radiation accuracy is restricted by the tumor intra-fractional motion due to respiration. Real-time tumor tracking radiation is an optimal solution to tumor intra-fractional motion. A review of the progress of real-time dynamic multi-leaf collimator(DMLC) tracking is provided in the present review, including DMLC tracking method, time lag of DMLC tracking system, and dosimetric verification.

  1. Nano-aggregates: emerging delivery tools for tumor therapy.

    Science.gov (United States)

    Sharma, Vinod Kumar; Jain, Ankit; Soni, Vandana

    2013-01-01

    A plethora of formulation techniques have been reported in the literature for site-specific targeting of water-soluble and -insoluble anticancer drugs. Along with other vesicular and particulate carrier systems, nano-aggregates have recently emerged as a novel supramolecular colloidal carrier with promise for using poorly water-soluble drugs in molecular targeted therapies. Nano-aggregates possess some inherent properties such as size in the nanometers, high loading efficiency, and in vivo stability. Nano-aggregates can provide site-specific drug delivery via either a passive or active targeting mechanism. Nano-aggregates are formed from a polymer-drug conjugated amphiphilic block copolymer. They are suitable for encapsulation of poorly water-soluble drugs by covalent conjugation as well as physical encapsulation. Because of physical encapsulation, a maximum amount of drug can be loaded in nano-aggregates, which helps to achieve a sufficiently high drug concentration at the target site. Active transport can be achieved by conjugating a drug with vectors or ligands that bind specifically to receptors being overexpressed in the tumor cells. In this review, we explore synthesis and tumor targeting potential of nano-aggregates with active and passive mechanisms, and we discuss various characterization parameters, ex vivo studies, biodistribution studies, clinical trials, and patents.

  2. Addressing challenges of heterogeneous tumor treatment through bispecific protein-mediated pretargeted drug delivery.

    Science.gov (United States)

    Yang, Qi; Parker, Christina L; McCallen, Justin D; Lai, Samuel K

    2015-12-28

    Tumors are frequently characterized by genomically and phenotypically distinct cancer cell subpopulations within the same tumor or between tumor lesions, a phenomenon termed tumor heterogeneity. These diverse cancer cell populations pose a major challenge to targeted delivery of diagnostic and/or therapeutic agents, as the conventional approach of conjugating individual ligands to nanoparticles is often unable to facilitate intracellular delivery to the full spectrum of cancer cells present in a given tumor lesion or patient. As a result, many cancers are only partially suppressed, leading to eventual tumor regrowth and/or the development of drug-resistant tumors. Pretargeting (multistep targeting) approaches involving the administration of 1) a cocktail of bispecific proteins that can collectively bind to the entirety of a mixed tumor population followed by 2) nanoparticles containing therapeutic and/or diagnostic agents that can bind to the bispecific proteins accumulated on the surface of target cells offer the potential to overcome many of the challenges associated with drug delivery to heterogeneous tumors. Despite its considerable success in improving the efficacy of radioimmunotherapy, the pretargeting strategy remains underexplored for a majority of nanoparticle therapeutic applications, especially for targeted delivery to heterogeneous tumors. In this review, we will present concepts in tumor heterogeneity, the shortcomings of conventional targeted systems, lessons learned from pretargeted radioimmunotherapy, and important considerations for harnessing the pretargeting strategy to improve nanoparticle delivery to heterogeneous tumors. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Etched ion track polymer membranes for sustained drug delivery

    International Nuclear Information System (INIS)

    Rao, Vijayalakshmi; Amar, J.V.; Avasthi, D.K.; Narayana Charyulu, R.

    2003-01-01

    The method of track etching has been successfully used for the production of polymer membranes with capillary pores. In the present paper, micropore membranes have been prepared by swift heavy ion irradiation of polycarbonate (PC). PC films were irradiated with ions of gold, silicon and oxygen of varying energies and fluence. The ion tracks thus obtained were etched chemically for various time intervals to get pores and these etched films were used as membranes for the drug release. Ciprofloxacine hydrochloride was used as model drug for the release studies. The drug content was estimated spectrophotometrically. Pore size and thus the drug release is dependent on the etching conditions, ions used, their energy and fluence. Sustained drug release has been observed in these membranes. The films can be selected for practical utilization by optimizing the irradiation and etching conditions. These films can be used as transdermal patches after medical treatment

  4. The dosimetric impact of inversely optimized arc radiotherapy plan modulation for real-time dynamic MLC tracking delivery

    International Nuclear Information System (INIS)

    Falk, Marianne; Larsson, Tobias; Keall, Paul; Chul Cho, Byung; Aznar, Marianne; Korreman, Stine; Poulsen, Per; Munck af Rosenschoeld, Per

    2012-01-01

    Purpose: Real-time dynamic multileaf collimator (MLC) tracking for management of intrafraction tumor motion can be challenging for highly modulated beams, as the leaves need to travel far to adjust for target motion perpendicular to the leaf travel direction. The plan modulation can be reduced by using a leaf position constraint (LPC) that reduces the difference in the position of adjacent MLC leaves in the plan. The purpose of this study was to investigate the impact of the LPC on the quality of inversely optimized arc radiotherapy plans and the effect of the MLC motion pattern on the dosimetric accuracy of MLC tracking delivery. Specifically, the possibility of predicting the accuracy of MLC tracking delivery based on the plan modulation was investigated. Methods: Inversely optimized arc radiotherapy plans were created on CT-data of three lung cancer patients. For each case, five plans with a single 358 deg. arc were generated with LPC priorities of 0 (no LPC), 0.25, 0.5, 0.75, and 1 (highest possible LPC), respectively. All the plans had a prescribed dose of 2 Gy x 30, used 6 MV, a maximum dose rate of 600 MU/min and a collimator angle of 45 deg. or 315 deg. To quantify the plan modulation, an average adjacent leaf distance (ALD) was calculated by averaging the mean adjacent leaf distance for each control point. The linear relationship between the plan quality [i.e., the calculated dose distributions and the number of monitor units (MU)] and the LPC was investigated, and the linear regression coefficient as well as a two tailed confidence level of 95% was used in the evaluation. The effect of the plan modulation on the performance of MLC tracking was tested by delivering the plans to a cylindrical diode array phantom moving with sinusoidal motion in the superior-inferior direction with a peak-to-peak displacement of 2 cm and a cycle time of 6 s. The delivery was adjusted to the target motion using MLC tracking, guided in real-time by an infrared optical system

  5. Nuclear track microfilters in controlled drug delivery against chronic skin disease

    International Nuclear Information System (INIS)

    Gopalani, D.; Jodha, A.S.; Saravanan, S.; Kumar, S.

    2003-01-01

    Nuclear track microfilters have been developed for transdermal therapeutic system. The transdermal therapeutic method reduces the toxicity of the drug as compared to other conventional methods. For this purpose a slow drug release system containing the nuclear track microfilter was developed. This device was applied to the patients suffering from psoriasis and cellulites diseases. The delivery of the drug to the patient was confirmed through high performance liquid chromatography. The preliminary results have shown that patients are responding to drugs with minimum toxicity

  6. Nuclear track microfilters in controlled drug delivery against chronic skin disease

    Energy Technology Data Exchange (ETDEWEB)

    Gopalani, D. E-mail: deflab@sancharnet.in; Jodha, A.S.; Saravanan, S.; Kumar, S

    2003-06-01

    Nuclear track microfilters have been developed for transdermal therapeutic system. The transdermal therapeutic method reduces the toxicity of the drug as compared to other conventional methods. For this purpose a slow drug release system containing the nuclear track microfilter was developed. This device was applied to the patients suffering from psoriasis and cellulites diseases. The delivery of the drug to the patient was confirmed through high performance liquid chromatography. The preliminary results have shown that patients are responding to drugs with minimum toxicity.

  7. Multitriggered Tumor-Responsive Drug Delivery Vehicles Based on Protein and Polypeptide Coassembly for Enhanced Photodynamic Tumor Ablation.

    Science.gov (United States)

    Zhang, Ning; Zhao, Fenfang; Zou, Qianli; Li, Yongxin; Ma, Guanghui; Yan, Xuehai

    2016-11-01

    Tumor-responsive nanocarriers are highly valuable and demanded for smart drug delivery particularly in the field of photodynamic therapy (PDT), where a quick release of photosensitizers in tumors is preferred. Herein, it is demonstrated that protein-based nanospheres, prepared by the electrostatic assembly of proteins and polypeptides with intermolecular disulfide cross-linking and surface polyethylene glycol coupling, can be used as versatile tumor-responsive drug delivery vehicles for effective PDT. These nanospheres are capable of encapsulation of various photosensitizers including Chlorin e6 (Ce6), protoporphyrin IX, and verteporfin. The Chlorin e6-encapsulated nanospheres (Ce6-Ns) are responsive to changes in pH, redox potential, and proteinase concentration, resulting in multitriggered rapid release of Ce6 in an environment mimicking tumor tissues. In vivo fluorescence imaging results indicate that Ce6-Ns selectively accumulate near tumors and the quick release of Ce6 from Ce6-Ns can be triggered by tumors. In tumors the fluorescence of released Ce6 from Ce6-Ns is observed at 0.5 h postinjection, while in normal tissues the fluorescence appeared at 12 h postinjection. Tumor ablation is demonstrated by in vivo PDT using Ce6-Ns and the biocompatibility of Ce6-Ns is evident from the histopathology imaging, confirming the enhanced in vivo PDT efficacy and the biocompatibility of the assembled drug delivery vehicles. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. SU-G-JeP1-11: Feasibility Study of Markerless Tracking Using Dual Energy Fluoroscopic Images for Real-Time Tumor-Tracking Radiotherapy System

    Energy Technology Data Exchange (ETDEWEB)

    Shiinoki, T; Shibuya, K [Yamaguchi University, Ube, Yamaguchi (Japan); Sawada, A [Kyoto college of medical science, Nantan, Kyoto (Japan); Uehara, T; Yuasa, Y; Koike, M; Kawamura, S [Yamaguchi University Hospital, Ube, Yamaguchi (Japan)

    2016-06-15

    Purpose: The new real-time tumor-tracking radiotherapy (RTRT) system was installed in our institution. This system consists of two x-ray tubes and color image intensifiers (I.I.s). The fiducial marker which was implanted near the tumor was tracked using color fluoroscopic images. However, the implantation of the fiducial marker is very invasive. Color fluoroscopic images enable to increase the recognition of the tumor. However, these images were not suitable to track the tumor without fiducial marker. The purpose of this study was to investigate the feasibility of markerless tracking using dual energy colored fluoroscopic images for real-time tumor-tracking radiotherapy system. Methods: The colored fluoroscopic images of static and moving phantom that had the simulated tumor (30 mm diameter sphere) were experimentally acquired using the RTRT system. The programmable respiratory motion phantom was driven using the sinusoidal pattern in cranio-caudal direction (Amplitude: 20 mm, Time: 4 s). The x-ray condition was set to 55 kV, 50 mA and 105 kV, 50 mA for low energy and high energy, respectively. Dual energy images were calculated based on the weighted logarithmic subtraction of high and low energy images of RGB images. The usefulness of dual energy imaging for real-time tracking with an automated template image matching algorithm was investigated. Results: Our proposed dual energy subtraction improve the contrast between tumor and background to suppress the bone structure. For static phantom, our results showed that high tracking accuracy using dual energy subtraction images. For moving phantom, our results showed that good tracking accuracy using dual energy subtraction images. However, tracking accuracy was dependent on tumor position, tumor size and x-ray conditions. Conclusion: We indicated that feasibility of markerless tracking using dual energy fluoroscopic images for real-time tumor-tracking radiotherapy system. Furthermore, it is needed to investigate the

  9. IMRT delivery to a moving target by dynamic MLC tracking: delivery for targets moving in two dimensions in the beam's eye view

    International Nuclear Information System (INIS)

    McQuaid, D; Webb, S

    2006-01-01

    A new modification of the dynamic multileaf collimator (dMLC) delivery technique for intensity-modulated therapy (IMRT) is outlined. This technique enables the tracking of a target moving through rigid-body translations in a 2D trajectory in the beam's eye view. The accuracy of the delivery versus that of deliveries with no tracking and of 1D tracking techniques is quantified with clinically derived intensity-modulated beams (IMBs). Leaf trajectories calculated in the target-reference frame were iteratively synchronized assuming regular target motion. This allowed the leaves defined in the lab-reference frame to simultaneously follow the target motion and to deliver the required IMB without violation of the leaf maximum-velocity constraint. The leaves are synchronized until the gradient of the leaf position at every instant is less than a calculated maximum. The delivered fluence in the target-reference frame was calculated with a simple primary-fluence model. The new 2D tracking technique was compared with the delivered fluence produced by no-tracking deliveries and by 1D tracking deliveries for 33 clinical IMBs. For the clinical IMBs normalized to a maximum fluence of 200 MUs, the rms difference between the desired and the delivered IMB was 15.6 ± 3.3 MU for the case of a no-tracking delivery, 7.9 ± 1.6 MU for the case where only the primary component of motion was corrected and 5.1 ± 1.1 MU for the 2D tracking delivery. The residual error is due to interpolation and sampling effects. The 2D tracking delivery technique requires an increase in the delivery time evaluated as between 0 and 50% of the unsynchronized delivery time for each beam with a mean increase of 13% for the IMBs tested. The 2D tracking dMLC delivery technique allows an optimized IMB to be delivered to moving targets with increased accuracy and with acceptable increases in delivery time. When combined with real-time knowledge of the target motion at delivery time, this technique facilitates

  10. Prospective phase II study of image-guided local boost using a real-time tumor-tracking radiotherapy (RTRT) system for locally advanced bladder cancer

    International Nuclear Information System (INIS)

    Nishioka, Kentaro; Shimizu, Shinichi; Shinohara, Nobuo

    2014-01-01

    The real-time tumor-tracking radiotherapy system with fiducial markers has the advantage that it can be used to verify the localization of the markers during radiation delivery in real-time. We conducted a prospective Phase II study of image-guided local-boost radiotherapy for locally advanced bladder cancer using a real-time tumor-tracking radiotherapy system for positioning, and here we report the results regarding the safety and efficacy of the technique. Twenty patients with a T2-T4N0M0 urothelial carcinoma of the bladder who were clinically inoperable or refused surgery were enrolled. Transurethral tumor resection and 40 Gy irradiation to the whole bladder was followed by the transurethral endoscopic implantation of gold markers in the bladder wall around the primary tumor. A boost of 25 Gy in 10 fractions was made to the primary tumor while maintaining the displacement from the planned position at less than ±2 mm during radiation delivery using a real-time tumor-tracking radiotherapy system. The toxicity, local control and survival were evaluated. Among the 20 patients, 14 were treated with concurrent chemoradiotherapy. The median follow-up period was 55.5 months. Urethral and bowel late toxicity (Grade 3) were each observed in one patient. The local-control rate, overall survival and cause-specific survival with the native bladder after 5 years were 64, 61 and 65%. Image-guided local-boost radiotherapy using a real-time tumor-tracking radiotherapy system can be safely accomplished, and the clinical outcome is encouraging. A larger prospective multi-institutional study is warranted for more precise evaluations of the technological efficacy and patients' quality of life. (author)

  11. Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors

    Science.gov (United States)

    2016-10-01

    development of the principal discipline(s) of the project? • We have learned that the drug PEGPH20, which degrades a component of connective tissue called...AWARD NUMBER: W81XWH-15-1-0114 TITLE: Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors PRINCIPAL INVESTIGATOR...14 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER NF140089 Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors 5b

  12. Liposomal Tumor Targeting in Drug Delivery Utilizing MMP-2- and MMP-9-Binding Ligands

    Directory of Open Access Journals (Sweden)

    Oula Penate Medina

    2011-01-01

    Full Text Available Nanotechnology offers an alternative to conventional treatment options by enabling different drug delivery and controlled-release delivery strategies. Liposomes being especially biodegradable and in most cases essentially nontoxic offer a versatile platform for several different delivery approaches that can potentially enhance the delivery and targeting of therapies to tumors. Liposomes penetrate tumors spontaneously as a result of fenestrated blood vessels within tumors, leading to known enhanced permeability and subsequent drug retention effects. In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them attractive carriers for molecular imaging applications. Phage display is a technique that can deliver various high-affinity and selectivity peptides to different targets. In this study, gelatinase-binding peptides, found by phage display, were attached to liposomes by covalent peptide-PEG-PE anchor creating a targeted drug delivery vehicle. Gelatinases as extracellular targets for tumor targeting offer a viable alternative for tumor targeting. Our findings show that targeted drug delivery is more efficient than non-targeted drug delivery.

  13. Overview of Methods Able to Overcome Impediments to tumor Drug Delivery with Special Attention to Tumor Interstitial Fluid.

    Directory of Open Access Journals (Sweden)

    Gianfranco eBaronzio

    2015-07-01

    Full Text Available Every drug used to treat cancer (chemotherapeutics, immunologic, monoclonal antibodies, nanoparticles, radionuclides must reach the targeted cells through the tumor environment at adequate concentrations, in order to exert their cell-killing effects. For any of these agents to reach the goal cells they must overcome a number of impediments created by the tumor microenvironment, beginning with tumor interstitial fluid pressure (TIFP and a multifactorial increase in composition of the extracellular matrix (ECM. A primary modifier of tumor microenvironment is hypoxia, which increases the production of growth factors such as vascular endothelial growth factor (VEGF and platelet-derived growth factor (PDGF. These growth factors released by both tumor cells and bone marrow recruited myeloid cells (MDS, form abnormal vasculature characterized by vessels that are tortuous and more permeable. Increased leakiness combined with increased inflammatory byproducts accumulates fluid within the tumor mass [tumor interstitial fluid (TIF], ultimately creating an increased pressure (TIFP. Fibroblasts are also up-regulated by the tumor microenvironment, and deposit fibers that further augment the density of the extracellular matrix (ECM, thus, further worsening the TIFP. Increased TIFP with the ECM are the major obstacles to adequate drug delivery. By decreasing TIFP and decreasing ECM density, we can expect an associated rise in drug concentration within the tumor itself. In this overview we will describe all the methods (drugs, nutraceuticals, physical methods of treatment able to lower TIFP and to modify ECM that can be used for increasing drug concentration within the tumor tissue.

  14. Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery.

    Science.gov (United States)

    Volak, Adrienn; LeRoy, Stanley G; Natasan, Jeya Shree; Park, David J; Cheah, Pike See; Maus, Andreas; Fitzpatrick, Zachary; Hudry, Eloise; Pinkham, Kelsey; Gandhi, Sheetal; Hyman, Bradley T; Mu, Dakai; GuhaSarkar, Dwijit; Stemmer-Rachamimov, Anat O; Sena-Esteves, Miguel; Badr, Christian E; Maguire, Casey A

    2018-05-16

    The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively. Delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells may provide a more stable and localized reservoir of therapy as they are more differentiated than fast-dividing tumor cells. Reactive astrocytes and tumor-associated macrophage/microglia (TAMs) are stromal cells that comprise a large portion of the tumor mass and are associated with tumorigenesis. In mouse models of GBM, we used IV delivery of exosome-associated AAV vectors driving green fluorescent protein expression by specific promoters (NF-κB-responsive promoter and a truncated glial fibrillary acidic protein promoter), to obtain targeted transduction of TAMs and reactive astrocytes, respectively, while avoiding transgene expression in the periphery. We used our approach to express the potent, yet toxic anti-tumor cytokine, interferon beta, in tumor stroma of a mouse model of GBM, and achieved a modest, yet significant enhancement in survival compared to controls. Noninvasive genetic modification of tumor microenvironment represents a promising approach for therapy against cancers. Additionally, the vectors described here may facilitate basic research in the study of tumor stromal cells in situ.

  15. Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery.

    Science.gov (United States)

    Kim, Soo Jung; Jung, Kyung Hee; Son, Mi Kwon; Park, Jung Hee; Yan, Hong Hua; Fang, Zhenghuan; Kang, Yeo Wool; Han, Boreum; Lim, Joo Han; Hong, Soon-Sun

    2017-09-10

    Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Reconstructed storm tracks reveal three centuries of changing moisture delivery to North America.

    Science.gov (United States)

    Wise, Erika K; Dannenberg, Matthew P

    2017-06-01

    Moisture delivery to western North America is closely linked to variability in the westerly storm tracks of midlatitude cyclones, which are, in turn, modified by larger-scale features such as the El Niño-Southern Oscillation system. Instrumental and modeling data suggest that extratropical storm tracks may be intensifying and shifting poleward due to anthropogenic climate change, but it is difficult to separate recent trends from natural variability because of the large amount of decadal and longer variation in storm tracks and their limited instrumental record. We reconstruct cool-season, midlatitude Pacific storm-track position and intensity from 1693 to 1995 CE using existing tree-ring chronologies along with a network of newly developed chronologies from the U.S. Pacific Northwest, where small variations in storm-track position can have a major influence on hydroclimate patterns. Our results show high interannual-to-multidecadal variability in storm-track position and intensity over the past 303 years, with spectral signatures characteristic of tropical and northern Pacific influences. Comparison with reconstructions of precipitation and tropical sea surface temperature confirms the relationship between shifting drought patterns in the Pacific Northwest and storm-track variability through time and demonstrates the long-term influence of El Niño. These results allow us to place recent storm-track changes in the context of decadal and multidecadal fluctuations across the long-term record, showing that recent changes in storm-track intensity likely represent a warming-related increase amplified by natural decadal variability.

  17. Addressing brain tumors with targeted gold nanoparticles: a new gold standard for hydrophobic drug delivery?

    Science.gov (United States)

    Cheng, Yu; Meyers, Joseph D; Agnes, Richard S; Doane, Tennyson L; Kenney, Malcolm E; Broome, Ann-Marie; Burda, Clemens; Basilion, James P

    2011-08-22

    EGF-modified Au NP-Pc 4 conjugates showed 10-fold improved selectivity to the brain tumor compared to untargeted conjugates. The hydrophobic photodynamic therapy drug Pc 4 can be delivered efficiently into glioma brain tumors by EGF peptide-targeted Au NPs. Compared to the untargeted conjugates, EGF-Au NP-Pc 4 conjugates showed 10-fold improved selectivity to the brain tumor. This delivery system holds promise for future delivery of a wider range of hydrophobic therapeutic drugs for the treatment of hard-to-reach cancers. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  19. Comparison of 2D and 3D modeled tumor motion estimation/prediction for dynamic tumor tracking during arc radiotherapy

    Science.gov (United States)

    Liu, Wu; Ma, Xiangyu; Yan, Huagang; Chen, Zhe; Nath, Ravinder; Li, Haiyun

    2017-05-01

    Many real-time imaging techniques have been developed to localize a target in 3D space or in a 2D beam’s eye view (BEV) plane for intrafraction motion tracking in radiation therapy. With tracking system latency, the 3D-modeled method is expected to be more accurate even in terms of 2D BEV tracking error. No quantitative analysis, however, has been reported. In this study, we simulated co-planar arc deliveries using respiratory motion data acquired from 42 patients to quantitatively compare the accuracy between 2D BEV and 3D-modeled tracking in arc therapy and to determine whether 3D information is needed for motion tracking. We used our previously developed low kV dose adaptive MV-kV imaging and motion compensation framework as a representative of 3D-modeled methods. It optimizes the balance between additional kV imaging dose and 3D tracking accuracy and solves the MLC blockage issue. With simulated Gaussian marker detection errors (zero mean and 0.39 mm standard deviation) and ~155/310/460 ms tracking system latencies, the mean percentage of time that the target moved  >2 mm from the predicted 2D BEV position are 1.1%/4.0%/7.8% and 1.3%/5.8%/11.6% for the 3D-modeled and 2D-only tracking, respectively. The corresponding average BEV RMS errors are 0.67/0.90/1.13 mm and 0.79/1.10/1.37 mm. Compared to the 2D method, the 3D method reduced the average RMS unresolved motion along the beam direction from ~3 mm to ~1 mm, resulting in on average only  <1% dosimetric advantage in the depth direction. Only for a small fraction of the patients, when tracking latency is long, the 3D-modeled method showed significant improvement of BEV tracking accuracy, indicating potential dosimetric advantage. However, if the tracking latency is short (~150 ms or less), those improvements are limited. Therefore, 2D BEV tracking has sufficient targeting accuracy for most clinical cases. The 3D technique is, however, still important in solving the MLC blockage problem

  20. [Advances of tumor targeting peptides drug delivery system with pH-sensitive activities].

    Science.gov (United States)

    Ma, Yin-yun; Li, Li; Huang, Hai-feng; Gou, San-hu; Ni, Jing-man

    2016-05-01

    The pH-sensitive peptides drug delivery systems, which target to acidic extracellular environment of tumor tissue, have many advantages in drug delivery. They exhibit a high specificity to tumor and low cytotoxicity, which significantly increase the efficacy of traditional anti-cancer drugs. In recent years the systems have received a great attention. The pH-sensitive peptides drug delivery systems can be divided into five types according to the difference in pH-responsive mechanism,type of peptides and carrier materials. This paper summarizes the recent progresses in the field with a focus on the five types of pH-sensitive peptides in drug delivery systems. This may provide a guideline to design and application of tumor targeting drugs.

  1. Simultaneous tumor and surrogate motion tracking with dynamic MRI for radiation therapy planning

    Science.gov (United States)

    Park, Seyoun; Farah, Rana; Shea, Steven M.; Tryggestad, Erik; Hales, Russell; Lee, Junghoon

    2018-01-01

    Respiration-induced tumor motion is a major obstacle for achieving high-precision radiotherapy of cancers in the thoracic and abdominal regions. Surrogate-based estimation and tracking methods are commonly used in radiotherapy, but with limited understanding of quantified correlation to tumor motion. In this study, we propose a method to simultaneously track the lung tumor and external surrogates to evaluate their spatial correlation in a quantitative way using dynamic MRI, which allows real-time acquisition without ionizing radiation exposure. To capture the lung and whole tumor, four MRI-compatible fiducials are placed on the patient’s chest and upper abdomen. Two different types of acquisitions are performed in the sagittal orientation including multi-slice 2D cine MRIs to reconstruct 4D-MRI and two-slice 2D cine MRIs to simultaneously track the tumor and fiducials. A phase-binned 4D-MRI is first reconstructed from multi-slice MR images using body area as a respiratory surrogate and groupwise registration. The 4D-MRI provides 3D template volumes for different breathing phases. 3D tumor position is calculated by 3D-2D template matching in which 3D tumor templates in the 4D-MRI reconstruction and the 2D cine MRIs from the two-slice tracking dataset are registered. 3D trajectories of the external surrogates are derived via matching a 3D geometrical model of the fiducials to their segmentations on the 2D cine MRIs. We tested our method on ten lung cancer patients. Using a correlation analysis, the 3D tumor trajectory demonstrates a noticeable phase mismatch and significant cycle-to-cycle motion variation, while the external surrogate was not sensitive enough to capture such variations. Additionally, there was significant phase mismatch between surrogate signals obtained from the fiducials at different locations.

  2. Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

    Science.gov (United States)

    Roy Chaudhuri, Tista

    An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

  3. Influence of vascular normalization on interstitial flow and delivery of liposomes in tumors

    International Nuclear Information System (INIS)

    Ozturk, Deniz; Yonucu, Sirin; Yilmaz, Defne; Unlu, Mehmet Burcin

    2015-01-01

    Elevated interstitial fluid pressure is one of the barriers of drug delivery in solid tumors. Recent studies have shown that normalization of tumor vasculature by anti-angiogenic factors may improve the delivery of conventional cytotoxic drugs, possibly by increasing blood flow, decreasing interstitial fluid pressure, and enhancing the convective transvascular transport of drug molecules. Delivery of large therapeutic agents such as nanoparticles and liposomes might also benefit from normalization therapy since their transport depends primarily on convection. In this study, a mathematical model is presented to provide supporting evidence that normalization therapy may improve the delivery of 100 nm liposomes into solid tumors, by both increasing the total drug extravasation and providing a more homogeneous drug distribution within the tumor. However these beneficial effects largely depend on tumor size and are stronger for tumors within a certain size range. It is shown that this size effect may persist under different microenvironmental conditions and for tumors with irregular margins or heterogeneous blood supply. (paper)

  4. Efficient systemic DNA delivery to the tumor by self-assembled nanoparticle

    Science.gov (United States)

    Tang, Hailin; Xie, Xinhua; Guo, Jiaoli; Wei, Weidong; Wu, Minqing; Liu, Peng; Kong, Yanan; Yang, Lu; Hung, Mien-Chie; Xie, Xiaoming

    2014-01-01

    There are few delivery agents that could deliver gene with high efficiency and low toxicity, especially for animal experiments. Therefore, creating vectors with good delivery efficiency and safety profile is a meaningful work. We have developed a self-assembled gene delivery system (XM001), which can more efficiently deliver DNA to multiple cell lines and breast tumor, as compared to commercial delivery agents. In addition, systemically administrated XM001-BikDD (BikDD is a mutant form of proapoptotic gene Bik) significantly inhibited the growth of human breast cancer cells and prolonged the life span in implanted nude mice. This study demonstrates that XM001 is an efficient and widespread transfection agent, which could be a promising tumor delivery vector for cancer targeted therapy.

  5. Development of the compact proton beam therapy system dedicated to spot scanning with real-time tumor-tracking technology

    Science.gov (United States)

    Umezawa, Masumi; Fujimoto, Rintaro; Umekawa, Tooru; Fujii, Yuusuke; Takayanagi, Taisuke; Ebina, Futaro; Aoki, Takamichi; Nagamine, Yoshihiko; Matsuda, Koji; Hiramoto, Kazuo; Matsuura, Taeko; Miyamoto, Naoki; Nihongi, Hideaki; Umegaki, Kikuo; Shirato, Hiroki

    2013-04-01

    Hokkaido University and Hitachi Ltd. have started joint development of the Gated Spot Scanning Proton Therapy with Real-Time Tumor-Tracking System by integrating real-time tumor tracking technology (RTRT) and the proton therapy system dedicated to discrete spot scanning techniques under the "Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)". In this development, we have designed the synchrotron-based accelerator system by using the advantages of the spot scanning technique in order to realize a more compact and lower cost proton therapy system than the conventional system. In the gated irradiation, we have focused on the issues to maximize irradiation efficiency and minimize the dose errors caused by organ motion. In order to understand the interplay effect between scanning beam delivery and target motion, we conducted a simulation study. The newly designed system consists of the synchrotron, beam transport system, one compact rotating gantry treatment room with robotic couch, and one experimental room for future research. To improve the irradiation efficiency, the new control function which enables multiple gated irradiations per synchrotron cycle has been applied and its efficacy was confirmed by the irradiation time estimation. As for the interplay effect, we confirmed that the selection of a strict gating width and scan direction enables formation of the uniform dose distribution.

  6. A novel method for quantification of beam's-eye-view tumor tracking performance.

    Science.gov (United States)

    Hu, Yue-Houng; Myronakis, Marios; Rottmann, Joerg; Wang, Adam; Morf, Daniel; Shedlock, Daniel; Baturin, Paul; Star-Lack, Josh; Berbeco, Ross

    2017-11-01

    In-treatment imaging using an electronic portal imaging device (EPID) can be used to confirm patient and tumor positioning. Real-time tumor tracking performance using current digital megavolt (MV) imagers is hindered by poor image quality. Novel EPID designs may help to improve quantum noise response, while also preserving the high spatial resolution of the current clinical detector. Recently investigated EPID design improvements include but are not limited to multi-layer imager (MLI) architecture, thick crystalline and amorphous scintillators, and phosphor pixilation and focusing. The goal of the present study was to provide a method of quantitating improvement in tracking performance as well as to reveal the physical underpinnings of detector design that impact tracking quality. The study employs a generalizable ideal observer methodology for the quantification of tumor tracking performance. The analysis is applied to study both the effect of increasing scintillator thickness on a standard, single-layer imager (SLI) design as well as the effect of MLI architecture on tracking performance. The present study uses the ideal observer signal-to-noise ratio (d') as a surrogate for tracking performance. We employ functions which model clinically relevant tasks and generalized frequency-domain imaging metrics to connect image quality with tumor tracking. A detection task for relevant Cartesian shapes (i.e., spheres and cylinders) was used to quantitate trackability of cases employing fiducial markers. Automated lung tumor tracking algorithms often leverage the differences in benign and malignant lung tissue textures. These types of algorithms (e.g., soft-tissue localization - STiL) were simulated by designing a discrimination task, which quantifies the differentiation of tissue textures, measured experimentally and fit as a power-law in trend (with exponent β) using a cohort of MV images of patient lungs. The modeled MTF and NPS were used to investigate the effect of

  7. Nanobody-Based Delivery Systems for Diagnosis and Targeted Tumor Therapy

    Directory of Open Access Journals (Sweden)

    Yaozhong Hu

    2017-11-01

    Full Text Available The development of innovative targeted therapeutic approaches are expected to surpass the efficacy of current forms of treatments and cause less damage to healthy cells surrounding the tumor site. Since the first development of targeting agents from hybridoma’s, monoclonal antibodies (mAbs have been employed to inhibit tumor growth and proliferation directly or to deliver effector molecules to tumor cells. However, the full potential of such a delivery strategy is hampered by the size of mAbs, which will obstruct the targeted delivery system to access the tumor tissue. By serendipity, a new kind of functional homodimeric antibody format was discovered in camelidae, known as heavy-chain antibodies (HCAbs. The cloning of the variable domain of HCAbs produces an attractive minimal-sized alternative for mAbs, referred to as VHH or nanobodies (Nbs. Apart from their dimensions in the single digit nanometer range, the unique characteristics of Nbs combine a high stability and solubility, low immunogenicity and excellent affinity and specificity against all possible targets including tumor markers. This stimulated the development of tumor-targeted therapeutic strategies. Some autonomous Nbs have been shown to act as antagonistic drugs, but more importantly, the targeting capacity of Nbs has been exploited to create drug delivery systems. Obviously, Nb-based targeted cancer therapy is mainly focused toward extracellular tumor markers, since the membrane barrier prevents antibodies to reach the most promising intracellular tumor markers. Potential strategies, such as lentiviral vectors and bacterial type 3 secretion system, are proposed to deliver target-specific Nbs into tumor cells and to block tumor markers intracellularly. Simultaneously, Nbs have also been employed for in vivo molecular imaging to diagnose diseased tissues and to monitor the treatment effects. Here, we review the state of the art and focus on recent developments with Nbs as

  8. Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

    Science.gov (United States)

    Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C

    2013-07-10

    Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Tumor cell survival dependence on helical tomotherapy, continuous arc and segmented dose delivery

    International Nuclear Information System (INIS)

    Yang Wensha; Wang Li; Larner, James; Read, Paul; Benedict, Stan; Sheng Ke

    2009-01-01

    The temporal pattern of radiation delivery has been shown to influence the tumor cell survival fractions for the same radiation dose. To study the effect more specifically for state of the art rotational radiation delivery modalities, 2 Gy of radiation dose was delivered to H460 lung carcinoma, PC3 prostate cancer cells and MCF-7 breast tumor cells by helical tomotherapy (HT), seven-field LINAC (7F), and continuous dose delivery (CDD) over 2 min that simulates volumetric rotational arc therapy. Cell survival was measured by the clonogenic assay. The number of viable H460 cell colonies was 23.2 ± 14.4% and 27.7 ± 15.6% lower when irradiated by CDD compared with HT and 7F, respectively, and the corresponding values were 36.8 ± 18.9% and 35.3 ± 18.9% lower for MCF7 cells (p < 0.01). The survival of PC3 was also lower when irradiated by CDD than by HT or 7F but the difference was not as significant (p = 0.06 and 0.04, respectively). The higher survival fraction from HT delivery was unexpected because 90% of the 2 Gy was delivered in less than 1 min at a significantly higher dose rate than the other two delivery techniques. The results suggest that continuous dose delivery at a constant dose rate results in superior in vitro tumor cell killing compared with prolonged, segmented or variable dose rate delivery.

  10. Radical stereotactic radiosurgery with real-time tumor motion tracking in the treatment of small peripheral lung tumors

    Directory of Open Access Journals (Sweden)

    Chang Thomas

    2007-10-01

    Full Text Available Abstract Background Recent developments in radiotherapeutic technology have resulted in a new approach to treating patients with localized lung cancer. We report preliminary clinical outcomes using stereotactic radiosurgery with real-time tumor motion tracking to treat small peripheral lung tumors. Methods Eligible patients were treated over a 24-month period and followed for a minimum of 6 months. Fiducials (3–5 were placed in or near tumors under CT-guidance. Non-isocentric treatment plans with 5-mm margins were generated. Patients received 45–60 Gy in 3 equal fractions delivered in less than 2 weeks. CT imaging and routine pulmonary function tests were completed at 3, 6, 12, 18, 24 and 30 months. Results Twenty-four consecutive patients were treated, 15 with stage I lung cancer and 9 with single lung metastases. Pneumothorax was a complication of fiducial placement in 7 patients, requiring tube thoracostomy in 4. All patients completed radiation treatment with minimal discomfort, few acute side effects and no procedure-related mortalities. Following treatment transient chest wall discomfort, typically lasting several weeks, developed in 7 of 11 patients with lesions within 5 mm of the pleura. Grade III pneumonitis was seen in 2 patients, one with prior conventional thoracic irradiation and the other treated with concurrent Gefitinib. A small statistically significant decline in the mean % predicted DLCO was observed at 6 and 12 months. All tumors responded to treatment at 3 months and local failure was seen in only 2 single metastases. There have been no regional lymph node recurrences. At a median follow-up of 12 months, the crude survival rate is 83%, with 3 deaths due to co-morbidities and 1 secondary to metastatic disease. Conclusion Radical stereotactic radiosurgery with real-time tumor motion tracking is a promising well-tolerated treatment option for small peripheral lung tumors.

  11. SU-G-JeP1-06: Correlation of Lung Tumor Motion with Tumor Location Using Electromagnetic Tracking

    Energy Technology Data Exchange (ETDEWEB)

    Muccigrosso, D; Maughan, N; Parikh, P [Washington University School of Medicine, Saint Louis, MO (United States); Schultejans, H; Bera, R [Lindbergh High School, St. Louis, MO (United States)

    2016-06-15

    Purpose: It is well known that lung tumors move with respiration. However, most measurements of lung tumor motion have studied long treatment times with intermittent imaging; those populations may not necessarily represent conventional LINAC patients. We summarized the correlation between tumor motion and location in a multi-institutional trial with electromagnetic tracking, and identified the patient cohort that would most benefit from respiratory gating. Methods: Continuous electromagnetic transponder data (Varian Medical, Seattle, WA) of lung tumor motion was collected from 14 patients (214 total fractions) across 3 institutions during external beam radiation therapy in a prospective clinical trial (NCT01396551). External intervention from the clinician, such as couch shifts, instructed breath-holds, and acquisition pauses, were manually removed from the 10 Hz tracking data according to recorded notes. The average three-dimensional displacement from the breathing cycle’s end-expiratory to end-inhalation phases (peak-to-peak distance) of the transponders’ isocenter was calculated for each patient’s treatment. A weighted average of each isocenter was used to assess the effects of location on motion. A total of 14 patients were included in this analysis, grouped by their transponders’ location in the lung: upper, medial, and lower. Results: 8 patients had transponders in the upper lung, and 3 patients each in the medial lobe and lower lung. The weighted average ± standard deviation of all peak-to-peak distances for each group was: 1.04 ± 0.39 cm in the lower lung, 0.56 ± 0.14 cm in the medial lung, and 0.30 ± 0.06 cm in the upper lung. Conclusion: Tumors in the lower lung are most susceptible to excessive motion and daily variation, and would benefit most from continuous motion tracking and gating. Those in the medial lobe might be at moderate risk. The upper lobes have limited motion. These results can guide different motion management strategies

  12. Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature

    International Nuclear Information System (INIS)

    Sonveaux, Pierre; Frerart, Francoise; Bouzin, Caroline; Brouet, Agnes; Wever, Julie de; Jordan, Benedicte F.; Gallez, Bernard; Feron, Olivier

    2007-01-01

    Purpose: To determine whether radiation-induced increases in nitric oxide (NO) production can influence tumor blood flow and improve delivery of Akt-targeting therapeutic DNA lipocomplexes to the tumor. Methods and Materials: The contribution of NO to the endothelial response to radiation was identified using NO synthase (NOS) inhibitors and endothelial NOS (eNOS)-deficient mice. Reporter-encoding plasmids complexed with cationic lipids were used to document the tumor vascular specificity and the efficacy of in vivo lipofection after irradiation. A dominant-negative Akt gene construct was used to evaluate the facilitating effects of radiotherapy on the therapeutic transgene delivery. Results: The abundance of eNOS protein was increased in both irradiated tumor microvessels and endothelial cells, leading to a stimulation of NO release and an associated increase in tumor blood flow. Transgene expression was subsequently improved in the irradiated vs. nonirradiated tumor vasculature. This effect was not apparent in eNOS-deficient mice and could not be reproduced in irradiated cultured endothelial cells. Finally, we combined low-dose radiotherapy with a dominant-negative Akt gene construct and documented synergistic antitumor effects. Conclusions: This study offers a new rationale to combine radiotherapy with gene therapy, by directly exploiting the stimulatory effects of radiation on NO production by tumor endothelial cells. The preferential expression of the transgene in the tumor microvasculature underscores the potential of such an adjuvant strategy to limit the angiogenic response of irradiated tumors

  13. Tumor target amplification: Implications for nano drug delivery systems.

    Science.gov (United States)

    Seidi, Khaled; Neubauer, Heidi A; Moriggl, Richard; Jahanban-Esfahlan, Rana; Javaheri, Tahereh

    2018-04-10

    Tumor cells overexpress surface markers which are absent from normal cells. These tumor-restricted antigenic signatures are a fundamental basis for distinguishing on-target from off-target cells for ligand-directed targeting of cancer cells. Unfortunately, tumor heterogeneity impedes the establishment of a solid expression pattern for a given target marker, leading to drastic changes in quality (availability) and quantity (number) of the target. Consequently, a subset of cancer cells remains untargeted during the course of treatment, which subsequently promotes drug-resistance and cancer relapse. Since target inefficiency is only problematic for cancer treatment and not for treatment of other pathological conditions such as viral/bacterial infections, target amplification or the generation of novel targets is key to providing eligible antigenic markers for effective targeted therapy. This review summarizes the limitations of current ligand-directed targeting strategies and provides a comprehensive overview of tumor target amplification strategies, including self-amplifying systems, dual targeting, artificial markers and peptide modification. We also discuss the therapeutic and diagnostic potential of these approaches, the underlying mechanism(s) and established methodologies, mostly in the context of different nanodelivery systems, to facilitate more effective ligand-directed cancer cell monitoring and targeting. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. PLGA Nanoparticles for Ultrasound-Mediated Gene Delivery to Solid Tumors

    Directory of Open Access Journals (Sweden)

    Marxa Figueiredo

    2012-01-01

    Full Text Available This paper focuses on novel approaches in the field of nanotechnology-based carriers utilizing ultrasound stimuli as a means to spatially target gene delivery in vivo, using nanoparticles made with either poly(lactic-co-glycolic acid (PLGA or other polymers. We specifically discuss the potential for gene delivery by particles that are echogenic (amenable to destruction by ultrasound composed either of polymers (PLGA, polystyrene or other contrast agent materials (Optison, SonoVue microbubbles. The use of ultrasound is an efficient tool to further enhance gene delivery by PLGA or other echogenic particles in vivo. Echogenic PLGA nanoparticles are an attractive strategy for ultrasound-mediated gene delivery since this polymer is currently approved by the US Food and Drug Administration for drug delivery and diagnostics in cancer, cardiovascular disease, and also other applications such as vaccines and tissue engineering. This paper will review recent successes and the potential of applying PLGA nanoparticles for gene delivery, which include (a echogenic PLGA used with ultrasound to enhance local gene delivery in tumors or muscle and (b PLGA nanoparticles currently under development, which could benefit in the future from ultrasound-enhanced tumor targeted gene delivery.

  15. SU-D-18A-04: Quantifying the Ability of Tumor Tracking to Spare Normal Tissue

    Energy Technology Data Exchange (ETDEWEB)

    Burger, A; Buzurovic, I; Hurwitz, M; Williams, C; Lewis, J [Brigham and Women' s Hospital, Dana-Farber Cancer Center, Harvard Medical Sc, Boston, MA (United States); Mishra, P [Varian Medical Systems, Palo Alto, CA (United States); Seco, J [Mass General Hospital, Harvard Medical, Boston, MA (United States)

    2014-06-01

    Purpose: Tumor tracking allows for smaller tissue volumes to be treated, potentially reducing normal tissue damage. However, tumor tracking is a more complex treatment and has little benefit in some scenarios. Here we quantify the benefit of tumor tracking for a range of patients by estimating the dose of radiation to organs at risk and the normal tissue complication probability (NTCP) for both standard and tracking treatment plans. This comparison is performed using both patient 4DCT data and extended Cardiac-Torso (XCAT) digital phantoms. Methods: We use 4DCT data for 10 patients. Additionally, we generate digital phantoms with motion derived from measured patient long tumor trajectories to compare standard and tracking treatment plans. The standard treatment is based on the average intensity projection (AIP) of 4DCT images taken over a breath cycle. The tracking treatment is based on doses calculated on images representing the anatomy at each time point. It is assumed that there are no errors in tracking the target. The NTCP values are calculated based on RTOG guidelines. Results: The mean reduction in the mean dose delivered was 5.5% to the lungs (from 7.3 Gy to 6.9 Gy) and 4.0% to the heart (from 12.5 Gy to 12.0 Gy). The mean reduction in the max dose delivered was 13% to the spinal cord (from 27.6 Gy to 24.0 Gy), 2.5% to the carina (from 31.7 Gy to 30.9 Gy), and 15% to the esophagus (from 69.6 Gy to 58.9 Gy). The mean reduction in the probability of 2nd degree radiation pneumonitis (RP) was 8.7% (3.1% to 2.8%) and the mean reduction in the effective volume was 6.8% (10.8% to 10.2%). Conclusions: Tumor tracking has the potential to reduce irradiation of organs at risk, and consequentially reduce the normal tissue complication probability. The benefits vary based on the clinical scenario. This study is supported by Varian Medical Systems, Inc.

  16. SU-E-J-59: Feasibility of Markerless Tumor Tracking by Sequential Dual-Energy Fluoroscopy On a Clinical Tumor Tracking System

    Energy Technology Data Exchange (ETDEWEB)

    Dhont, J; Poels, K; Verellen, D; Tournel, K; Gevaert, T; Steenbeke, F; Burghelea, M; De Ridder, M [Department of Radiotherapy, Universitair Ziekenhuis Brussel, Brussels (Belgium)

    2015-06-15

    Purpose: To evaluate the feasibility of markerless tumor tracking through the implementation of a novel dual-energy imaging approach into the clinical dynamic tracking (DT) workflow of the Vero SBRT system. Methods: Two sequential 20 s (11 Hz) fluoroscopy sequences were acquired at the start of one fraction for 7 patients treated for primary and metastatic lung cancer with DT on the Vero system. Sequences were acquired using 2 on-board kV imaging systems located at ±45° from the MV beam axis, at respectively 60 kVp (3.2 mAs) and 120 kVp (2.0 mAs). Offline, a normalized cross-correlation algorithm was applied to match the high (HE) and low energy (LE) images. Per breathing phase (inhale, exhale, maximum inhale and maximum exhale), the 5 best-matching HE and LE couples were extracted for DE subtraction. A contrast analysis according to gross tumor volume was conducted based on contrast-to-noise ratio (CNR). Improved tumor visibility was quantified using an improvement ratio. Results: Using the implanted fiducial as a benchmark, HE-LE sequence matching was effective for 13 out of 14 imaging angles. Overlying bony anatomy was removed on all DE images. With the exception of two imaging angles, the DE images showed no significantly improved tumor visibility compared to HE images, with an improvement ratio averaged over all patients of 1.46 ± 1.64. Qualitatively, it was observed that for those imaging angles that showed no significantly improved CNR, the tumor tissue could not be reliably visualized on neither HE nor DE images due to a total or partial overlap with other soft tissue. Conclusion: Dual-energy subtraction imaging by sequential orthogonal fluoroscopy was shown feasible by implementing an additional LE fluoroscopy sequence. However, for most imaging angles, DE images did not provide improved tumor visibility over single-energy images. Optimizing imaging angles is likely to improve tumor visibility and the efficacy of dual-energy imaging. This work was in

  17. Ultrasound-enhanced delivery of doxorubicin/all-trans retinoic acid-loaded nanodiamonds into tumors.

    Science.gov (United States)

    Li, Huanan; Zeng, Deping; Wang, Zhenyu; Fang, Liaoqiong; Li, Faqi; Wang, Zhibiao

    2018-03-14

    To build up a combined therapy strategy to address limitations of the enhanced permeability and retention (EPR) effect and improve the efficiency of tumor therapy. A pH-sensitive nanocomplex for co-delivery of doxorubicin (DOX) and all-trans retinoic acid (ATRA) was developed based on nanodiamonds (DOX/ATRA-NDs) to enhance intracellular retention of drugs. Meanwhile, ultrasound was employed to enhance tumor vascular penetration of DOX-ATRA-NDs. The distribution of DOX/ATRA-NDs in the tumor tissues increased threefold when ultrasound was applied at 1 MHz and 0.6 W/cm 2 . Comparing with unmodified chemotherapeutics, the combined therapy induced more tumor cells apoptosis and greater tumor growth inhibition in both liver and breast tumor models. DOX-ATRA-NDs demonstrate great potential in clinical applications.

  18. SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

    International Nuclear Information System (INIS)

    Soltani, M; Bazmara, H; Sefidgar, M; Subramaniam, R; Rahmim, A

    2015-01-01

    Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm 3 , were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm 3 , was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm 3 , the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic tumors is not

  19. SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Soltani, M [ohns Hopkins University School of Medicine, Baltimore, Maryland, and KNT university, Tehran (Iran, Islamic Republic of); Bazmara, H [KNT university, Tehran (Iran, Islamic Republic of); Sefidgar, M [IKI University, Qazvin (Iran, Islamic Republic of); Subramaniam, R; Rahmim, A [Johns Hopkins University School of Medicine, Baltimore, MD (United States)

    2015-06-15

    Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm{sup 3}, were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm{sup 3}, was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm{sup 3}, the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic

  20. TH-C-BRD-07: Minimizing Dose Uncertainty for Spot Scanning Beam Proton Therapy of Moving Tumor with Optimization of Delivery Sequence

    International Nuclear Information System (INIS)

    Li, H; Zhang, X; Zhu, X; Li, Y

    2014-01-01

    Purpose: Intensity modulated proton therapy (IMPT) has been shown to be able to reduce dose to normal tissue compared to intensity modulated photon radio-therapy (IMRT), and has been implemented for selected lung cancer patients. However, respiratory motion-induced dose uncertainty remain one of the major concerns for the radiotherapy of lung cancer, and the utility of IMPT for lung patients was limited because of the proton dose uncertainty induced by motion. Strategies such as repainting and tumor tracking have been proposed and studied but repainting could result in unacceptable long delivery time and tracking is not yet clinically available. We propose a novel delivery strategy for spot scanning proton beam therapy. Method: The effective number of delivery (END) for each spot position in a treatment plan was calculated based on the parameters of the delivery system, including time required for each spot, spot size and energy. The dose uncertainty was then calculated with an analytical formula. The spot delivery sequence was optimized to maximize END and minimize the dose uncertainty. 2D Measurements with a detector array on a 1D moving platform were performed to validate the calculated results. Results: 143 2D measurements on a moving platform were performed for different delivery sequences of a single layer uniform pattern. The measured dose uncertainty is a strong function of the delivery sequence, the worst delivery sequence results in dose error up to 70% while the optimized delivery sequence results in dose error of <5%. END vs. measured dose uncertainty follows the analytical formula. Conclusion: With optimized delivery sequence, it is feasible to minimize the dose uncertainty due to motion in spot scanning proton therapy

  1. Which drug or drug delivery system can change clinical practice for brain tumor therapy?

    OpenAIRE

    Siegal, Tali

    2013-01-01

    The prognosis and treatment outcome for primary brain tumors have remained unchanged despite advances in anticancer drug discovery and development. In clinical trials, the majority of promising experimental agents for brain tumors have had limited impact on survival or time to recurrence. These disappointing results are partially explained by the inadequacy of effective drug delivery to the CNS. The impediments posed by the various specialized physiological barriers and active efflux mechanis...

  2. Targeting Potassium Channels for Increasing Delivery of Imaging Agents and Therapeutics to Brain Tumors

    OpenAIRE

    Nagendra Sanyasihally Ningaraj; Divya eKhaitan

    2013-01-01

    Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/ capillaries that form the blood–brain barrier (BBB) not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB). Studies in our laboratory have identifi...

  3. [Malignant tumors of the female genital track in the elderly].

    Science.gov (United States)

    Gottwald, Leszek; Akoel, Kindah Mo; Wójcik-Krowiranda, Katarzyna; Bieńkiewicz, Andrzej

    2003-09-01

    In senium the increase in the incidence of most malignant neoplasms, as well as gynecological cancers is found. In this period of life the vast number of women do not apply for the preventive and follow-up examinations, which increases the number of malignant diseases diagnosed at advanced clinical stages. The coexisting another diseases often limits the possibility of the operative treatment in those cases. To assess the profile of malignant tumors of the genital tract and their treatment in women above 70 year old. 61 women aged from 71 yrs. to 88 yrs. treated operatively between 1997-2001 due to gynecological cancers were included into the study. The structure and detectability of the neoplasms, as well as the type of performed surgical procedures were analysed. 30 endometrial cancers (49.2%), 16 ovarian cancers (26.2%), 14 vulvar cancers (22.9%) and 1 cervical cancer were diagnosed and surgically treated. The endometrial cancer stage I was detected in 18 cases, stage II in 4 cases and stage III in 8 cases. In each case the radical operation was done (total hysterectomy, lymphadenectomy and appendectomy). The ovarian cancer stage I was detected in 3 cases, stage II in 2 cases, stage III in 5 cases, and stage IV in 6 cases. Only in 5 cases out of this group the radical surgery was performed (total hysterectomy, omentectomy and appendectomy). The vulvar cancer stage I was detected in 2 cases, stage II in 11 cases, and FIGO stage III in 4 cases. In each of these women the vulva and bilateral inguinal lymph nodes were resected, and in 2 cases additionally at the same time the Miles operation was performed. The cervical cancer clinical stage I was detected, and the Wertheim operation was performed. The most often diagnosed malignant neoplasm in women above 70 yrs. was the endometrial cancer. The worst first-time diagnosis structure was observed in the ovarian cancer, what significantly decreased the ability of surgical treatment in this group.

  4. PEGylated Polyamidoamine dendrimer conjugated with tumor homing peptide as a potential targeted delivery system for glioma.

    Science.gov (United States)

    Jiang, Yan; Lv, Lingyan; Shi, Huihui; Hua, Yabing; Lv, Wei; Wang, Xiuzhen; Xin, Hongliang; Xu, Qunwei

    2016-11-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system (CNS) tumor with a short survival time. The failure of chemotherapy is ascribed to the low transport of chemotherapeutics across the Blood Brain Tumor Barrier (BBTB) and poor penetration into tumor tissue. In order to overcome the two barriers, small nanoparticles with active targeted capability are urgently needed for GBM drug delivery. In this study, we proposed PEGylated Polyamidoamine (PAMAM) dendrimer nanoparticles conjugated with glioma homing peptides (Pep-1) as potential glioma targeting delivery system (Pep-PEG-PAMAM), where PEGylated PAMAM dendrimer nanoparticle was utilized as carrier due to its small size and perfect penetration into tumor and Pep-1 was used to overcome BBTB via interleukin 13 receptor α2 (IL-13Rα2) mediated endocytosis. The preliminary availability and safety of Pep-PEG-PAMAM as a nanocarrier for glioma was evaluated. In vitro results indicated that a significantly higher amount of Pep-PEG-PAMAM was endocytosed by U87 MG cells. In vivo fluorescence imaging of U87MG tumor-bearing mice confirmed that the fluorescence intensity at glioma site of targeted group was 2.02 folds higher than that of untargeted group (**p<0.01), and glioma distribution experiment further revealed that Pep-PEG-PAMAM exhibited a significantly enhanced accumulation and improved penetration at tumor site. In conclusion, Pep-1 modified PAMAM was a promising nanocarrier for targeted delivery of brain glioma. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Tumor Targeting and Drug Delivery by Anthrax Toxin

    OpenAIRE

    Bachran, Christopher; Leppla, Stephen H.

    2016-01-01

    Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associ...

  6. Tumor targeted delivery of doxorubicin in malignant peripheral nerve sheath tumors.

    Directory of Open Access Journals (Sweden)

    A B Madhankumar

    Full Text Available Peripheral nerve sheath tumors are benign tumors that have the potential to transform into malignant peripheral nerve sheath tumors (MPNSTs. Interleukin-13 receptor alpha 2 (IL13Rα2 is a cancer associated receptor expressed in glioblastoma and other invasive cancers. We analyzed IL13Rα2 expression in several MPNST cell lines including the STS26T cell line, as well as in several peripheral nerve sheath tumors to utilize the IL13Rα2 receptor as a target for therapy. In our studies, we demonstrated the selective expression of IL13Rα2 in several peripheral nerve sheath tumors by immunohistochemistry (IHC and immunoblots. We established a sciatic nerve MPNST mouse model in NIH III nude mice using a luciferase transfected STS26T MPNST cell line. Similarly, analysis of the mouse sciatic nerves after tumor induction revealed significant expression of IL13Rα2 by IHC when compared to a normal sciatic nerve. IL13 conjugated liposomal doxorubicin was formulated and shown to bind and internalized in the MPNST cell culture model demonstrating cytotoxic effect. Our subsequent in vivo investigation in the STS26T MPNST sciatic nerve tumor model indicated that IL13 conjugated liposomal doxorubicin (IL13LIPDXR was more effective in inhibiting tumor progression compared to unconjugated liposomal doxorubicin (LIPDXR. This further supports that IL13 receptor targeted nanoliposomes is a potential approach for treating MPNSTs.

  7. hTe exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

    Institute of Scientific and Technical Information of China (English)

    Vivek Agrahari

    2017-01-01

    Delivering therapeutics to the central nervous system (CNS) and brain-tumor has been a major challenge. hTe current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in provid-ing signiifcant beneifts to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB). hTe BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nan-otherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer signiifcant ad vantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are brielfy discussed. hTe drug transport mechanisms at the BBB are outlined. hTe approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic ap-proaches for their enhanced clinical application in brain-tumor therapy are discussed.

  8. The exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

    Directory of Open Access Journals (Sweden)

    Vivek Agrahari

    2017-01-01

    Full Text Available Delivering therapeutics to the central nervous system (CNS and brain-tumor has been a major challenge. The current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in providing significant benefits to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB. The BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nanotherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer significant advantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are briefly discussed. The drug transport mechanisms at the BBB are outlined. The approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic approaches for their enhanced clinical application in brain-tumor therapy are discussed.

  9. Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery

    Science.gov (United States)

    Kesharwani, Prashant; Iyer, Arun K.

    2015-01-01

    Advances in the application of nanotechnology in medicine have given rise to multifunctional smart nanocarriers that can be engineered with tunable physicochemical characteristics to deliver one or more therapeutic agent(s) safely and selectively to cancer cells, including intracellular organelle-specific targeting. Dendrimers having properties resembling biomolecules, with well-defined 3D nanopolymeric architectures, are emerging as a highly attractive class of drug and gene delivery vector. The presence of numerous peripheral functional groups on hyperbranched dendrimers affords efficient conjugation of targeting ligands and biomarkers that can recognize and bind to receptors overexpressed on cancer cells for tumor-cell-specific delivery. The present review compiles the recent advances in dendrimer-mediated drug and gene delivery to tumors by passive and active targeting principles with illustrative examples. PMID:25555748

  10. Cell mediated therapeutics for cancer treatment: Tumor homing cells as therapeutic delivery vehicles

    Science.gov (United States)

    Balivada, Sivasai

    Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V

  11. Delivery of viral vectors to tumor cells: extracellular transport, systemic distribution, and strategies for improvement.

    Science.gov (United States)

    Wang, Yong; Yuan, Fan

    2006-01-01

    It is a challenge to deliver therapeutic genes to tumor cells using viral vectors because (i) the size of these vectors are close to or larger than the space between fibers in extracellular matrix and (ii) viral proteins are potentially toxic in normal tissues. In general, gene delivery is hindered by various physiological barriers to virus transport from the site of injection to the nucleus of tumor cells and is limited by normal tissue tolerance of toxicity determined by local concentrations of transgene products and viral proteins. To illustrate the obstacles encountered in the delivery and yet limit the scope of discussion, this review focuses only on extracellular transport in solid tumors and distribution of viral vectors in normal organs after they are injected intravenously or intratumorally. This review also discusses current strategies for improving intratumoral transport and specificity of viral vectors.

  12. Field distribution and DNA transport in solid tumors during electric field-mediated gene delivery.

    Science.gov (United States)

    Henshaw, Joshua W; Yuan, Fan

    2008-02-01

    Gene therapy has a great potential in cancer treatment. However, the efficacy of cancer gene therapy is currently limited by the lack of a safe and efficient means to deliver therapeutic genes into the nucleus of tumor cells. One method under investigation for improving local gene delivery is based on the use of pulsed electric field. Despite repeated demonstration of its effectiveness in vivo, the underlying mechanisms behind electric field-mediated gene delivery remain largely unknown. Without a thorough understanding of these mechanisms, it will be difficult to further advance the gene delivery. In this review, the electric field-mediated gene delivery in solid tumors will be examined by following individual transport processes that must occur in vivo for a successful gene transfer. The topics of examination include: (i) major barriers for gene delivery in the body, (ii) distribution of electric fields at both cell and tissue levels during the application of external fields, and (iii) electric field-induced transport of genes across each of the barriers. Through this approach, the review summarizes what is known about the mechanisms behind electric field-mediated gene delivery and what require further investigations in future studies.

  13. Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment

    Directory of Open Access Journals (Sweden)

    Daria S. Chulpanova

    2018-03-01

    Full Text Available Mesenchymal stem cells (MSCs are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs, which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.

  14. Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.

    Science.gov (United States)

    Liu, Rong; Colby, Aaron H; Gilmore, Denis; Schulz, Morgan; Zeng, Jialiu; Padera, Robert F; Shirihai, Orian; Grinstaff, Mark W; Colson, Yolonda L

    2016-09-01

    The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Targeting Potassium Channels for Increasing Delivery of Imaging Agents and Therapeutics to Brain Tumors

    Directory of Open Access Journals (Sweden)

    Nagendra Sanyasihally Ningaraj

    2013-05-01

    Full Text Available Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/ capillaries that form the blood–brain barrier (BBB not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB. Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells. In this study, we validated the non-invasive and clinically relevant Dynamic Contrast Enhancing-Magnetic Resonance Imaging (DCE-MRI method with invasive, clinically irrelevant but highly accurate Quantitative Autoradiography (QAR method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa channel activator NS-1619. Our results show that human gliomas and brain tumor endothelial cells that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents’ delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome.

  16. Development of real-time tumor tracking system for stereotactic radiotherapy

    International Nuclear Information System (INIS)

    Yamanaka, Seiji; Sasagawa, Tsuyoshi; Uno, Yukimichi

    2011-01-01

    We are now developing the real-time tumor tracking system for stereotactic radiotherapy (SRT) to provide precise information on the location of a tumor and to reduce the irradiation to healthy tissue in a patient. The system has the following features: A motion tracking and processing unit recognizes a gold marker inserted in or near a tumor in real time by the pattern matching of a predetermined template image and acquired X-ray fluoroscopic images. When the gold marker is within a planned area, that is to say, when a tumor enters a target irradiation area, a gate signal is sent to a linear accelerator. A railway unit is equipped with two X-ray tubes and two detectors, which are controlled separately with their own drive mechanism. They travel with high accuracy and reproducibility to the best position for monitoring the gold marker. A synchronization controller controls the timing for X-ray fluoroscopy and the gate signals to the linear accelerator. The controller works for two types of detectors: a color X-ray detector and a flat panel detector (FPD). (author)

  17. Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

    Directory of Open Access Journals (Sweden)

    Millard M

    2017-10-01

    Full Text Available Marie Millard,1,2 Ilya Yakavets,1–3 Vladimir Zorin,3,4 Aigul Kulmukhamedova,1,2,5 Sophie Marchal,1,2 Lina Bezdetnaya1,2 1Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, 2Research Department, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France; 3Laboratory of Biophysics and Biotechnology, 4International Sakharov Environmental Institute, Belarusian State University, Minsk, Belarus; 5Department of Radiology, Medical Company Sunkar, Almaty, Kazakhstan Abstract: The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a

  18. Noninvasive diffuse optical monitoring of head and neck tumor blood flow and oxygenation during radiation delivery

    Science.gov (United States)

    Dong, Lixin; Kudrimoti, Mahesh; Cheng, Ran; Shang, Yu; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

    2012-01-01

    This study explored using a novel diffuse correlation spectroscopy (DCS) flow-oximeter to noninvasively monitor blood flow and oxygenation changes in head and neck tumors during radiation delivery. A fiber-optic probe connected to the DCS flow-oximeter was placed on the surface of the radiologically/clinically involved cervical lymph node. The DCS flow-oximeter in the treatment room was remotely operated by a computer in the control room. From the early measurements, abnormal signals were observed when the optical device was placed in close proximity to the radiation beams. Through phantom tests, the artifacts were shown to be caused by scattered x rays and consequentially avoided by moving the optical device away from the x-ray beams. Eleven patients with head and neck tumors were continually measured once a week over a treatment period of seven weeks, although there were some missing data due to the patient related events. Large inter-patient variations in tumor hemodynamic responses were observed during radiation delivery. A significant increase in tumor blood flow was observed at the first week of treatment, which may be a physiologic response to hypoxia created by radiation oxygen consumption. Only small and insignificant changes were found in tumor blood oxygenation, suggesting that oxygen utilizations in tumors during the short period of fractional radiation deliveries were either minimal or balanced by other effects such as blood flow regulation. Further investigations in a large patient population are needed to correlate the individual hemodynamic responses with the clinical outcomes for determining the prognostic value of optical measurements. PMID:22312579

  19. Three-dimensional tumor spheroids for in vitro analysis of bacteria as gene delivery vectors in tumor therapy.

    Science.gov (United States)

    Osswald, Annika; Sun, Zhongke; Grimm, Verena; Ampem, Grace; Riegel, Karin; Westendorf, Astrid M; Sommergruber, Wolfgang; Otte, Kerstin; Dürre, Peter; Riedel, Christian U

    2015-12-12

    Several studies in animal models demonstrated that obligate and facultative anaerobic bacteria of the genera Bifidobacterium, Salmonella, or Clostridium specifically colonize solid tumors. Consequently, these and other bacteria are discussed as live vectors to deliver therapeutic genes to inhibit tumor growth. Therapeutic approaches for cancer treatment using anaerobic bacteria have been investigated in different mouse models. In the present study, solid three-dimensional (3D) multicellular tumor spheroids (MCTS) of the colorectal adenocarcinoma cell line HT-29 were generated and tested for their potential to study prodrug-converting enzyme therapies using bacterial vectors in vitro. HT-29 MCTS resembled solid tumors displaying all relevant features with an outer zone of proliferating cells and hypoxic and apoptotic regions in the core. Upon incubation with HT-29 MCTS, Bifidobacterium bifidum S17 and Salmonella typhimurium YB1 selectively localized, survived and replicated in hypoxic areas inside MCTS. Furthermore, spores of the obligate anaerobe Clostridium sporogenes germinated in these hypoxic areas. To further evaluate the potential of MCTS to investigate therapeutic approaches using bacteria as gene delivery vectors, recombinant bifidobacteria expressing prodrug-converting enzymes were used. Expression of a secreted cytosine deaminase in combination with 5-fluorocytosine had no effect on growth of MCTS due to an intrinsic resistance of HT-29 cells to 5-fluorouracil, i.e. the converted drug. However, a combination of the prodrug CB1954 and a strain expressing a secreted chromate reductase effectively inhibited MCTS growth. Collectively, the presented results indicate that MCTS are a suitable and reliable model to investigate live bacteria as gene delivery vectors for cancer therapy in vitro.

  20. Digesting a Path Forward: The Utility of Collagenase Tumor Treatment for Improved Drug Delivery.

    Science.gov (United States)

    Dolor, Aaron; Szoka, Francis C

    2018-06-04

    Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment. Although collagen synthesis inhibitors are in clinical development, the use of collagenases is contentious and clinically untested in cancer patients. Pretreatment of murine tumors with collagenases increased drug uptake and diffusion 2-10-fold. This modest improvement resulted in decreased tumor growth, but the benefits of collagenase treatment are confounded by risks of toxicity from collagen breakdown in healthy tissues. In this review, we evaluate the published in vitro and in vivo benefits and limitations of collagenase treatment to improve drug delivery.

  1. Lipid conjugated prodrugs for enzyme-triggered liposomal drug delivery to tumors

    DEFF Research Database (Denmark)

    Clausen, Mads Hartvig

    2011-01-01

    For some time we have been developing novel enzyme-triggered prodrugs for drug delivery targeting cancer. The liposomal prodrugs take advantage of the EPR effect to localize to tumors and of the local over-expression of secretory phospholipase A2 in tumors. Compared to conventional liposomal drug...... delivery systems, our prodrug-lipid conjugates have two main advantages: 1) the drugs are covalently linked to the lipids and thus leakage is circumvented and 2) the lipophilic bilayer of the formulated liposomes effectively shields the drugs from the aqueous environment in vivo. Consequently, the strategy...... targeting nuclear receptors and structural proteins. The presentation will highlight various strategies and recent progress towards improved systems, including chemical synthesis, enzyme activity and cytotoxicity....

  2. Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

    Science.gov (United States)

    Etame, Arnold B.

    The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non

  3. An accuracy analysis of Cyberknife tumor tracking radiotherapy according to unpredictable change of respiration

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Jung Min; Lee, Chang Yeol; Huh, Hyun Do; Kim, Wan Sun [Dept. of Radiation Oncology, Inha university hospital, Incheon (Korea, Republic of)

    2015-12-15

    Cyber-Knife tumor tracking system, based on the correlation relationship between the position of a tumor which moves in response to the real time respiratory cycle signal and respiration was obtained by the LED marker attached to the outside of the patient, the location of the tumor to predict in advance, the movement of the tumor in synchronization with the therapeutic device to track real-time tumor, is a system for treating. The purpose of this study, in the cyber knife tumor tracking radiation therapy, trying to evaluate the accuracy of tumor tracking radiation therapy system due to the change in the form of unpredictable sudden breathing due to cough and sleep. Materials and Methods : Breathing Log files that were used in the study, based on the Respiratory gating radiotherapy and Cyber-knife tracking radiosurgery breathing Log files of patients who received herein, measured using the Log files in the form of a Sinusoidal pattern and Sudden change pattern. it has been reconstituted as possible. Enter the reconstructed respiratory Log file cyber knife dynamic chest Phantom, so that it is possible to implement a motion due to respiration, add manufacturing the driving apparatus of the existing dynamic chest Phantom, Phantom the form of respiration we have developed a program that can be applied to. Movement of the phantom inside the target (Ball cube target) was driven by the displacement of three sizes of according to the size of the respiratory vertical (Superior-Inferior) direction to the 5 mm, 10 mm, 20 mm. Insert crosses two EBT3 films in phantom inside the target in response to changes in the target movement, the End-to-End (E2E) test provided in Cyber-Knife manufacturer depending on the form of the breathing five times each. It was determined by carrying. Accuracy of tumor tracking system is indicated by the target error by analyzing the inserted film, additional E2E test is analyzed by measuring the correlation error while being advanced. If the target

  4. An accuracy analysis of Cyberknife tumor tracking radiotherapy according to unpredictable change of respiration

    International Nuclear Information System (INIS)

    Seo, Jung Min; Lee, Chang Yeol; Huh, Hyun Do; Kim, Wan Sun

    2015-01-01

    Cyber-Knife tumor tracking system, based on the correlation relationship between the position of a tumor which moves in response to the real time respiratory cycle signal and respiration was obtained by the LED marker attached to the outside of the patient, the location of the tumor to predict in advance, the movement of the tumor in synchronization with the therapeutic device to track real-time tumor, is a system for treating. The purpose of this study, in the cyber knife tumor tracking radiation therapy, trying to evaluate the accuracy of tumor tracking radiation therapy system due to the change in the form of unpredictable sudden breathing due to cough and sleep. Materials and Methods : Breathing Log files that were used in the study, based on the Respiratory gating radiotherapy and Cyber-knife tracking radiosurgery breathing Log files of patients who received herein, measured using the Log files in the form of a Sinusoidal pattern and Sudden change pattern. it has been reconstituted as possible. Enter the reconstructed respiratory Log file cyber knife dynamic chest Phantom, so that it is possible to implement a motion due to respiration, add manufacturing the driving apparatus of the existing dynamic chest Phantom, Phantom the form of respiration we have developed a program that can be applied to. Movement of the phantom inside the target (Ball cube target) was driven by the displacement of three sizes of according to the size of the respiratory vertical (Superior-Inferior) direction to the 5 mm, 10 mm, 20 mm. Insert crosses two EBT3 films in phantom inside the target in response to changes in the target movement, the End-to-End (E2E) test provided in Cyber-Knife manufacturer depending on the form of the breathing five times each. It was determined by carrying. Accuracy of tumor tracking system is indicated by the target error by analyzing the inserted film, additional E2E test is analyzed by measuring the correlation error while being advanced. If the target

  5. The effect of tumor location and respiratory function on tumor movement estimated by real-time tracking radiotherapy (RTRT) system

    International Nuclear Information System (INIS)

    Onimaru, Rikiya; Shirato, Hiroki; Fujino, Masaharu; Suzuki, Keishiro; Yamazaki, Kouichi; Nishimura, Masaharu; Dosaka-Akita, Hirotoshi; Miyasaka, Kazuo

    2005-01-01

    Purpose: The effects of tumor location and pulmonary function on the motion of fiducial markers near lung tumors were evaluated to deduce simple guidelines for determining the internal margin in radiotherapy without fiducial markers. Methods and Materials: Pooled data collected by a real-time tumor-tracking radiotherapy system on 42 markers in 39 patients were analyzed. The pulmonary functions of all patients were assessed before radiotherapy. Using chest X-ray film, the position of the marker was expressed relative to the geometry of the unilateral lung. Posterior location meant the area of the posterior half of the lung in a lateral chest X-ray film, and caudal location meant the caudal half of the chest X-ray film; these categories were determined by measuring the distance between the marker and anatomic landmarks, including the apex, costophrenic angle, midline of spinal canal, lateral, anterior, and posterior boundary of the lung. Results: Before the radiotherapy, 18 patients had obstructive respiratory dysfunction (ratio of forced expiratory volume in 1 s to forced vital capacity [FEV 1.0 /FVC] 1.0 /FVC and %VC were 97.0% and 66.5%, respectively. Median tumor movements in the x (left-right), y (anteroposterior), and z (craniocaudal) directions were 1.1 mm, 2.3 mm, and 5.4 mm, respectively. There was no significant correlation between respiratory function and magnitude of marker movement in any direction. Median marker movement in the z direction was 2.6 mm for the cranial location and 11.8 mm for the caudal location, respectively (p < 0.001). Median movement in the z direction was 11.8 mm for posterior location and 3.4 mm for anterior location, respectively (p < 0.01). Conclusions: Simple measurement of the relative location on plain chest X-ray film was related, but respiratory function test was not related, to the craniocaudal amplitude of the motion of the fiducial marker near lung tumors

  6. Bacteria-mediated in vivo delivery of quantum dots into solid tumor

    International Nuclear Information System (INIS)

    Liu, Ying; Zhou, Mei; Luo, Dan; Wang, Lijun; Hong, Yuankai; Yang, Yepeng; Sha, Yinlin

    2012-01-01

    Highlights: ► New approach using the probiotic Bifidobacterium bifidum as a vehicle to deliver QDs into the deep tissue of solid tumors in vivo was achieved. ► Bifidobacterium bifidum delivery system has intrinsic biocompatibility. ► The targeting efficacy was improved by folic acids. -- Abstract: Semiconductor nanocrystals, so-called quantum dots (QDs), promise potential application in bioimaging and diagnosis in vitro and in vivo owing to their high-quality photoluminescence and excellent photostability as well as size-tunable spectra. Here, we describe a biocompatible, comparatively safe bacteria-based system that can deliver QDs specifically into solid tumor of living animals. In our strategy, anaerobic bacterium Bifidobacterium bifidum (B. bifidum) that colonizes selectively in hypoxic regions of animal body was successfully used as a vehicle to load with QDs and transported into the deep tissue of solid tumors. The internalization of lipid-encapsuled QDs into B. bifidum was conveniently carried by electroporation. To improve the efficacy and specificity of tumor targeting, the QDs-carrying bacterium surface was further conjugated with folic acids (FAs) that can bind to the folic acid receptor overexpressed tumor cells. This new approach opens a pathway for delivering different types of functional cargos such as nanoparticles and drugs into solid tumor of live animals for imaging, diagnosis and therapy.

  7. Bacteria-mediated in vivo delivery of quantum dots into solid tumor

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ying [Single-molecule and Nanobiology Lab., Dept. of Biophysics, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Zhou, Mei [Dept. of Radiation Medicine, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Luo, Dan; Wang, Lijun; Hong, Yuankai [Single-molecule and Nanobiology Lab., Dept. of Biophysics, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Yang, Yepeng, E-mail: yangyepeng@bjmu.edu.cn [Dept. of Radiation Medicine, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Sha, Yinlin, E-mail: shyl@hsc.pku.edu.cn [Single-molecule and Nanobiology Lab., Dept. of Biophysics, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Biomed-X Center, Peking University, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer New approach using the probiotic Bifidobacterium bifidum as a vehicle to deliver QDs into the deep tissue of solid tumors in vivo was achieved. Black-Right-Pointing-Pointer Bifidobacterium bifidum delivery system has intrinsic biocompatibility. Black-Right-Pointing-Pointer The targeting efficacy was improved by folic acids. -- Abstract: Semiconductor nanocrystals, so-called quantum dots (QDs), promise potential application in bioimaging and diagnosis in vitro and in vivo owing to their high-quality photoluminescence and excellent photostability as well as size-tunable spectra. Here, we describe a biocompatible, comparatively safe bacteria-based system that can deliver QDs specifically into solid tumor of living animals. In our strategy, anaerobic bacterium Bifidobacterium bifidum (B. bifidum) that colonizes selectively in hypoxic regions of animal body was successfully used as a vehicle to load with QDs and transported into the deep tissue of solid tumors. The internalization of lipid-encapsuled QDs into B. bifidum was conveniently carried by electroporation. To improve the efficacy and specificity of tumor targeting, the QDs-carrying bacterium surface was further conjugated with folic acids (FAs) that can bind to the folic acid receptor overexpressed tumor cells. This new approach opens a pathway for delivering different types of functional cargos such as nanoparticles and drugs into solid tumor of live animals for imaging, diagnosis and therapy.

  8. Imaging tumor hypoxia: Blood-borne delivery of imaging agents is fundamentally different in hypoxia subtypes

    Directory of Open Access Journals (Sweden)

    Peter Vaupel

    2014-03-01

    Full Text Available Hypoxic tissue subvolumes are a hallmark feature of solid malignant tumors, relevant for cancer therapy and patient outcome because they increase both the intrinsic aggressiveness of tumor cells and their resistance to several commonly used anticancer strategies. Pathogenetic mechanisms leading to hypoxia are diverse, may coexist within the same tumor and are commonly grouped according to the duration of their effects. Chronic hypoxia is mainly caused by diffusion limitations resulting from enlarged intercapillary distances and adverse diffusion geometries and — to a lesser extent — by hypoxemia, compromised perfusion or long-lasting microregional flow stops. Conversely, acute hypoxia preferentially results from transient disruptions in perfusion. While each of these features of the tumor microenvironment can contribute to a critical reduction of oxygen availability, the delivery of imaging agents (as well as nutrients and anticancer agents may be compromised or remain unaffected. Thus, a critical appraisal of the effects of the various mechanisms leading to hypoxia with regard to the blood-borne delivery of imaging agents is necessary to judge their ability to correctly represent the hypoxic phenotype of solid malignancies.

  9. Integrated intravital microscopy and mathematical modeling to optimize nanotherapeutics delivery to tumors

    Directory of Open Access Journals (Sweden)

    Anne L. van de Ven

    2012-03-01

    Full Text Available Inefficient vascularization hinders the optimal transport of cell nutrients, oxygen, and drugs to cancer cells in solid tumors. Gradients of these substances maintain a heterogeneous cell-scale microenvironment through which drugs and their carriers must travel, significantly limiting optimal drug exposure. In this study, we integrate intravital microscopy with a mathematical model of cancer to evaluate the behavior of nanoparticle-based drug delivery systems designed to circumvent biophysical barriers. We simulate the effect of doxorubicin delivered via porous 1000 x 400 nm plateloid silicon particles to a solid tumor characterized by a realistic vasculature, and vary the parameters to determine how much drug per particle and how many particles need to be released within the vasculature in order to achieve remission of the tumor. We envision that this work will contribute to the development of quantitative measures of nanoparticle design and drug loading in order to optimize cancer treatment via nanotherapeutics.

  10. The potential of positron emission tomography for intratreatment dynamic lung tumor tracking: A phantom study

    International Nuclear Information System (INIS)

    Yang, Jaewon; Yamamoto, Tokihiro; Mazin, Samuel R.; Graves, Edward E.; Keall, Paul J.

    2014-01-01

    Purpose: This study aims to evaluate the potential and feasibility of positron emission tomography for dynamic lung tumor tracking during radiation treatment. The authors propose a center of mass (CoM) tumor tracking algorithm using gated-PET images combined with a respiratory monitor and investigate the geometric accuracy of the proposed algorithm. Methods: The proposed PET dynamic lung tumor tracking algorithm estimated the target position information through the CoM of the segmented target volume on gated PET images reconstructed from accumulated coincidence events. The information was continuously updated throughout a scan based on the assumption that real-time processing was supported (actual processing time at each frame ≈10 s). External respiratory motion and list-mode PET data were acquired from a phantom programmed to move with measured respiratory traces (external respiratory motion and internal target motion) from human subjects, for which the ground truth target position was known as a function of time. The phantom was cylindrical with six hollow sphere targets (10, 13, 17, 22, 28, and 37 mm in diameter). The measured respiratory traces consisted of two sets: (1) 1D-measured motion from ten healthy volunteers and (2) 3D-measured motion from four lung cancer patients. The authors evaluated the geometric accuracy of the proposed algorithm by quantifying estimation errors (Euclidean distance) between the actual motion of targets (1D-motion and 3D-motion traces) and CoM trajectories estimated by the proposed algorithm as a function of time. Results: The time-averaged error of 1D-motion traces over all trajectories of all targets was 1.6 mm. The error trajectories decreased with time as coincidence events were accumulated. The overall error trajectory of 1D-motion traces converged to within 2 mm in approximately 90 s. As expected, more accurate results were obtained for larger targets. For example, for the 37 mm target, the average error over all 1D

  11. Targeted delivery of immunotoxin by antibody to ganglioside GD3: a novel drug delivery route for tumor cells.

    Directory of Open Access Journals (Sweden)

    Vanina Torres Demichelis

    Full Text Available Gangliosides are sialic acid-containing glycolipids expressed on plasma membranes from nearly all vertebrate cells. The expression of ganglioside GD3, which plays essential roles in normal brain development, decreases in adults but is up regulated in neuroectodermal and epithelial derived cancers. R24 antibody, directed against ganglioside GD3, is a validated tumor target which is specifically endocytosed and accumulated in endosomes. Here, we exploit the internalization feature of the R24 antibody for the selective delivery of saporin, a ribosome-inactivating protein, to GD3-expressing cells [human (SK-Mel-28 and mouse (B16 melanoma cells and Chinese hamster ovary (CHO-K1 cells]. This immunotoxin showed a specific cytotoxicity on tumor cells grew on 2D monolayers, which was further evident by the lack of any effect on GD3-negative cells. To estimate the potential antitumor activity of R24-saporin complex, we also evaluated the effect of the immunotoxin on the clonogenic growth of SK-Mel-28 and CHO-K1(GD3+ cells cultured in attachment-free conditions. A drastic growth inhibition (>80-90% of the cell colonies was reached after 3 days of immunotoxin treatment. By the contrary, colonies continue to growth at the same concentration of the immuntoxin, but in the absence of R24 antibody, or in the absence of both immunotoxin and R24, undoubtedly indicating the specificity of the effect observed. Thus, the ganglioside GD3 emerge as a novel and attractive class of cell surface molecule for targeted delivery of cytotoxic agents and, therefore, provides a rationale for future therapeutic intervention in cancer.

  12. Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors: Its utility for local siRNA delivery.

    Science.gov (United States)

    Xu, Leyuan; Yeudall, W Andrew; Yang, Hu

    2017-07-15

    The utility of folic acid (FA)-decorated polyamidoamine dendrimer G4 (G4-FA) as a vector was investigated for local delivery of siRNA. In a xenograft HN12 (or HN12-YFP) tumor mouse model of head and neck squamous cell carcinomas (HNSCC), intratumorally (i.t.) injected G4-FA exhibited high tumor uptake and sustained highly localized retention in the tumors according to near infrared (NIR) imaging assessment. siRNA against vascular endothelial growth factor A (siVEGFA) was chosen as a therapeutic modality. Compared to the nontherapeutic treatment groups (PBS solution or dendrimer complexed with nontherapeutic siRNA against green fluorescent protein (siGFP)), G4-FA/siVEGFA showed tumor inhibition effects in single-dose and two-dose regimen studies. In particular, two doses of G4-FA/siVEGFA i.t. administered eight days apart resulted in a more profound inhibition of tumor growth, accompanied with significant reduction in angiogenesis, as judged by CD31 staining and microvessel counts. Tumor size reduction in the two-dose regimen study was ascertained semi-quantitatively by live fluorescence imaging of YFP tumors and independently supported antitumor effects of G4-FA/siVEGFA. Taken together, G4-FA shows high tumor uptake and sustained retention properties, making it a suitable platform for local delivery of siRNAs to treat cancers that are readily accessible such as HNSCC. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is difficult to transfect for gene therapy. We developed folate receptor (FR)-targeted polyamidoamine (PAMAM) dendrimer for enhanced delivery of genes to HNSCC and gained in-depth understanding of how gene delivery and transfection in head and neck squamous cancer cells can be enhanced via FR-targeted PAMAM dendrimers. The results we report here are encouraging and present latest advances in using dendrimers for cancer therapies, in particular for HNSCC. Our work has demonstrated that localized delivery of FR

  13. Insertion and fixation of fiducial markers for setup and tracking of lung tumors in radiotherapy

    International Nuclear Information System (INIS)

    Imura, Mikado; Yamazaki, Koichi; Shirato, Hiroki; Onimaru, Rikiya; Fujino, Masaharu; Shimizu, Shinichi; Harada, Toshiyuki; Ogura, Shigeaki; Dosaka-Akita, Hirotoshi; Miyasaka, Kazuo; Nishimura, Masaharu

    2005-01-01

    Purpose: Internal 1.5-mm fiducial markers were used in real-time tumor-tracking radiotherapy (RT) for lung cancer. The fixation rate of the markers using the bronchial insertion technique, reliability of the setup using markers around the target volume, dislocation of the markers after real-time tumor-tracking RT, and long-term toxicity of marker insertion were investigated. Methods and Materials: Between July 2000 and April 2004, 154 gold markers were inserted into 57 patients with peripheral lung cancer. The distances between the implanted markers in 198 measurements in 71 setups in 11 patients were measured using two sets of orthogonal diagnostic X-ray images of the real-time tumor-tracking RT system. The distance between the markers and the chest wall was also measured in a transaxial CT image on 186 occasions in 48 patients during treatment planning and during follow-up. The median treatment time was 6 days (range, 4-14 days). Results: In 115 (75%) of the 154 inserted markers, the gold marker was detected throughout the treatment period. In 122 markers detected at CT planning, 115 (94%) were detected until the end of treatment. The variation in the distances between the implanted markers was within ±2 mm in 95% and ±1 mm in 80% during treatment. The variation in the distances between the implanted markers was >2 mm in at least one direction in 9% of the setups for which reexamination with a CT scan was indicated. The fixation rate in the left upper lobe was lower than in the other lobes. A statistically significant relationship was found between a shorter distance between the markers and the chest wall and the fixation rate, suggesting that the markers in the smaller bronchial lumens fixed better than those in the larger lumens. A learning curve among the endoscopists was suggested in the fixation rate. The distance between the markers and the chest wall changed significantly within a median of 44 days (range, 16-181 days) after treatment. Conclusion: The

  14. Tumor delivery of antisense oligomer using trastuzumab within a streptavidin nanoparticle

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yi [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Yale University, Yale PET Center, Department of Diagnostic Radiology, New Haven, CT (United States); Liu, Xinrong; Chen, Ling; Cheng, Dengfeng; Rusckowski, Mary [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Hnatowich, Donald J. [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Umass Medical School, Department of Radiology, Worcester, MA (United States)

    2009-12-15

    Trastuzumab (Herceptin trademark) is often internalized following binding to Her2+ tumor cells. The objective of this study was to investigate whether trastuzumab can be used as a specific carrier to deliver antisense oligomers into Her2+ tumor cells both in vitro and in vivo. A biotinylated MORF oligomer antisense to RhoC mRNA and its biotinylated sense control were labeled with either lissamine for fluorescence detection or {sup 99m}Tc for radioactivity detection and were linked to biotinylated trastuzumab via streptavidin. The nanoparticles were studied in SUM190 (RhoC+, Her2+) study and SUM149 (RhoC+, Her2-) control cells in culture and as xenografts in mice. As evidence of unimpaired Her2+ binding of trastuzumab within the nanoparticle, accumulations were clearly higher in SUM190 compared to SUM149 cells and, by whole-body imaging, targeting of SUM190 tumor was similar to that expected for a radiolabeled trastuzumab. As evidence of internalization, fluorescence microscopy images of cells grown in culture and obtained from xenografts showed uniform cytoplasm distribution of the lissamine-MORF. An invasion assay showed decreased RhoC expression in SUM190 cells when incubated with the antisense MORF nanoparticles at only 100 nM. Both in cell culture and in animals, the nanoparticle with trastuzumab as specific carrier greatly improved tumor delivery of the antisense oligomer against RhoC mRNA into tumor cells overexpressing Her2 and may be of general utility. (orig.)

  15. Poster - 51: A tumor motion-compensating system with tracking and prediction – a proof-of-concept study

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Kaiming; Teo, Peng; Kawalec, Philip; Pistorius, Stephen [CancerCare Manitoba (Canada)

    2016-08-15

    Purpose: This work reports on the development of a mechanical slider system for the counter-steering of tumor motion in adaptive Radiation Therapy (RT). The tumor motion was tracked using a weighted optical flow algorithm and its position is being predicted with a neural network (NN). Methods: The components of the proposed mechanical counter-steering system includes: (1) an actuator which provides the tumor motion, (2) the motion detection using an optical flow algorithm, (3) motion prediction using a neural network, (4) a control module and (5) a mechanical slider to counter-steer the anticipated motion of the tumor phantom. An asymmetrical cosine function and five patient traces (P1–P5) were used to evaluate the tracking of a 3D printed lung tumor. In the proposed mechanical counter-steering system, both actuator (Zaber NA14D60) and slider (Zaber A-BLQ0070-E01) were programed to move independently with LabVIEW and their positions were recorded by 2 potentiometers (ETI LCP12S-25). The accuracy of this counter-steering system is given by the difference between the two potentiometers. Results: The inherent accuracy of the system, measured using the cosine function, is −0.15 ± 0.06 mm. While the errors when tracking and prediction were included, is (0.04 ± 0.71) mm. Conclusion: A prototype tumor motion counter-steering system with tracking and prediction was implemented. The inherent errors are small in comparison to the tracking and prediction errors, which in turn are small in comparison to the magnitude of tumor motion. The results show that this system is suited for evaluating RT tracking and prediction.

  16. Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

    Directory of Open Access Journals (Sweden)

    Sharma Kamal

    2008-12-01

    Full Text Available Abstract Background Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells. Methods Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging. Results We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells. Conclusion The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.

  17. Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery

    Directory of Open Access Journals (Sweden)

    Liu J

    2013-12-01

    Full Text Available Jianfeng Liu, Jinjian Liu, Hongyan Xu, Yumin Zhang, Liping Chu, Qingfen Liu, Naling Song, Cuihong YangTianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, People's Republic of ChinaAbstract: The poor aqueous solubility and low bioavailability of curcumin restrict its clinical application for cancer treatment. In this study, a novel tumor-targeting nanofiber carrier was developed to improve the solubility and tumor-targeting ability of curcumin using a self-assembled Nap-GFFYG-RGD peptide. The morphologies of the peptide nanofiber and the curcumin-encapsulated nanofiber were visualized by transmission electron microscopy. The tumor-targeting activity of the curcumin-encapsulated Nap-GFFYG-RGD peptide nanofiber (f-RGD-Cur was studied in vitro and in vivo, using Nap-GFFYG-RGE peptide nanofiber (f-RGE-Cur as the control. Curcumin was encapsulated into the peptide nanofiber, which had a diameter of approximately 10–20 nm. Curcumin showed sustained-release behavior from the nanofibers in vitro. f-RGD-Cur showed much higher cellular uptake in αvβ3 integrin-positive HepG2 liver carcinoma cells than did non-targeted f-RGE-Cur, thereby leading to significantly higher cytotoxicity. Ex vivo studies further demonstrated that curcumin could accumulate markedly in mouse tumors after administration of f-RGD-Cur via the tail vein. These results indicate that Nap-GFFYG-RGD peptide self-assembled nanofibers are a promising hydrophobic drug delivery system for targeted treatment of cancer.Keywords: nanofiber, tumor-targeting, self-assembling, curcumin, drug delivery

  18. Initial assessment of tumor tracking with a gimbaled linac system in clinical circumstances: A patient simulation study

    International Nuclear Information System (INIS)

    Depuydt, Tom; Poels, Kenneth; Verellen, Dirk; Engels, Benedikt; Collen, Christine; Haverbeke, Chloe; Gevaert, Thierry; Buls, Nico; Van Gompel, Gert; Reynders, Truus; Duchateau, Michael; Tournel, Koen; Boussaer, Marlies; Steenbeke, Femke; Vandenbroucke, Frederik; De Ridder, Mark

    2013-01-01

    Purpose: To have an initial assessment of the Vero Dynamic Tracking workflow in clinical circumstances and quantify the performance of the tracking system, a simulation study was set up on 5 lung and liver patients. Methods and materials: The preparatory steps of a tumor tracking treatment, based on fiducial markers implanted in the tumor, were executed allowing pursuit of the tumor with the gimbaled linac and monitoring X-rays acquisition, however, without activating the 6 MV beam. Data were acquired on workflow time-efficiency, tracking accuracy and imaging exposure. Results: The average time between the patient entering the treatment room and the first treatment field was about 9 min. The time for building the correlation model was 3.2 min. Tracking errors of 0.55 and 0.95 mm (1σ) were observed in PAN/TILT direction and a 2D range of 3.08 mm. A skin dose was determined of 0.08 mGy/image, with a source-to-skin distance of 900 mm and kV exposure of 1 mAs. On average 1.8 mGy/min kV skin dose was observed for 1 Hz monitoring. Conclusion: The Vero tracking solution proved to be fully functional and showed performance comparable with other real-time tracking systems

  19. RGD-modified lipid disks as drug carriers for tumor targeted drug delivery

    Science.gov (United States)

    Gao, Jie; Xie, Cao; Zhang, Mingfei; Wei, Xiaoli; Yan, Zhiqiang; Ren, Yachao; Ying, Man; Lu, Weiyue

    2016-03-01

    Melittin, the major component of the European bee venom, is a potential anticancer candidate due to its lytic properties. However, in vivo applications of melittin are limited due to its main side effect, hemolysis, especially when applied through intravenous administration. The polyethylene glycol-stabilized lipid disk is a novel type of nanocarrier, and the rim of lipid disks has a high affinity to amphiphilic peptides. In our study, a c(RGDyK) modified lipid disk was developed as a tumor targeted drug delivery system for melittin. Cryo-TEM was used to confirm the shape and size of lipid disks with or without c(RGDyK) modification. In vitro and in vivo hemolysis analyses revealed that the hemolysis effect significantly decreased after melittin associated with lipid disks. Importantly, the results of our in vivo biodistribution and tumor growth inhibitory experiments showed that c(RGDyK) modification increased the distribution of lipid disks in the tumor and the anticancer efficacy of melittin loaded lipid disks. Thus, we successfully achieved a targeted drug delivery system for melittin and other amphiphilic peptides with a good therapeutic effect and low side effects.

  20. Characterization and anti-tumor effects of chondroitin sulfate-chitosan nanoparticles delivery system

    Science.gov (United States)

    Hu, Chieh-Shen; Tang, Sung-Ling; Chiang, Chiao-Hsi; Hosseinkhani, Hossein; Hong, Po-Da; Yeh, Ming-Kung

    2014-11-01

    We prepared chondroitin sulfate (ChS)-chitosan (CS) nanoparticles (NPs) as a delivery carrier, and doxorubicin (Dox) was used as a model drug. The physicochemical properties and biological activities of the Dox-ChS-CS NPs including the release profile, cell cytotoxicity, cellular internalization, and in vivo anti-tumor effects were evaluated. The ChS-CS NPs and Dox-ChS-CS NPs had a mean size of 262.0 ± 15.0 and 369.4 ± 77.4 nm, and a zeta potential of 30.2 ± 0.9 and 20.6 ± 3.1 mV, respectively. In vitro release tests showed that the 50 % release time for the Dox-ChS-CS NPs was 20 h. Two hepatoma cell models, HepG2 and HuH6, were used for evaluating the cytotoxicity and cell uptake efficiency of the Dox-ChS-CS NPs. A significant difference was observed between doxorubicin solution and the Dox-ChS-CS NPs in the cellular uptake within 60 min ( p < 0.01). For the in vivo human xenograft-nude mouse model, the Dox-ChS-CS NPs were more effective with less body weight loss and anti-tumor growth suppression in comparison with the Dox solution. The prepared Dox-ChS-CS NPs offer a new effective targeting nanoparticle delivery system platform for anti-tumor therapy.

  1. Interstitial fluid flow and drug delivery in vascularized tumors: a computational model.

    Directory of Open Access Journals (Sweden)

    Michael Welter

    Full Text Available Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider-with the help of a theoretical model-the tumor IFP, interstitial fluid flow (IFF and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law and sources (vessels and sinks (lymphatics for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss

  2. Interstitial fluid flow and drug delivery in vascularized tumors: a computational model.

    Science.gov (United States)

    Welter, Michael; Rieger, Heiko

    2013-01-01

    Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider-with the help of a theoretical model-the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various

  3. Tumor and normal tissue responses to fractioned non-uniform dose delivery

    Energy Technology Data Exchange (ETDEWEB)

    Kaellman, P; Aegren, A; Brahme, A [Karolinska Inst., Stockholm (Sweden). Dept. of Radiation Physics

    1996-08-01

    The volume dependence of the radiation response of a tumor is straight forward to quantify because it depends primarily on the eradication of all its clonogenic cells. A tumor therefore has a parallel organization as any surviving clonogen in principle can repopulate the tumor. The difficulty with the response of the tumor is instead to know the density and sensitivity distribution of the most resistant clonogenic cells. The increase in the 50% tumor control dose and the decrease in the maximum normalized slope of the dose response relation, {gamma}, in presence of small compartments of resistant tumor cells have therefore been quantified to describe their influence on the dose response relation. Injury to normal tissue is a much more complex and gradual process. It depends on earlier effects induced long before depletion of the differentiated and clonogenic cells that in addition may have a complex structural and functional organization. The volume dependence of the dose response relation of normal tissues is therefore described here by the relative seriality, s, of the infrastructure of the organ. The model can also be generalized to describe the response of heterogeneous tissues to non uniform dose distributions. The new model is compared with clinical and experimental data on normal tissue response, and shows good agreement both with regard to the shape of dose response relation and the volume dependence of the isoeffect dose. The response of tumors and normal tissues are quantified for arbitrary dose fractionations using the linear quadratic cell survival parameters {alpha} and {beta}. The parameters of the dose response relation are derived both for a constant dose per fraction and a constant number of dose fractions, thus in the latter case accounting also for non uniform dose delivery. (author). 26 refs, 4 figs.

  4. Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts.

    Science.gov (United States)

    José, Anabel; Sobrevals, Luciano; Miguel Camacho-Sánchez, Juan; Huch, Meritxell; Andreu, Núria; Ayuso, Eduard; Navarro, Pilar; Alemany, Ramon; Fillat, Cristina

    2013-01-01

    Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p less than 0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors.

  5. Optical eye tracking system for real-time noninvasive tumor localization in external beam radiotherapy.

    Science.gov (United States)

    Via, Riccardo; Fassi, Aurora; Fattori, Giovanni; Fontana, Giulia; Pella, Andrea; Tagaste, Barbara; Riboldi, Marco; Ciocca, Mario; Orecchia, Roberto; Baroni, Guido

    2015-05-01

    External beam radiotherapy currently represents an important therapeutic strategy for the treatment of intraocular tumors. Accurate target localization and efficient compensation of involuntary eye movements are crucial to avoid deviations in dose distribution with respect to the treatment plan. This paper describes an eye tracking system (ETS) based on noninvasive infrared video imaging. The system was designed for capturing the tridimensional (3D) ocular motion and provides an on-line estimation of intraocular lesions position based on a priori knowledge coming from volumetric imaging. Eye tracking is performed by localizing cornea and pupil centers on stereo images captured by two calibrated video cameras, exploiting eye reflections produced by infrared illumination. Additionally, torsional eye movements are detected by template matching in the iris region of eye images. This information allows estimating the 3D position and orientation of the eye by means of an eye local reference system. By combining ETS measurements with volumetric imaging for treatment planning [computed tomography (CT) and magnetic resonance (MR)], one is able to map the position of the lesion to be treated in local eye coordinates, thus enabling real-time tumor referencing during treatment setup and irradiation. Experimental tests on an eye phantom and seven healthy subjects were performed to assess ETS tracking accuracy. Measurements on phantom showed an overall median accuracy within 0.16 mm and 0.40° for translations and rotations, respectively. Torsional movements were affected by 0.28° median uncertainty. On healthy subjects, the gaze direction error ranged between 0.19° and 0.82° at a median working distance of 29 cm. The median processing time of the eye tracking algorithm was 18.60 ms, thus allowing eye monitoring up to 50 Hz. A noninvasive ETS prototype was designed to perform real-time target localization and eye movement monitoring during ocular radiotherapy treatments. The

  6. Optical eye tracking system for real-time noninvasive tumor localization in external beam radiotherapy

    International Nuclear Information System (INIS)

    Via, Riccardo; Fassi, Aurora; Fattori, Giovanni; Fontana, Giulia; Pella, Andrea; Tagaste, Barbara; Ciocca, Mario; Riboldi, Marco; Baroni, Guido; Orecchia, Roberto

    2015-01-01

    Purpose: External beam radiotherapy currently represents an important therapeutic strategy for the treatment of intraocular tumors. Accurate target localization and efficient compensation of involuntary eye movements are crucial to avoid deviations in dose distribution with respect to the treatment plan. This paper describes an eye tracking system (ETS) based on noninvasive infrared video imaging. The system was designed for capturing the tridimensional (3D) ocular motion and provides an on-line estimation of intraocular lesions position based on a priori knowledge coming from volumetric imaging. Methods: Eye tracking is performed by localizing cornea and pupil centers on stereo images captured by two calibrated video cameras, exploiting eye reflections produced by infrared illumination. Additionally, torsional eye movements are detected by template matching in the iris region of eye images. This information allows estimating the 3D position and orientation of the eye by means of an eye local reference system. By combining ETS measurements with volumetric imaging for treatment planning [computed tomography (CT) and magnetic resonance (MR)], one is able to map the position of the lesion to be treated in local eye coordinates, thus enabling real-time tumor referencing during treatment setup and irradiation. Experimental tests on an eye phantom and seven healthy subjects were performed to assess ETS tracking accuracy. Results: Measurements on phantom showed an overall median accuracy within 0.16 mm and 0.40° for translations and rotations, respectively. Torsional movements were affected by 0.28° median uncertainty. On healthy subjects, the gaze direction error ranged between 0.19° and 0.82° at a median working distance of 29 cm. The median processing time of the eye tracking algorithm was 18.60 ms, thus allowing eye monitoring up to 50 Hz. Conclusions: A noninvasive ETS prototype was designed to perform real-time target localization and eye movement monitoring

  7. Chondroitin sulfate-functionalized polyamidoamine as a tumor-targeted carrier for miR-34a delivery.

    Science.gov (United States)

    Chen, Wenqi; Liu, Yong; Liang, Xiao; Huang, Yu; Li, Quanshun

    2017-07-15

    Chondroitin sulfate (CS) was modified on a polyamidoamine dendrimer (PAMAM) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The derivative CS-PAMAM was demonstrated to achieve an efficient cellular uptake of miR-34a in a CD44-dependent endocytosis way and further facilitate the endosomal escape of miR-34a after 4h. Through the miR-34a delivery, obvious inhibition of cell proliferation could be detected which was attributed to the enhancement of cell apoptosis and cell cycle arrest, and meanwhile the cell migration and invasion has been observed to be inhibited. Finally, the intravenous injection of CS-PAMAM/miR-34a formulation into mice bearing human lung adenocarcinoma cell A549 xenografts could efficiently inhibit the tumor growth and induce the tumor apoptosis owing to the enhanced accumulation of miR-34a in tumor tissue. Overall, CS-PAMAM is potential to be used as a tumor-targeted oligonucleotide carrier for achieving tumor gene therapy. The cationic dendrimer PAMAM was modified by chondroitin sulfate (CS) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The introduction of CS could achieve an efficient cellular uptake and intracellular transfection of miR-34a in a CD44-dependent endocytosis manner. The miR-34a delivery could execute the anti-proliferation activity by simultaneously inducing cell apoptosis and cell cycle arrest, and also the anti-migration activity. The CS-PAMAM-mediated systemic delivery of miR-34a showed significant inhibition of tumor growth and induction of tumor apoptosis using a mice model of subcutaneously implanted tumors. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  8. Four-dimensional dose distributions of step-and-shoot IMRT delivered with real-time tumor tracking for patients with irregular breathing: Constant dose rate vs dose rate regulation

    International Nuclear Information System (INIS)

    Yang Xiaocheng; Han-Oh, Sarah; Gui Minzhi; Niu Ying; Yu, Cedric X.; Yi Byongyong

    2012-01-01

    Purpose: Dose-rate-regulated tracking (DRRT) is a tumor tracking strategy that programs the MLC to track the tumor under regular breathing and adapts to breathing irregularities during delivery using dose rate regulation. Constant-dose-rate tracking (CDRT) is a strategy that dynamically repositions the beam to account for intrafractional 3D target motion according to real-time information of target location obtained from an independent position monitoring system. The purpose of this study is to illustrate the differences in the effectiveness and delivery accuracy between these two tracking methods in the presence of breathing irregularities. Methods: Step-and-shoot IMRT plans optimized at a reference phase were extended to remaining phases to generate 10-phased 4D-IMRT plans using segment aperture morphing (SAM) algorithm, where both tumor displacement and deformation were considered. A SAM-based 4D plan has been demonstrated to provide better plan quality than plans not considering target deformation. However, delivering such a plan requires preprogramming of the MLC aperture sequence. Deliveries of the 4D plans using DRRT and CDRT tracking approaches were simulated assuming the breathing period is either shorter or longer than the planning day, for 4 IMRT cases: two lung and two pancreatic cases with maximum GTV centroid motion greater than 1 cm were selected. In DRRT, dose rate was regulated to speed up or slow down delivery as needed such that each planned segment is delivered at the planned breathing phase. In CDRT, MLC is separately controlled to follow the tumor motion, but dose rate was kept constant. In addition to breathing period change, effect of breathing amplitude variation on target and critical tissue dose distribution is also evaluated. Results: Delivery of preprogrammed 4D plans by the CDRT method resulted in an average of 5% increase in target dose and noticeable increase in organs at risk (OAR) dose when patient breathing is either 10% faster or

  9. An effective tumor-targeting strategy utilizing hypoxia-sensitive siRNA delivery system for improved anti-tumor outcome.

    Science.gov (United States)

    Kang, Lin; Fan, Bo; Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Gao, Zhonggao

    2016-10-15

    Hypoxia is a feature of most solid tumors, targeting hypoxia is considered as the best validated yet not extensively exploited strategy in cancer therapy. Here, we reported a novel tumor-targeting strategy using a hypoxia-sensitive siRNA delivery system. In the study, 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazole (AI) through bioreduction under hypoxic conditions, was conjugated to the alkylated polyethyleneimine (bPEI1.8k-C6) to form amphiphilic bPEI1.8k-C6-NI polycations. bPEI1.8k-C6-NI could self-assemble into micelle-like aggregations in aqueous, which contributed to the improved stability of the bPEI1.8k-C6-NI/siRNA polyplexes, resulted in increased cellular uptake. After being transported into the hypoxic tumor cells, the selective nitro-to-amino reduction would cause structural change and elicit a relatively loose structure to facilitate the siRNA dissociation in the cytoplasm, for enhanced gene silencing efficiency ultimately. Therefore, the conflict between the extracellular stability and the intracellular siRNA release ability of the polyplexes was solved by introducing the hypoxia-responsive unit. Consequently, the survivin-targeted siRNA loaded polyplexes shown remarkable anti-tumor effect not only in hypoxic cells, but also in tumor spheroids and tumor-bearing mice, indicating that the hypoxia-sensitive siRNA delivery system had great potential for tumor-targeted therapy. Hypoxia is one of the most remarkable features of most solid tumors, and targeting hypoxia is considered as the best validated strategy in cancer therapy. However, in the past decades, there were few reports about using this strategy in the drug delivery system, especially in siRNA delivery system. Therefore, we constructed a hypoxia-sensitive siRNA delivery system utilizing a hypoxia-responsive unit, 2-nitroimidazole, by which the unavoidable conflict between improved extracellular stability and promoted intracellular si

  10. Multi-small molecule conjugations as new targeted delivery carriers for tumor therapy

    Directory of Open Access Journals (Sweden)

    Shan L

    2015-09-01

    Full Text Available Lingling Shan,1 Ming Liu,2 Chao Wu,1 Liang Zhao,1 Siwen Li,3 Lisheng Xu,1 Wengen Cao,1 Guizhen Gao,1 Yueqing Gu3 1Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China; 2Department of Biology, University of South Dakota, Vermillion, SD, USA; 3Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting ability, and harmful side effects, we developed a new tumor-targeted multi-small molecule drug delivery platform. Using paclitaxel (PTX as a model therapeutic, we prepared two prodrugs, ie, folic acid-fluorescein-5(6-isothiocyanate-arginine-paclitaxel (FA-FITC-Arg-PTX and folic acid-5-aminofluorescein-glutamic-paclitaxel (FA-5AF-Glu-PTX, composed of folic acid (FA, target, amino acids (Arg or Glu, linker, and fluorescent dye (fluorescein in vitro or near-infrared fluorescent dye in vivo in order to better understand the mechanism of PTX prodrug targeting. In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug. In vitro and in vivo studies indicated that folate receptor-mediated uptake of PTX-conjugated multi-small molecule carriers induced high antitumor activity. Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX. These results support the use of multi-small molecules as tumor-targeting drug delivery systems. Keywords: multi-small molecules, paclitaxel, prodrugs, targeting, tumor therapy

  11. Tumor-activated prodrug (TAP)-conjugated nanoparticles with cleavable domains for safe doxorubicin delivery.

    Science.gov (United States)

    Guarnieri, Daniela; Biondi, Marco; Yu, Hui; Belli, Valentina; Falanga, Andrea P; Cantisani, Marco; Galdiero, Stefania; Netti, Paolo A

    2015-03-01

    A major issue in chemotherapy is the lack of specificity of many antitumor drugs, which cause severe side effects and an impaired therapeutic response. Here we report on the design and characterization of model tumor activated prodrug-conjugated polystyrene (PS) nanoparticles (TAP-NPs) for the release of doxorubicin (Dox) triggered by matrix metalloprotease-2 (MMP2) enzyme, which is overexpressed in the extracellular matrix of tumors. In particular, TAP-NPs were produced by attaching Dox to poly(ethylene glycol) (PEG) through two MMP2-cleavable enzymes. The resulting adduct was then tethered to PS NPs. Results showed that Dox release was actually triggered by MMP2 cleavage and was dependent on enzyme concentration, with a plateau around 20 nM. Furthermore, significant cell cytotoxicity was observed towards three cell lines only in the presence of MMP2, but not in cells without enzyme pre-treatment, even after NP internalization by cells. These findings indicate the potential of TAP-NPs as suitable nanocarriers for an on demand, tumor--specific delivery of antitumor drugs after the response to an endogenous stimulus. Further advancements will focus on the translation of this production technology to biodegradable systems for the safe transport of cytotoxic drug to tumor tissues. © 2014 Wiley Periodicals, Inc.

  12. A novel four-dimensional radiotherapy planning strategy from a tumor-tracking beam's eye view

    Science.gov (United States)

    Li, Guang; Cohen, Patrice; Xie, Huchen; Low, Daniel; Li, Diana; Rimner, Andreas

    2012-11-01

    To investigate the feasibility of four-dimensional radiotherapy (4DRT) planning from a tumor-tracking beam's eye view (ttBEV) with reliable gross tumor volume (GTV) delineation, realistic normal tissue representation, high planning accuracy and low clinical workload, we propose and validate a novel 4D conformal planning strategy based on a synthesized 3.5D computed tomographic (3.5DCT) image with a motion-compensated tumor. To recreate patient anatomy from a ttBEV in the moving tumor coordinate system for 4DRT planning (or 4D planning), the centers of delineated GTVs in all phase CT images of 4DCT were aligned, and then the aligned CTs were averaged to produce a new 3.5DCT image. This GTV-motion-compensated CT contains a motionless target (with motion artifacts minimized) and motion-blurred normal tissues (with a realistic temporal density average). Semi-automatic threshold-based segmentation of the tumor, lung and body was applied, while manual delineation was used for other organs at risk (OARs). To validate this 3.5DCT-based 4D planning strategy, five patients with peripheral lung lesions of small size (tumor and a minor beam aperture and weighting adjustment to maintain plan conformality. The dose-volume histogram (DVH) of the 4DCT plan was created with two methods: one is an integrated DVH (iDVH4D), which is defined as the temporal average of all 3D-phase-plan DVHs, and the other (DVH4D) is based on the dose distribution in a reference phase CT image by dose warping from all phase plans using the displacement vector field (DVF) from a free-form deformable image registration (DIR). The DVH3.5D (for the 3.5DCT plan) was compared with both iDVH4D and DVH4D. To quantify the DVH difference between the 3.5DCT plan and the 4DCT plan, two methods were used: relative difference (%) of the areas underneath the DVH curves and the volumes receiving more than 20% (V20) and 50% (V50) of prescribed dose of these 4D plans. The volume of the delineated GTV from different phase

  13. Lung tumor tracking during stereotactic radiotherapy treatment with the CyberKnife: Marker placement and early results

    International Nuclear Information System (INIS)

    Nuyttens, J.J.; Prevost, J.B.; Praag, J.; Hoogeman, M.; Levendag, P.C.; Klaveren, R.J. van; Pattynama, P.M.T.

    2006-01-01

    Lung tumor tracking during stereotactic radiotherapy with the CyberKnife requires the insertion of markers in or close to the tumor. To reduce the risk of pneumothorax, three methods of marker placement were used: 1) intravascular coil placement, 2) percutaneous intrathoracal, and 3) percutaneous extrathoracal placement. We investigated the toxicity of marker placement and the tumor response of the lung tumor tracking treatment. Markers were placed in 20 patients with 22 tumors: 13 patients received a curative treatment, seven a palliative. The median Charlson Comorbidity Score was 4 (range: 1-8). Platinum fiducials and intravascular embolisation coils were used as markers. In total, 78 markers were placed: 34 intrathoracal, 23 intravascular and 21 extrathoracal. The PTV equaled the GTV + 5 mm. A median dose of 45 Gy (range: 30-60 Gy, in 3 fractions) was prescribed to the 70-85% isodose. The response was evaluated with a CTscan performed 6-8 weeks after the last treatment and routinely thereafter. The median follow-up was 4 months (range: 2-11). No severe toxicity due to the marker placement was seen. Pneumothorax was not seen. The local control was 100%. Four tumors in four patients showed a complete response, 15 tumors in 14 patients a partial response, and three tumors in two patients with metastatic disease had stable disease. No severe toxicity of marker placement was seen due to the appropriate choice of one of the three methods. CyberKnife tumor tracking with markers is feasible and resulted in excellent tumor response. Longer follow-up is needed to validate the local control

  14. Speed and amplitude of lung tumor motion precisely detected in four-dimensional setup and in real-time tumor-tracking radiotherapy

    International Nuclear Information System (INIS)

    Shirato, Hiroki; Suzuki, Keishiro; Sharp, Gregory C.; Fujita, Katsuhisa R.T.; Onimaru, Rikiya; Fujino, Masaharu; Kato, Norio; Osaka, Yasuhiro; Kinoshita, Rumiko; Taguchi, Hiroshi; Onodera, Shunsuke; Miyasaka, Kazuo

    2006-01-01

    Background: To reduce the uncertainty of registration for lung tumors, we have developed a four-dimensional (4D) setup system using a real-time tumor-tracking radiotherapy system. Methods and Materials: During treatment planning and daily setup in the treatment room, the trajectory of the internal fiducial marker was recorded for 1 to 2 min at the rate of 30 times per second by the real-time tumor-tracking radiotherapy system. To maximize gating efficiency, the patient's position on the treatment couch was adjusted using the 4D setup system with fine on-line remote control of the treatment couch. Results: The trajectory of the marker detected in the 4D setup system was well visualized and used for daily setup. Various degrees of interfractional and intrafractional changes in the absolute amplitude and speed of the internal marker were detected. Readjustments were necessary during each treatment session, prompted by baseline shifting of the tumor position. Conclusion: The 4D setup system was shown to be useful for reducing the uncertainty of tumor motion and for increasing the efficiency of gated irradiation. Considering the interfractional and intrafractional changes in speed and amplitude detected in this study, intercepting radiotherapy is the safe and cost-effective method for 4D radiotherapy using real-time tracking technology

  15. Changes in tumor cell response due to prolonged dose delivery times in fractionated radiation therapy

    International Nuclear Information System (INIS)

    Paganetti, Harald

    2005-01-01

    Purpose: Dynamic radiation therapy, such as intensity-modulated radiation therapy, delivers more complex treatment fields than conventional techniques. The increased complexity causes longer dose delivery times for each fraction. The cellular damage after a full treatment may depend on the dose rate, because sublethal radiation damage can be repaired more efficiently during prolonged dose delivery. The goal of this study was to investigate the significance of this effect in fractionated radiation therapy. Methods and Materials: The lethal/potentially lethal model was used to calculate lesion induction rates for repairable and nonrepairable lesions. Dose rate effects were analyzed for 9 different cell lines (8 human tumor xenografts and a C3H10T1/2 cell line). The effects of single-fraction as well as fractionated irradiation for different dose rates were studied. Results: Significant differences can be seen for dose rates lower than about 0.1 Gy/min for all cell lines considered. For 60 Gy delivered in 30 fractions, the equivalent dose is reduced by between 1.3% and 12% comparing 2 Gy delivery over 30 min per fraction with 2 Gy delivery over 1 min per fraction. The effect is higher for higher doses per fraction. Furthermore, the results show that dose rate effects do not show a simple correlation with the α/β ratio for ratios between 3 Gy and 31 Gy. Conclusions: If the total dose delivery time for a treatment fraction in radiation therapy increases to about 20 min, a correction for dose rate effects may have to be considered in treatment planning. Adjustments in effective dose may be necessary when comparing intensity-modulated radiation therapy with conventional treatment plans

  16. Near real-time bi-planar fluoroscopic tracking system for the video tumor fighter

    International Nuclear Information System (INIS)

    Lawson, M.A.; Wika, K.G.; Gillies, G.T.; Ritter, R.C.

    1991-01-01

    The authors have developed software capable of the three-dimensional tracking of objects in the brain volume, and the subsequent overlaying of an image of the object onto previously obtained MR or CT scans. This software has been developed for use with the Magnetic Stereotaxis System (MSS), also called the Video Tumor Fighter (VTF). The software was written for s Sun 4/110 SPARC workstation with an ANDROX ICS-400 image processing card installed to manage this task. At present, the system uses input from two orthogonally- oriented, visible-light cameras and simulated scene to determine the three-dimensional position of the object of interest. The coordinates are then transformed into MR or CT coordinates and an image of the object is displayed in the appropriate intersecting MR slice on a computer screen. This paper describes the tracking algorithm and discusses how it was implemented in software. The system's hardware is also described. The limitations of the present system are discussed and plans for incorporating bi-planar, x-ray fluoroscopy are presented

  17. SU-G-BRA-05: Application of a Feature-Based Tracking Algorithm to KV X-Ray Fluoroscopic Images Toward Marker-Less Real-Time Tumor Tracking

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, M; Matsuo, Y; Mukumoto, N; Iizuka, Y; Yokota, K; Mizowaki, T; Hiraoka, M [Kyoto University, Graduate School of Medicine, Kyoto (Japan); Nakao, M [Kyoto University, Graduate School of Informatics, Kyoto (Japan)

    2016-06-15

    Purpose: To detect target position on kV X-ray fluoroscopic images using a feature-based tracking algorithm, Accelerated-KAZE (AKAZE), for markerless real-time tumor tracking (RTTT). Methods: Twelve lung cancer patients treated with RTTT on the Vero4DRT (Mitsubishi Heavy Industries, Japan, and Brainlab AG, Feldkirchen, Germany) were enrolled in this study. Respiratory tumor movement was greater than 10 mm. Three to five fiducial markers were implanted around the lung tumor transbronchially for each patient. Before beam delivery, external infrared (IR) markers and the fiducial markers were monitored for 20 to 40 s with the IR camera every 16.7 ms and with an orthogonal kV x-ray imaging subsystem every 80 or 160 ms, respectively. Target positions derived from the fiducial markers were determined on the orthogonal kV x-ray images, which were used as the ground truth in this study. Meanwhile, tracking positions were identified by AKAZE. Among a lot of feature points, AKAZE found high-quality feature points through sequential cross-check and distance-check between two consecutive images. Then, these 2D positional data were converted to the 3D positional data by a transformation matrix with a predefined calibration parameter. Root mean square error (RMSE) was calculated to evaluate the difference between 3D tracking and target positions. A total of 393 frames was analyzed. The experiment was conducted on a personal computer with 16 GB RAM, Intel Core i7-2600, 3.4 GHz processor. Results: Reproducibility of the target position during the same respiratory phase was 0.6 +/− 0.6 mm (range, 0.1–3.3 mm). Mean +/− SD of the RMSEs was 0.3 +/− 0.2 mm (range, 0.0–1.0 mm). Median computation time per frame was 179 msec (range, 154–247 msec). Conclusion: AKAZE successfully and quickly detected the target position on kV X-ray fluoroscopic images. Initial results indicate that the differences between 3D tracking and target position would be clinically acceptable.

  18. SU-G-BRA-05: Application of a Feature-Based Tracking Algorithm to KV X-Ray Fluoroscopic Images Toward Marker-Less Real-Time Tumor Tracking

    International Nuclear Information System (INIS)

    Nakamura, M; Matsuo, Y; Mukumoto, N; Iizuka, Y; Yokota, K; Mizowaki, T; Hiraoka, M; Nakao, M

    2016-01-01

    Purpose: To detect target position on kV X-ray fluoroscopic images using a feature-based tracking algorithm, Accelerated-KAZE (AKAZE), for markerless real-time tumor tracking (RTTT). Methods: Twelve lung cancer patients treated with RTTT on the Vero4DRT (Mitsubishi Heavy Industries, Japan, and Brainlab AG, Feldkirchen, Germany) were enrolled in this study. Respiratory tumor movement was greater than 10 mm. Three to five fiducial markers were implanted around the lung tumor transbronchially for each patient. Before beam delivery, external infrared (IR) markers and the fiducial markers were monitored for 20 to 40 s with the IR camera every 16.7 ms and with an orthogonal kV x-ray imaging subsystem every 80 or 160 ms, respectively. Target positions derived from the fiducial markers were determined on the orthogonal kV x-ray images, which were used as the ground truth in this study. Meanwhile, tracking positions were identified by AKAZE. Among a lot of feature points, AKAZE found high-quality feature points through sequential cross-check and distance-check between two consecutive images. Then, these 2D positional data were converted to the 3D positional data by a transformation matrix with a predefined calibration parameter. Root mean square error (RMSE) was calculated to evaluate the difference between 3D tracking and target positions. A total of 393 frames was analyzed. The experiment was conducted on a personal computer with 16 GB RAM, Intel Core i7-2600, 3.4 GHz processor. Results: Reproducibility of the target position during the same respiratory phase was 0.6 +/− 0.6 mm (range, 0.1–3.3 mm). Mean +/− SD of the RMSEs was 0.3 +/− 0.2 mm (range, 0.0–1.0 mm). Median computation time per frame was 179 msec (range, 154–247 msec). Conclusion: AKAZE successfully and quickly detected the target position on kV X-ray fluoroscopic images. Initial results indicate that the differences between 3D tracking and target position would be clinically acceptable.

  19. pH-Sensitive nanoparticles as smart carriers for selective intracellular drug delivery to tumor.

    Science.gov (United States)

    Li, Xin-Xin; Chen, Jing; Shen, Jian-Min; Zhuang, Ran; Zhang, Shi-Qi; Zhu, Zi-Yun; Ma, Jing-Bo

    2018-05-05

    Herein, a smart pH-sensitive nanoparticle (DGL-PEG-Tat-KK-DMA-DOX) was prepared to achieve the selective intracellular drug delivery. In this nanoparticle, a PEG-grafted cell penetrating peptide (PEG-Tat-KK) was designed and acted as the cell penetrating segment. By introducing the pH-sensitive amide bonds between the peptide and blocking agent (2,3-dimethylmaleic anhydride, DMA), the controllable moiety (PEG-Tat-KK-DMA) endowed the nanoparticle with a charge-switchable shell and temporarily blocked penetrating function, thus improving the specific internalization. Besides, dendrigraft poly-L-lysine (DGL) used as the skeleton can greatly improve the drug loading because of the highly dendritic framework. Under the stimuli of acidic pH, this nanoparticle exhibited a remarkable charge-switchable property. The drug release showed an expected behavior with little release in the neutral pH media but relatively fast release in the acidic media. The in vitro experiments revealed that the cellular uptake and cytotoxicity were significantly enhanced after the pH was decreased. In vivo biodistribution and antitumor research indicated that the nanoparticle had noteworthy specificity and antitumor efficacy with a tumor inhibition rate of 79.7%. These results verified this nanoparticle could efficiently improve the selective intracellular delivery and possessed a great potential in tumor treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Hybrid protein-inorganic nanoparticles: From tumor-targeted drug delivery to cancer imaging.

    Science.gov (United States)

    Elzoghby, Ahmed O; Hemasa, Ayman L; Freag, May S

    2016-12-10

    Recently, a great interest has been paid to the development of hybrid protein-inorganic nanoparticles (NPs) for drug delivery and cancer diagnostics in order to combine the merits of both inorganic and protein nanocarriers. This review primarily discusses the most outstanding advances in the applications of the hybrids of naturally-occurring proteins with iron oxide, gadolinium, gold, silica, calcium phosphate NPs, carbon nanotubes, and quantum dots in drug delivery and cancer imaging. Various strategies that have been utilized for the preparation of protein-functionalized inorganic NPs and the mechanisms involved in the drug loading process are discussed. How can the protein functionalization overcome the limitations of colloidal stability, poor dispersibility and toxicity associated with inorganic NPs is also investigated. Moreover, issues relating to the influence of protein hybridization on the cellular uptake, tumor targeting efficiency, systemic circulation, mucosal penetration and skin permeation of inorganic NPs are highlighted. A special emphasis is devoted to the novel approaches utilizing the protein-inorganic nanohybrids in combined cancer therapy, tumor imaging, and theranostic applications as well as stimuli-responsive drug release from the nanohybrids. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. TH-AB-BRA-08: Simulated Tumor Tracking in An MRI Linac for Lung Tumor Lesions Using the Monaco Treatment Planning System

    Energy Technology Data Exchange (ETDEWEB)

    Al-Ward, S; Kim, A; McCann, C; Ruschin, M; Cheung, P; Sahgal, A; Keller, B [Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada)

    2016-06-15

    Purpose: To simulate tumor tracking in an Elekta MRI-linac (MRL) and to compare this tracking method with our current ITV approach in terms of OAR sparing for lung cancer patients. Methods: Five SABR-NSCLC patients with central lung tumors were selected for reasons of potential enhancement of tumor-tissue delineation using MRI. The Monaco TPS was used to compare the current clinical ITV approach to a simulated, novel tracking method which used a 7MV MRL beam in the presence of an orthogonal 1.5 T magnetic field (4D-MRL method). In the simulated tracking scenario, achieved using the virtual couch shift (VCS), the PTV was defined using an isotropic 5mm margin applied to the GTV of each phase, as acquired from an 8-phase amplitude-binned 4DCT. These VCS plans were optimized and weighted on each phase. The dose weighting was performed using the patient-specific breathing traces. The doses were accumulated on the inhale phase. The two methods were compared by assessing the OAR DVHs. Results: The 4D-MRL method resulted in a reduced target volume (by an average of 29% over all patients). The benefits of using an MRL tracking system depended on the tumor motion amplitude and the relative OAR motion (ROM) to the target. The reduction in mean doses to parallel organs was up to 3 Gy for the heart and 2.1 Gy for the lung. The reductions in maximum doses to serial organs were up to 9.4 Gy, 5.6 Gy, and 8.7 Gy for the esophagus, spinal cord, and the trachea, respectively. Serial organs benefited from MRL tracking when the ROM was ≥ 0.3 cm despite small tumor motion amplitude in some cases. Conclusions: This work demonstrated the potential benefit for an MRL tracking system to spare OARs in SABR-NSCLC patients with central tumors. The benefits are embodied in the target volume reduction. This project was made possible with the financial support of Elekta.

  2. Dynamics of different-sized solid-state nanocrystals as tracers for a drug-delivery system in the interstitium of a human tumor xenograft

    Science.gov (United States)

    Kawai, Masaaki; Higuchi, Hideo; Takeda, Motohiro; Kobayashi, Yoshio; Ohuchi, Noriaki

    2009-01-01

    Introduction Recent anticancer drugs have been made larger to pass selectively through tumor vessels and stay in the interstitium. Understanding drug movement in association with its size at the single-molecule level and estimating the time needed to reach the targeted organ is indispensable for optimizing drug delivery because single cell-targeted therapy is the ongoing paradigm. This report describes the tracking of single solid nanoparticles in tumor xenografts and the estimation of arrival time. Methods Different-sized nanoparticles measuring 20, 40, and 100 nm were injected into the tail vein of the female Balb/c nu/nu mice bearing human breast cancer on their backs. The movements of the nanoparticles were visualized through the dorsal skin-fold chamber with the high-speed confocal microscopy that we manufactured. Results An analysis of the particle trajectories revealed diffusion to be inversely related to the particle size and position in the tumor, whereas the velocity of the directed movement was related to the position. The difference in the velocity was the greatest for 40-nm particles in the perivascular to the intercellular region: difference = 5.8 nm/s. The arrival time of individual nanoparticles at tumor cells was simulated. The estimated times for the 20-, 40-, and 100-nm particles to reach the tumor cells were 158.0, 218.5, and 389.4 minutes, respectively, after extravasation. Conclusions This result suggests that the particle size can be individually designed for each goal. These data and methods are also important for understanding drug pharmacokinetics. Although this method may be subject to interference by surface molecules attached on the particles, it has the potential to elucidate the pharmacokinetics involved in constructing novel drug-delivery systems involving cell-targeted therapy. PMID:19575785

  3. Cyclic hexapeptide-conjugated nanoparticles enhance curcumin delivery to glioma tumor cells and tissue

    Directory of Open Access Journals (Sweden)

    Zhang X

    2017-08-01

    Full Text Available Xuemei Zhang,1–3 Xuejuan Li,1,4 Hongchen Hua,1 Aiping Wang,1 Wanhui Liu,1–3 Youxin Li,1–3 Fenghua Fu,1–3 Yanan Shi,5 Kaoxiang Sun1 1School of Pharmacy, Yantai University, Yantai, Shandong Province, People’s Republic of China; 2State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, Shandong Province, People’s Republic of China; 3Luye Pharmaceutical Co., Ltd., Shandong Province, People’s Republic of China; 4National Engineering and Technology Research Center of Chirality Pharmaceutical, Lunan Pharmaceutical Group Co., Ltd., Shandong Province, People’s Republic of China; 5School of Pharmacy, Binzhou Medical University, Shandong Province, People’s Republic of China Abstract: Glioma has one of the highest mortality rates among primary brain tumors. The clinical treatment for glioma is very difficult due to its infiltration and specific growth locations. To achieve improved drug delivery to a brain tumor, we report the preparation and in vitro and in vivo evaluation of curcumin nanoparticles (Cur-NPs. The cyclic hexapeptide c(RGDf(N-meVK-C (cHP has increased affinity for cells that overexpress integrins and was designed to target Cur-NPs to tumors. Functional polyethyleneglycol-modified poly(D,L-lactide-co-glycolide (PEG-PLGA conjugated to cHP was synthesized, and targeted Cur-NPs were prepared using a self-assembly nanoprecipitation process. The physicochemical properties and the in vitro cytotoxicity, accuracy, and penetration capabilities of Cur-NPs targeting cells with high levels of integrin expression were investigated. The in vivo targeting and penetration capabilities of the NPs were also evaluated against glioma in rats using in vivo imaging equipment. The results showed that the in vitro cytotoxicity of the targeted cHP-modified curcumin nanoparticles (cHP/Cur-NPs was higher than that of either free curcumin or non-targeted Cur-NPs due to the superior ability of the cHP/Cur-NPs to target tumor cells

  4. Stability of Markers Used for Real-Time Tumor Tracking After Percutaneous Intrapulmonary Placement

    International Nuclear Information System (INIS)

    Voort van Zyp, Noelle C. van der; Hoogeman, Mischa S.; Water, Steven van de; Levendag, Peter C.; Holt, Bronno van der; Heijmen, Ben J.M.; Nuyttens, Joost J.

    2011-01-01

    Purpose: To determine the stability of markers used for real-time tumor tracking after percutaneous intrapulmonary placement. Methods and Materials: A total of 42 patients with 44 lesions, 111 markers, and ≥2 repeat computed tomography (CT) scans were studied. The tumor on the repeat CT scans was registered with the tumor on the planning CT scan. Next, the three-dimensional marker coordinates were determined on the planning CT scan and repeat CT scans. Marker stability was analyzed by the displacement of the markers and the displacement of the center of mass (COM) of the marker configurations. In addition, we assessed the reliability of using the intermarker distance as a check for displacements in the COM of the marker configurations. Results: The median marker displacement was 1.3 mm (range, 0.1-53.6). The marker displacement was >5 mm in 12% of the markers and >10 mm in 5% of the markers. The causes of marker displacement >5 mm included marker migration (2 of 13) and target volume changes (5 of 13). Nonsynchronous tumor and marker movement during breathing might have been responsible for the displacements >5 mm in the other 6 of 13 markers. The median displacement in the COM of the marker configurations was 1.0 mm (range, 0.1-23.3). Displacements in the COM of the marker configurations of ≥2.0 mm were detected by changes in the intermarker distance of >1.5 mm in 96% of the treatment fractions. Conclusion: The median marker displacement was small (1.3 mm). Nevertheless, displacements >5 mm occurred in 12% of the markers. Therefore, we recommend the implantation of multiple markers because multiple markers will enable a quick and reliable check of marker displacement by determining the change in the intermarker distance. A displacement in the COM of the marker configuration of ≥2.0 mm was almost always detected (96%) by a change in the distance between the markers of >1.5 mm. This enabled the displaced marker to be disabled, such that tumor localization was

  5. Co-delivery of paclitaxel and cetuximab by nanodiamond enhances mitotic catastrophe and tumor inhibition.

    Science.gov (United States)

    Lin, Yu-Wei; Raj, Emmanuel Naveen; Liao, Wei-Siang; Lin, Johnson; Liu, Kuang-Kai; Chen, Ting-Hua; Cheng, Hsiao-Chun; Wang, Chi-Ching; Li, Lily Yi; Chen, Chinpiao; Chao, Jui-I

    2017-08-29

    The poor intracellular uptake and non-specific binding of anticancer drugs into cancer cells are the bottlenecks in cancer therapy. Nanocarrier platforms provide the opportunities to improve the drug efficacy. Here we show a carbon-based nanomaterial nanodiamond (ND) that carried paclitaxel (PTX), a microtubule inhibitor, and cetuximab (Cet), a specific monoclonal antibody against epidermal growth factor receptor (EGFR), inducing mitotic catastrophe and tumor inhibition in human colorectal cancer (CRC). ND-PTX blocked the mitotic progression, chromosomal separation, and induced apoptosis in the CRC cells; however, NDs did not induce these effects. Conjugation of ND-PTX with Cet (ND-PTX-Cet) was specifically binding to the EGFR-positive CRC cells and enhanced the mitotic catastrophe and apoptosis induction. Besides, ND-PTX-Cet markedly decreased tumor size in the xenograft EGFR-expressed human CRC tumors of nude mice. Moreover, ND-PTX-Cet induced the mitotic marker protein phospho-histone 3 (Ser10) and apoptotic protein active-caspase 3 for mitotic catastrophe and apoptosis. Taken together, this study demonstrated that the co-delivery of PTX and Cet by ND enhanced the effects of mitotic catastrophe and apoptosis in vitro and in vivo, which may be applied in the human CRC therapy.

  6. Using dual-energy x-ray imaging to enhance automated lung tumor tracking during real-time adaptive radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Menten, Martin J., E-mail: martin.menten@icr.ac.uk; Fast, Martin F.; Nill, Simeon; Oelfke, Uwe, E-mail: uwe.oelfke@icr.ac.uk [Joint Department of Physics at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London SM2 5NG (United Kingdom)

    2015-12-15

    Purpose: Real-time, markerless localization of lung tumors with kV imaging is often inhibited by ribs obscuring the tumor and poor soft-tissue contrast. This study investigates the use of dual-energy imaging, which can generate radiographs with reduced bone visibility, to enhance automated lung tumor tracking for real-time adaptive radiotherapy. Methods: kV images of an anthropomorphic breathing chest phantom were experimentally acquired and radiographs of actual lung cancer patients were Monte-Carlo-simulated at three imaging settings: low-energy (70 kVp, 1.5 mAs), high-energy (140 kVp, 2.5 mAs, 1 mm additional tin filtration), and clinical (120 kVp, 0.25 mAs). Regular dual-energy images were calculated by weighted logarithmic subtraction of high- and low-energy images and filter-free dual-energy images were generated from clinical and low-energy radiographs. The weighting factor to calculate the dual-energy images was determined by means of a novel objective score. The usefulness of dual-energy imaging for real-time tracking with an automated template matching algorithm was investigated. Results: Regular dual-energy imaging was able to increase tracking accuracy in left–right images of the anthropomorphic phantom as well as in 7 out of 24 investigated patient cases. Tracking accuracy remained comparable in three cases and decreased in five cases. Filter-free dual-energy imaging was only able to increase accuracy in 2 out of 24 cases. In four cases no change in accuracy was observed and tracking accuracy worsened in nine cases. In 9 out of 24 cases, it was not possible to define a tracking template due to poor soft-tissue contrast regardless of input images. The mean localization errors using clinical, regular dual-energy, and filter-free dual-energy radiographs were 3.85, 3.32, and 5.24 mm, respectively. Tracking success was dependent on tumor position, tumor size, imaging beam angle, and patient size. Conclusions: This study has highlighted the influence of

  7. Using dual-energy x-ray imaging to enhance automated lung tumor tracking during real-time adaptive radiotherapy

    International Nuclear Information System (INIS)

    Menten, Martin J.; Fast, Martin F.; Nill, Simeon; Oelfke, Uwe

    2015-01-01

    Purpose: Real-time, markerless localization of lung tumors with kV imaging is often inhibited by ribs obscuring the tumor and poor soft-tissue contrast. This study investigates the use of dual-energy imaging, which can generate radiographs with reduced bone visibility, to enhance automated lung tumor tracking for real-time adaptive radiotherapy. Methods: kV images of an anthropomorphic breathing chest phantom were experimentally acquired and radiographs of actual lung cancer patients were Monte-Carlo-simulated at three imaging settings: low-energy (70 kVp, 1.5 mAs), high-energy (140 kVp, 2.5 mAs, 1 mm additional tin filtration), and clinical (120 kVp, 0.25 mAs). Regular dual-energy images were calculated by weighted logarithmic subtraction of high- and low-energy images and filter-free dual-energy images were generated from clinical and low-energy radiographs. The weighting factor to calculate the dual-energy images was determined by means of a novel objective score. The usefulness of dual-energy imaging for real-time tracking with an automated template matching algorithm was investigated. Results: Regular dual-energy imaging was able to increase tracking accuracy in left–right images of the anthropomorphic phantom as well as in 7 out of 24 investigated patient cases. Tracking accuracy remained comparable in three cases and decreased in five cases. Filter-free dual-energy imaging was only able to increase accuracy in 2 out of 24 cases. In four cases no change in accuracy was observed and tracking accuracy worsened in nine cases. In 9 out of 24 cases, it was not possible to define a tracking template due to poor soft-tissue contrast regardless of input images. The mean localization errors using clinical, regular dual-energy, and filter-free dual-energy radiographs were 3.85, 3.32, and 5.24 mm, respectively. Tracking success was dependent on tumor position, tumor size, imaging beam angle, and patient size. Conclusions: This study has highlighted the influence of

  8. Using dual-energy x-ray imaging to enhance automated lung tumor tracking during real-time adaptive radiotherapy.

    Science.gov (United States)

    Menten, Martin J; Fast, Martin F; Nill, Simeon; Oelfke, Uwe

    2015-12-01

    Real-time, markerless localization of lung tumors with kV imaging is often inhibited by ribs obscuring the tumor and poor soft-tissue contrast. This study investigates the use of dual-energy imaging, which can generate radiographs with reduced bone visibility, to enhance automated lung tumor tracking for real-time adaptive radiotherapy. kV images of an anthropomorphic breathing chest phantom were experimentally acquired and radiographs of actual lung cancer patients were Monte-Carlo-simulated at three imaging settings: low-energy (70 kVp, 1.5 mAs), high-energy (140 kVp, 2.5 mAs, 1 mm additional tin filtration), and clinical (120 kVp, 0.25 mAs). Regular dual-energy images were calculated by weighted logarithmic subtraction of high- and low-energy images and filter-free dual-energy images were generated from clinical and low-energy radiographs. The weighting factor to calculate the dual-energy images was determined by means of a novel objective score. The usefulness of dual-energy imaging for real-time tracking with an automated template matching algorithm was investigated. Regular dual-energy imaging was able to increase tracking accuracy in left-right images of the anthropomorphic phantom as well as in 7 out of 24 investigated patient cases. Tracking accuracy remained comparable in three cases and decreased in five cases. Filter-free dual-energy imaging was only able to increase accuracy in 2 out of 24 cases. In four cases no change in accuracy was observed and tracking accuracy worsened in nine cases. In 9 out of 24 cases, it was not possible to define a tracking template due to poor soft-tissue contrast regardless of input images. The mean localization errors using clinical, regular dual-energy, and filter-free dual-energy radiographs were 3.85, 3.32, and 5.24 mm, respectively. Tracking success was dependent on tumor position, tumor size, imaging beam angle, and patient size. This study has highlighted the influence of patient anatomy on the success rate of real

  9. WE-G-BRF-06: Positron Emission Tomography (PET)-Guided Dynamic Lung Tumor Tracking for Cancer Radiotherapy: First Patient Simulations

    International Nuclear Information System (INIS)

    Yang, J; Loo, B; Graves, E; Yamamoto, T; Keall, P

    2014-01-01

    Purpose: PET-guided dynamic tumor tracking is a novel concept of biologically targeted image guidance for radiotherapy. A dynamic tumor tracking algorithm based on list-mode PET data has been developed and previously tested on dynamic phantom data. In this study, we investigate if dynamic tumor tracking is clinically feasible by applying the method to lung cancer patient PET data. Methods: PET-guided tumor tracking estimates the target position of a segmented volume in PET images reconstructed continuously from accumulated coincidence events correlated with external respiratory motion, simulating real-time applications, i.e., only data up to the current time point is used to estimate the target position. A target volume is segmented with a 50% threshold, consistently, of the maximum intensity in the predetermined volume of interest. Through this algorithm, the PET-estimated trajectories are quantified from four lung cancer patients who have distinct tumor location and size. The accuracy of the PET-estimated trajectories is evaluated by comparing to external respiratory motion because the ground-truth of tumor motion is not known in patients; however, previous phantom studies demonstrated sub-2mm accuracy using clinically derived 3D tumor motion. Results: The overall similarity of motion patterns between the PET-estimated trajectories and the external respiratory traces implies that the PET-guided tracking algorithm can provide an acceptable level of targeting accuracy. However, there are variations in the tracking accuracy between tumors due to the quality of the segmentation which depends on target-to-background ratio, tumor location and size. Conclusion: For the first time, a dynamic tumor tracking algorithm has been applied to lung cancer patient PET data, demonstrating clinical feasibility of real-time tumor tracking for integrated PET-linacs. The target-to-background ratio is a significant factor determining accuracy: screening during treatment planning would

  10. In Vivo Tumor Gene Delivery Using Novel Peptideticles: pH-Responsive and Ligand Targeted Core-Shell Nanoassembly.

    Science.gov (United States)

    Alipour, Mohsen; Majidi, Asia; Molaabasi, Fatemeh; Sheikhnejad, Reza; Hosseinkhani, Saman

    2018-04-30

    Modulating cancer causing genes with nucleic acid based-molecules as cutting-edge approaches need efficient delivery systems to succeed in clinic. Herein, we report design and fabrication of a novel tissue penetrating Peptideticle with charge-structure switching in tumor microenvironment for an effective gene delivery. The comparative in vitro studies indicate that peptideticles identify and bind to tumor endothelial cells and efficiently penetrate into multicellular tumor spheroid. In addition, negatively charged peptideticle at pH 7.4, prevent unwanted interaction while it's sharp charge-structure switching at pH 6.2-6.9 (e.g.in tumor tissue) facilitates malignant cells penetration. More importantly, upon systemic administration into tumor bearing mice, peptideticles effectively localized in tumor tissue and delivered luciferase gene with a 200-fold higher efficiency compared to their non-pH-responsive counterparts. In conclusion, this study presents a robust nanoassembly of safe materials for high efficient tumor gene delivery. This article is protected by copyright. All rights reserved. © 2018 UICC.

  11. Histopathologic Consideration of Fiducial Gold Markers Inserted for Real-Time Tumor-Tracking Radiotherapy Against Lung Cancer

    International Nuclear Information System (INIS)

    Imura, Mikado; Yamazaki, Koichi; Kubota, Kanako C.; Itoh, Tomoo; Onimaru, Rikiya; Cho, Yasushi; Hida, Yasuhiro; Kaga, Kichizo; Onodera, Yuya; Ogura, Shigeaki; Dosaka-Akita, Hirotoshi; Shirato, Hiroki; Nishimura, Masaharu

    2008-01-01

    Purpose: Internal fiducial gold markers, safely inserted with bronchoscopy, have been used in real-time tumor-tracking radiotherapy for lung cancer. We investigated the histopathologic findings at several points after the insertion of the gold markers. Methods and Materials: Sixteen gold markers were inserted for preoperative marking in 7 patients who subsequently underwent partial resection of tumors by video-assisted thoracoscopic surgery within 7 days. Results: Fibrotic changes and hyperplasia of type 2 pneumocytes around the markers were seen 5 or 7 days after insertion, and fibrin exudation without fibrosis was detected 1 or 2 days after insertion. Conclusions: Because fibroblastic changes start approximately 5 days after gold marker insertion, real-time tumor-tracking radiotherapy should be started >5 days after gold marker insertion

  12. Electroporation driven delivery of both an IL-12 expressing plasmid and cisplatin synergizes to inhibit B16 melanoma tumor growth through an NK cell mediated tumor killing mechanism.

    Science.gov (United States)

    Kim, Ha; Sin, Jeong-Im

    2012-11-01

    Combined therapy using chemotherapeutic drugs and immunotherapeutics offers some promise for treating patients with cancer. In this study, we evaluated whether cisplatin delivered by intratumoral (IT)-electroporation (EP) might enhance antitumor activity against established B16 melanoma and whether further addition of intramuscular (IM)-EP of IL-12 cDNA to IT-EP of cisplatin might augment antitumor therapeutic activity, with a focus on the underlining antitumor mechanism(s). When tumor (7 mm)-bearing animals were treated locally with cisplatin by IT-EP, they showed tumor growth inhibition significantly more than those without IT-EP. Moreover, IL-12 cDNA delivered by IM-EP was also able to inhibit tumor growth significantly more than control vector delivery. This tumor growth inhibition was mediated by NK cells, but not CD4+ T or CD8+ T cells, as determined by immune cell subset depletion and IFN-γ induction. Moreover, concurrent therapy using IT-EP of cisplatin plus IM-EP of IL-12 cDNA displayed antitumor therapeutic synergy. This therapeutic synergy appeared to be mediated by increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. Taken together, these data support that cisplatin delivery by IT-EP plus IL-12 gene delivery by IM-EP are more effective at inducing antitumor therapeutic responses through increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. This combined approach might have some implication for treating melanoma in patients.

  13. Inhibition of Xenograft tumor growth by gold nanoparticle-DNA oligonucleotide conjugates-assisted delivery of BAX mRNA.

    Directory of Open Access Journals (Sweden)

    Ji-Hyun Yeom

    Full Text Available Use of non-biological agents for mRNA delivery into living systems in order to induce heterologous expression of functional proteins may provide more advantages than the use of DNA and/or biological vectors for delivery. However, the low efficiency of mRNA delivery into live animals, using non-biological systems, has hampered the use of mRNA as a therapeutic molecule. Here, we show that gold nanoparticle-DNA oligonucleotide (AuNP-DNA conjugates can serve as universal vehicles for more efficient delivery of mRNA into human cells, as well as into xenograft tumors generated in mice. Injections of BAX mRNA loaded on AuNP-DNA conjugates into xenograft tumors resulted in highly efficient mRNA delivery. The delivered mRNA directed the efficient production of biologically functional BAX protein, a pro-apoptotic factor, consequently inhibiting tumor growth. These results demonstrate that mRNA delivery by AuNP-DNA conjugates can serve as a new platform for the development of safe and efficient gene therapy.

  14. Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration

    OpenAIRE

    Chertok, Beata; David, Allan E.; Yang, Victor C.

    2010-01-01

    This study aimed to examine the applicability of polyethyleneimine (PEI)-modified magnetic nanoparticles (GPEI) as a potential vascular drug/gene carrier to brain tumors. In vitro, GPEI exhibited high cell association and low cell toxicity – properties which are highly desirable for intracellular drug/gene delivery. In addition, a high saturation magnetization of 93 emu/g Fe was expected to facilitate magnetic targeting of GPEI to brain tumor lesions. However, following intravenous administra...

  15. Liposomes containing alkylated methotrexate analogues for phospholipase A(2) mediated tumor targeted drug delivery

    DEFF Research Database (Denmark)

    Kaasgaard, Thomas; Andresen, Thomas Lars; Jensen, Simon Skøde

    2009-01-01

    of alkylated compounds in liposomes, it was demonstrated that the MTX-analogue partitioned into the water phase and thereby became available for cell uptake. It was concluded that liposomes containing alkylated MTX-analogues show promise as a drug delivery system, although the MTX-analogue needs to be more......Two lipophilic methotrexate analogues have been synthesized and evaluated for cytotoxicity against KATO III and HT-29 human colon cancer cells. Both analogues contained a C-16-alkyl chain attached to the gamma-carboxylic acid and one of the analogues had an additional benzyl group attached...... cytotoxicity was incorporated into liposomes that were designed to be particularly Susceptible to a liposome degrading enzyme, secretory phospholipase A(2) (sPLA(2)), which is found in high concentrations in tumors of several different cancer types. Liposome incorporation was investigated by differential...

  16. Evaluation of Hydrogel Suppositories for Delivery of 5-Aminolevulinic Acid and Hematoporphyrin Monomethyl Ether to Rectal Tumors.

    Science.gov (United States)

    Ye, Xuying; Yin, Huijuan; Lu, Yu; Zhang, Haixia; Wang, Han

    2016-10-12

    We evaluated the potential utility of hydrogels for delivery of the photosensitizing agents 5-aminolevulinic acid (ALA) and hematoporphyrin monomethyl ether (HMME) to rectal tumors. Hydrogel suppositories containing ALA or HMME were administered to the rectal cavity of BALB/c mice bearing subcutaneous tumors of SW837 rectal carcinoma cells. For comparison, ALA and HMME were also administered by three common photosensitizer delivery routes; local administration to the skin and intratumoral or intravenous injection. The concentration of ALA-induced protoporphyrin IX or HMME in the rectal wall, skin, and subcutaneous tumor was measured by fluorescence spectrophotometry, and their distribution in vertical sections of the tumor was measured using a fluorescence spectroscopy system. The concentration of ALA-induced protoporphyrin IX in the rectal wall after local administration of suppositories to the rectal cavity was 9.76-fold (1 h) and 5.8-fold (3 h) higher than in the skin after cutaneous administration. The maximal depth of ALA penetration in the tumor was ~3-6 mm at 2 h after cutaneous administration. Much lower levels of HMME were observed in the rectal wall after administration as a hydrogel suppository, and the maximal depth of tumor penetration was <2 mm after cutaneous administration. These data show that ALA more readily penetrates the mucosal barrier than the skin. Administration of ALA as an intrarectal hydrogel suppository is thus a potential delivery route for photodynamic therapy of rectal cancer.

  17. 3D Porous Chitosan-Alginate Scaffolds as an In Vitro Model for Evaluating Nanoparticle-Mediated Tumor Targeting and Gene Delivery to Prostate Cancer.

    Science.gov (United States)

    Wang, Kui; Kievit, Forrest M; Florczyk, Stephen J; Stephen, Zachary R; Zhang, Miqin

    2015-10-12

    Cationic nanoparticles (NPs) for targeted gene delivery are conventionally evaluated using 2D in vitro cultures. However, this does not translate well to corresponding in vivo studies because of the marked difference in NP behavior in the presence of the tumor microenvironment. In this study, we investigated whether prostate cancer (PCa) cells cultured in three-dimensional (3D) chitosan-alginate (CA) porous scaffolds could model cationic NP-mediated gene targeted delivery to tumors in vitro. We assessed in vitro tumor cell proliferation, formation of tumor spheroids, and expression of marker genes that promote tumor malignancy in CA scaffolds. The efficacy of NP-targeted gene delivery was evaluated in PCa cells in 2D cultures, PCa tumor spheroids grown in CA scaffolds, and PCa tumors in a mouse TRAMP-C2 flank tumor model. PCa cells cultured in CA scaffolds grew into tumor spheroids and displayed characteristics of higher malignancy as compared to those in 2D cultures. Significantly, targeted gene delivery was only observed in cells cultured in CA scaffolds, whereas cells cultured on 2D plates showed no difference in gene delivery between targeted and nontarget control NPs. In vivo NP evaluation confirmed targeted gene delivery, indicating that only CA scaffolds correctly modeled NP-mediated targeted delivery in vivo. These findings suggest that CA scaffolds serve as a better in vitro platform than 2D cultures for evaluation of NP-mediated targeted gene delivery to PCa.

  18. Alternative fiducial markers for Vero real-time tumor tracking radiotherapy: A phantom study

    Science.gov (United States)

    Park, Shin-Hyung; Kim, Jae-Chul; Kim, Sung Joon

    2016-12-01

    The objective of this study was to investigate the feasibility of potential fiducial markers consisting of various materials in a Vero real-time tumor-tracking (RTTT) system. In order to determine the applicability of fiducial markers for the Vero RTTT system, we tested various markers consisting of 8 kinds of material (titanium, stainless steel, high-carbon steel, pure steel, copper, silver, tantalum, and gold) with various diameters ranging from 0.3 mm to 1.6 mm and a length of 5 mm. Additionally, a commercial gold coil marker (Visicoil™, IBA dosimetry, Schwarzenbruck, Germany) of diameter 0.5 mm and length 1 cm was included for evaluation. The radiologic visibility on kV fluoroscopy/kV CT scan images of the fiducial markers was evaluated. The detectability on the RTTT system was tested using a two-dimensional moving phantom (Brainlab AG, Feldkirchen, Germany), producing sinusoidal motion. The target center's accuracy was evaluated by calculating the deviation of the position of a metal sphere from the center on the dose profile. Dose profiles were measured using Gafchromic EBT2 films (International Specialty Products, NJ, USA). All markers were visible on kV fluoroscopy/kV CT while markers with atomic number ≥ 25.7 were detectable on the Vero RTTT system. All the detected markers showed excellent geometric accuracy.

  19. Precise engineering of siRNA delivery vehicles to tumors using polyion complexes and gold nanoparticles.

    Science.gov (United States)

    Kim, Hyun Jin; Takemoto, Hiroyasu; Yi, Yu; Zheng, Meng; Maeda, Yoshinori; Chaya, Hiroyuki; Hayashi, Kotaro; Mi, Peng; Pittella, Frederico; Christie, R James; Toh, Kazuko; Matsumoto, Yu; Nishiyama, Nobuhiro; Miyata, Kanjiro; Kataoka, Kazunori

    2014-09-23

    For systemic delivery of siRNA to solid tumors, a size-regulated and reversibly stabilized nanoarchitecture was constructed by using a 20 kDa siRNA-loaded unimer polyion complex (uPIC) and 20 nm gold nanoparticle (AuNP). The uPIC was selectively prepared by charge-matched polyionic complexation of a poly(ethylene glycol)-b-poly(L-lysine) (PEG-PLL) copolymer bearing ∼40 positive charges (and thiol group at the ω-end) with a single siRNA bearing 40 negative charges. The thiol group at the ω-end of PEG-PLL further enabled successful conjugation of the uPICs onto the single AuNP through coordinate bonding, generating a nanoarchitecture (uPIC-AuNP) with a size of 38 nm and a narrow size distribution. In contrast, mixing thiolated PEG-PLLs and AuNPs produced a large aggregate in the absence of siRNA, suggesting the essential role of the preformed uPIC in the formation of nanoarchitecture. The smart uPIC-AuNPs were stable in serum-containing media and more resistant against heparin-induced counter polyanion exchange, compared to uPICs alone. On the other hand, the treatment of uPIC-AuNPs with an intracellular concentration of glutathione substantially compromised their stability and triggered the release of siRNA, demonstrating the reversible stability of these nanoarchitectures relative to thiol exchange and negatively charged AuNP surface. The uPIC-AuNPs efficiently delivered siRNA into cultured cancer cells, facilitating significant sequence-specific gene silencing without cytotoxicity. Systemically administered uPIC-AuNPs showed appreciably longer blood circulation time compared to controls, i.e., bare AuNPs and uPICs, indicating that the conjugation of uPICs onto AuNP was crucial for enhancing blood circulation time. Finally, the uPIC-AuNPs efficiently accumulated in a subcutaneously inoculated luciferase-expressing cervical cancer (HeLa-Luc) model and achieved significant luciferase gene silencing in the tumor tissue. These results demonstrate the strong

  20. Theranostic Niosomes for Efficient siRNA/microRNA Delivery and Activatable Near-Infrared Fluorescent Tracking of Stem Cells

    DEFF Research Database (Denmark)

    Yang, Chuanxu; Shan, Gao; Song, Ping

    2018-01-01

    RNA interference (RNAi) mediated gene regulation in stem cells offers great potential in regenerative medicine. In this study, we developed a theranostic platform for efficient delivery of small RNAs (siRNA/miRNA) to human mesenchymal stem cells (hMSCs) to promote differentiation, and meanwhile...... OFF/ON activatable fluorescence upon cellular internalization, resulting in efficient NIR labeling and the capability to dynamically monitor stem cells in mice. In addition, iSPN/siRNA achieved simultaneous long-term cell tracking and in vivo gene silencing after implantation in mice. These results...

  1. Physico-Chemical Strategies to Enhance Stability and Drug Retention of Polymeric Micelles for Tumor-Targeted Drug Delivery

    NARCIS (Netherlands)

    Shi, Y.; Lammers, Twan Gerardus Gertudis Maria; Storm, Gerrit; Hennink, W.E.

    2017-01-01

    Polymeric micelles (PM) have been extensively used for tumor-targeted delivery of hydrophobic anti-cancer drugs. The lipophilic core of PM is naturally suitable for loading hydrophobic drugs and the hydrophilic shell endows them with colloidal stability and stealth properties. Decades of research on

  2. Effect of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymer-based drug delivery systems

    Czech Academy of Sciences Publication Activity Database

    Lammers, T.; Peschke, P.; Kühnlein, R.; Šubr, Vladimír; Ulbrich, Karel; Debus, J.; Huber, P. E.; Hennink, W. E.; Storm, G.

    2007-01-01

    Roč. 117, č. 3 (2007), s. 333-341 ISSN 0168-3659 R&D Projects: GA ČR GA204/05/2255 Institutional research plan: CEZ:AV0Z40500505 Keywords : HPMA * drug delivery * tumor targeting Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.756, year: 2007

  3. Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: Clinical outcome

    International Nuclear Information System (INIS)

    Voort van Zyp, Noelle C. van der; Prevost, Jean-Briac; Hoogeman, Mischa S.; Praag, John; Holt, Bronno van der; Levendag, Peter C.; Klaveren, Robertus J. van; Pattynama, Peter; Nuyttens, Joost J.

    2009-01-01

    Purpose: To report the clinical outcome of treatment using real-time tumor tracking for 70 patients with inoperable stage I non-small cell lung cancer (NSCLC). Materials and methods: Seventy inoperable patients with peripherally located early-stage NSCLC were treated with 45 or 60 Gy in three fractions using CyberKnife. Pathology was available in 51% of patients. Thirty-nine patients had a T1-tumor and 31 had a T2-tumor. Markers were placed using the vascular, percutaneous intra-, or extra-pulmonary approach, depending on the risk of pneumothorax. Results: The actuarial 2-year local control rate for patients treated with 60 Gy was 96%, compared to 78% for patients treated with a total dose of 45 Gy (p = 0.197). All local recurrences (n = 4) occurred in patients with T2-tumors. Overall survival for the whole group at two years was 62% and the cause specific survival was 85%. The median follow-up was 15 months. Grade 3 toxicity occurred in two patients (3%) after marker placement. Treatment-related late grade 3 toxicity occurred in 7 patients (10%). No grade ≥4 toxicity occurred. Conclusion: Excellent local control of 96% at 1- and 2-years was achieved using 60 Gy in three fractions for NSCLC patients treated with the real-time tumor tracking. Toxicity was low.

  4. Development and clinical evaluation of automatic fiducial detection for tumor tracking in cine megavoltage images during volumetric modulated arc therapy

    International Nuclear Information System (INIS)

    Azcona, Juan Diego; Li Ruijiang; Mok, Edward; Hancock, Steven; Xing Lei

    2013-01-01

    Purpose: Real-time tracking of implanted fiducials in cine megavoltage (MV) imaging during volumetric modulated arc therapy (VMAT) delivery is complicated due to the inherent low contrast of MV images and potential blockage of dynamic leaves configurations. The purpose of this work is to develop a clinically practical autodetection algorithm for motion management during VMAT. Methods: The expected field-specific segments and the planned fiducial position from the Eclipse (Varian Medical Systems, Palo Alto, CA) treatment planning system were projected onto the MV images. The fiducials were enhanced by applying a Laplacian of Gaussian filter in the spatial domain for each image, with a blob-shaped object as the impulse response. The search of implanted fiducials was then performed on a region of interest centered on the projection of the fiducial when it was within an open field including the case when it was close to the field edge or partially occluded by the leaves. A universal template formula was proposed for template matching and normalized cross correlation was employed for its simplicity and computational efficiency. The search region for every image was adaptively updated through a prediction model that employed the 3D position of the fiducial estimated from the localized positions in previous images. This prediction model allowed the actual fiducial position to be tracked dynamically and was used to initialize the search region. The artifacts caused by electronic interference during the acquisition were effectively removed. A score map was computed by combining both morphological information and image intensity. The pixel location with the highest score was selected as the detected fiducial position. The sets of cine MV images taken during treatment were analyzed with in-house developed software written in MATLAB (The Mathworks, Inc., Natick, MA). Five prostate patients were analyzed to assess the algorithm performance by measuring their positioning

  5. Domino-Like Intercellular Delivery of Undecylenic Acid-Conjugated Porous Silicon Nanoparticles for Deep Tumor Penetration.

    Science.gov (United States)

    Yong, Tuying; Hu, Jun; Zhang, Xiaoqiong; Li, Fuying; Yang, Hao; Gan, Lu; Yang, Xiangliang

    2016-10-05

    Improving the intratumoral distribution of anticancer agents remains the critical challenge for developing efficient cancer chemotherapy. Luminescent porous silicon nanoparticles (PSiNPs) have attracted considerable attention in the biomedical field especially in drug delivery. Here, we described the lysosomal exocytosis-mediated domino-like intercellular delivery of undecylenic acid-conjugated PSiNPs (UA-PSiNPs) for deep tumor penetration. UA-PSiNPs with significantly improved stability in physiological conditions were internalized into tumor cells by macropinocytosis-, caveolae-, and clathrin-mediated endocytosis and mainly colocalized with Golgi apparatus and lysosomes. Substantial evidence showed that UA-PSiNPs was excreted from cells via lysosomal exocytosis after cellular uptake. The exocytosed UA-PSiNPs induced a domino-like infection of adjacent cancer cells and allowed encapsulated doxorubicin (DOX) to deeply penetrate into both three-dimensional tumor spheroids and in vivo tumors. In addition, DOX-loaded UA-PSiNPs exhibited strong antitumor activity and few side effects in vivo. This study demonstrated that UA-PSiNPs as a drug carrier might be applied for deep tumor penetration, offering a new insight into the design of more efficient delivery systems of anticancer drugs.

  6. Development of amphiphilic gamma-PGA-nanoparticle based tumor vaccine: potential of the nanoparticulate cytosolic protein delivery carrier.

    Science.gov (United States)

    Yoshikawa, Tomoaki; Okada, Naoki; Oda, Atsushi; Matsuo, Kazuhiko; Matsuo, Keisuke; Mukai, Yohei; Yoshioka, Yasuo; Akagi, Takami; Akashi, Mitsuru; Nakagawa, Shinsaku

    2008-02-08

    Nanoscopic therapeutic systems that incorporate biomacromolecules, such as protein and peptides, are emerging as the next generation of nanomedicine aimed at improving the therapeutic efficacy of biomacromolecular drugs. In this study, we report that poly(gamma-glutamic acid)-based nanoparticles (gamma-PGA NPs) are excellent protein delivery carriers for tumor vaccines that delivered antigenic proteins to antigen-presenting cells and elicited potent immune responses. Importantly, gamma-PGA NPs efficiently delivered entrapped antigenic proteins through cytosolic translocation from the endosomes, which is a key process of gamma-PGA NP-mediated anti-tumor immune responses. Our findings suggest that the gamma-PGA NP system is suitable for the intracellular delivery of protein-based drugs as well as tumor vaccines.

  7. Preventative vaccine-loaded mannosylated chitosan nanoparticles intended for nasal mucosal delivery enhance immune responses and potent tumor immunity.

    Science.gov (United States)

    Yao, Wenjun; Peng, Yixing; Du, Mingzhu; Luo, Juan; Zong, Li

    2013-08-05

    Chitosan (CS) has been extensively used as a protein drug and gene delivery carrier, but its delivery efficiency is unsatisfactory. In this study, a mannose ligand was used to modify CS, which could enhance the delivery efficiency of CS via mannose receptor-mediated endocytosis. A preventative anti-GRP DNA vaccine (pCR3.1-VS-HSP65-TP-GRP6-M2, pGRP) was condensed with mannosylated chitosan (MCS) to form MCS/pGRP nanoparticles. Nanoparticles were intranasally administered in a subcutaneous mice prostate carcinoma model to evaluate the efficacy on inhibition of the growth of tumor cells. The titers of anti-GRP IgG that lasted for 11 weeks were significantly higher than that for administration of CS/pGRP nanoparticles (p intramuscular administration of a pGRP solution (p nanoparticles could suppress the growth of tumor cells. The average tumor weight (0.79 ± 0.30 g) was significantly lower than that in the CS/pGRP nanoparticle group (1.69 ± 0.15 g) (p nanoparticles bound with C-type lectin receptors on macrophages. MCS was an efficient targeting gene delivery carrier and could be used in antitumor immunotherapy.

  8. TH-AB-202-02: Real-Time Verification and Error Detection for MLC Tracking Deliveries Using An Electronic Portal Imaging Device

    International Nuclear Information System (INIS)

    J Zwan, B; Colvill, E; Booth, J; J O’Connor, D; Keall, P; B Greer, P

    2016-01-01

    Purpose: The added complexity of the real-time adaptive multi-leaf collimator (MLC) tracking increases the likelihood of undetected MLC delivery errors. In this work we develop and test a system for real-time delivery verification and error detection for MLC tracking radiotherapy using an electronic portal imaging device (EPID). Methods: The delivery verification system relies on acquisition and real-time analysis of transit EPID image frames acquired at 8.41 fps. In-house software was developed to extract the MLC positions from each image frame. Three comparison metrics were used to verify the MLC positions in real-time: (1) field size, (2) field location and, (3) field shape. The delivery verification system was tested for 8 VMAT MLC tracking deliveries (4 prostate and 4 lung) where real patient target motion was reproduced using a Hexamotion motion stage and a Calypso system. Sensitivity and detection delay was quantified for various types of MLC and system errors. Results: For both the prostate and lung test deliveries the MLC-defined field size was measured with an accuracy of 1.25 cm 2 (1 SD). The field location was measured with an accuracy of 0.6 mm and 0.8 mm (1 SD) for lung and prostate respectively. Field location errors (i.e. tracking in wrong direction) with a magnitude of 3 mm were detected within 0.4 s of occurrence in the X direction and 0.8 s in the Y direction. Systematic MLC gap errors were detected as small as 3 mm. The method was not found to be sensitive to random MLC errors and individual MLC calibration errors up to 5 mm. Conclusion: EPID imaging may be used for independent real-time verification of MLC trajectories during MLC tracking deliveries. Thresholds have been determined for error detection and the system has been shown to be sensitive to a range of delivery errors.

  9. The in vivo study on the radiobiologic effect of prolonged delivery time to tumor control in C57BL mice implanted with Lewis lung cancer

    International Nuclear Information System (INIS)

    Wang, Xin; Xiong, Xiao-Peng; Lu, Jiade; Zhu, Guo-Pei; He, Shao-Qin; Hu, Chao-Su; Ying, Hong-Mei

    2011-01-01

    High-precision radiation therapy techniques such as IMRT or sterotactic radiosurgery, delivers more complex treatment fields than conventional techniques. The increased complexity causes longer dose delivery times for each fraction. The purpose of this work is to explore the radiobiologic effect of prolonged fraction delivery time on tumor response and survival in vivo. 1-cm-diameter Lewis lung cancer tumors growing in the legs of C57BL mice were used. To evaluate effect of dose delivery prolongation, 18 Gy was divided into different subfractions. 48 mice were randomized into 6 groups: the normal control group, the single fraction with 18 Gy group, the two subfractions with 30 min interval group, the seven subfractions with 5 min interval group, the two subfractions with 60 min interval group and the seven subfractions with 10 min interval group. The tumor growth tendency, the tumor growth delay and the mice survival time were analyzed. The tumor growth delay of groups with prolonged delivery time was shorter than the group with single fraction of 18 Gy (P < 0.05). The tumor grow delay of groups with prolonged delivery time 30 min was longer than that of groups with prolonged delivery time 60 min P < 0.05). There was no significant difference between groups with same delivery time (P > 0.05). Compared to the group with single fraction of 18 Gy, the groups with prolonged delivery time shorten the mice survival time while there was no significant difference between the groups with prolonged delivery time 30 min and the groups with prolonged delivery time 60 min. The prolonged delivery time with same radiation dose shorten the tumor growth delay and survival time in the mice implanted with Lewis lung cancer. The anti-tumor effect decreased with elongation of the total interfractional time

  10. In vitro detection of circulating tumor cells compared by the CytoTrack and CellSearch methods

    DEFF Research Database (Denmark)

    Hillig, T.; Horn, P.; Nygaard, Ann-Britt

    2015-01-01

    .23/p = 0.09). Overall, the recovery of CytoTrack and CellSearch was 68.8 +/- 3.9 %/71.1 +/- 2.9 %, respectively (p = 0.58). In spite of different methodologies, CytoTrack and CellSearch found similar number of CTCs, when spiking was performed with the EpCAM and pan cytokeratin-positive cell line MCF-7......Comparison of two methods to detect circulating tumor cells (CTC) CytoTrack and CellSearch through recovery of MCF-7 breast cancer cells, spiked into blood collected from healthy donors. Spiking of a fixed number of EpCAM and pan-cytokeratin positive MCF-7 cells into 7.5 mL donor blood...... was performed by FACSAria flow sorting. The samples were shipped to either CytoTrack or CellSearch research facilities within 48 h, where evaluation of MCF-7 recovery was performed. CytoTrack and CellSearch analyses were performed simultaneously. Recoveries of MCF-7 single cells, cells in clusters, and clusters...

  11. Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors

    Directory of Open Access Journals (Sweden)

    Thangavel P

    2017-04-01

    Full Text Available Prakash Thangavel,1 Buddolla Viswanath,1 Sanghyo Kim1,2 1Department of Bionanotechnology, Gachon University, Bokjeong-Dong, Sujeong-Gu, Seongnam-Si, Gyeonggi-Do, 2Graduate Gachon Medical Research Institute, Gil Medical Center, Incheon, Republic of Korea Abstract: In recent years, the field of metal-based drugs has been dominated by other existing precious metal drugs, and many researchers have focused their attention on the synthesis of various ruthenium (Ru complexes due to their potential medical and pharmaceutical applications. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidation states, low toxicity, high selectivity for diseased cells, ligand exchange properties, and the ability to mimic iron binding to biomolecules. In addition, Ru complexes have favorable adsorption properties, along with excellent photochemical and photophysical properties, which make them promising tools for photodynamic therapy. At present, nanostructured materials functionalized with Ru complexes have become an efficient way to administer Ru-based anticancer drugs for cancer treatment. In this review, the recent developments in the nanostructured materials functionalized with Ru complexes for targeted drug delivery to tumors are discussed. In addition, information on “traditional” (ie, non-nanostructured Ru-based cancer therapies is included in a precise manner. Keywords: metallodrugs, nanotechnology, cancer treatment, cell apoptosis, DNA damage, toxicity

  12. Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment

    Directory of Open Access Journals (Sweden)

    Chendi Ding

    2016-12-01

    Full Text Available Benefiting from the development of nanotechnology, drug delivery systems (DDSs with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs, quantum dots (QDs and carbon nanotubes (CNTs. The second section presents the main types of stimuli-responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules and extrinsic (temperature, light irradiation, magnetic field and ultrasound ones. Clinical applications of DDS, future challenges and perspectives are also mentioned.

  13. Synchronized moving aperture radiation therapy (SMART): superimposing tumor motion on IMRT MLC leaf sequences under realistic delivery conditions

    International Nuclear Information System (INIS)

    Xu Jun; Papanikolaou, Nikos; Shi Chengyu; Jiang, Steve B

    2009-01-01

    Synchronized moving aperture radiation therapy (SMART) has been proposed to account for tumor motions during radiotherapy in prior work. The basic idea of SMART is to synchronize the moving radiation beam aperture formed by a dynamic multileaf collimator (DMLC) with the tumor motion induced by respiration. In this paper, a two-dimensional (2D) superimposing leaf sequencing method is presented for SMART. A leaf sequence optimization strategy was generated to assure the SMART delivery under realistic delivery conditions. The study of delivery performance using the Varian LINAC and the Millennium DMLC showed that clinical factors such as collimator angle, dose rate, initial phase and machine tolerance affect the delivery accuracy and efficiency. An in-house leaf sequencing software was developed to implement the 2D superimposing leaf sequencing method and optimize the motion-corrected leaf sequence under realistic clinical conditions. The analysis of dynamic log (Dynalog) files showed that optimization of the leaf sequence for various clinical factors can avoid beam hold-offs which break the synchronization of SMART and fail the SMART dose delivery. Through comparison between the simulated delivered fluence map and the planed fluence map, it was shown that the motion-corrected leaf sequence can greatly reduce the dose error.

  14. CNR considerations for rapid real-time MRI tumor tracking in radiotherapy hybrid devices: Effects of B0 field strength

    International Nuclear Information System (INIS)

    Wachowicz, K.; De Zanche, N.; Yip, E.; Volotovskyy, V.; Fallone, B. G.

    2016-01-01

    Purpose: This work examines the subject of contrast-to-noise ratio (CNR), specifically between tumor and tissue background, and its dependence on the MRI field strength, B 0 . This examination is motivated by the recent interest and developments in MRI/radiotherapy hybrids where real-time imaging can be used to guide treatment beams. The ability to distinguish a tumor from background tissue is of primary importance in this field, and this work seeks to elucidate the complex relationship between the CNR and B 0 that is too often assumed to be purely linear. Methods: Experimentally based models of B 0 -dependant relaxation for various tumor and normal tissues from the literature were used in conjunction with signal equations for MR sequences suitable for rapid real-time imaging to develop field-dependent predictions for CNR. These CNR models were developed for liver, lung, breast, glioma, and kidney tumors for spoiled gradient-echo, balanced steady-state free precession (bSSFP), and single-shot half-Fourier fast spin echo sequences. Results: Due to the pattern in which the relaxation properties of tissues are found to vary over B 0 field (specifically the T 1 time), there was always an improved CNR at lower fields compared to linear dependency. Further, in some tumor sites, the CNR at lower fields was found to be comparable to, or sometimes higher than those at higher fields (i.e., bSSFP CNR for glioma, kidney, and liver tumors). Conclusions: In terms of CNR, lower B 0 fields have been shown to perform as well or better than higher fields for some tumor sites due to superior T 1 contrast. In other sites this effect was less pronounced, reversing the CNR advantage. This complex relationship between CNR and B 0 reveals both low and high magnetic fields as viable options for tumor tracking in MRI/radiotherapy hybrids.

  15. Mitigation of motion artifacts in CBCT of lung tumors based on tracked tumor motion during CBCT acquisition

    International Nuclear Information System (INIS)

    Lewis, John H; Li Ruijiang; Jia Xun; Watkins, W Tyler; Song, William Y; Jiang, Steve B; Lou, Yifei

    2011-01-01

    An algorithm capable of mitigating respiratory motion blurring artifacts in cone-beam computed tomography (CBCT) lung tumor images based on the motion of the tumor during the CBCT scan is developed. The tumor motion trajectory and probability density function (PDF) are reconstructed from the acquired CBCT projection images using a recently developed algorithm Lewis et al (2010 Phys. Med. Biol. 55 2505-22). Assuming that the effects of motion blurring can be represented by convolution of the static lung (or tumor) anatomy with the motion PDF, a cost function is defined, consisting of a data fidelity term and a total variation regularization term. Deconvolution is performed through iterative minimization of this cost function. The algorithm was tested on digital respiratory phantom, physical respiratory phantom and patient data. A clear qualitative improvement is evident in the deblurred images as compared to the motion-blurred images for all cases. Line profiles show that the tumor boundaries are more accurately and clearly represented in the deblurred images. The normalized root-mean-squared error between the images used as ground truth and the motion-blurred images are 0.29, 0.12 and 0.30 in the digital phantom, physical phantom and patient data, respectively. Deblurring reduces the corresponding values to 0.13, 0.07 and 0.19. Application of a -700 HU threshold to the digital phantom results in tumor dimension measurements along the superior-inferior axis of 2.8, 1.8 and 1.9 cm in the motion-blurred, ground truth and deblurred images, respectively. Corresponding values for the physical phantom are 3.4, 2.7 and 2.7 cm. A threshold of -500 HU applied to the patient case gives measurements of 3.1, 1.6 and 1.7 cm along the SI axis in the CBCT, 4DCT and deblurred images, respectively. This technique could provide more accurate information about a lung tumor's size and shape on the day of treatment.

  16. Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

    Science.gov (United States)

    2009-12-01

    diabetic retinopathy . Therefore, se- lectively targeting existing blood vessels (vascular- disrupting therapy) and/or inhibiting the forma- tion of new...adhesion led to the formation of thrombi that can occlude blood vessels, causing vascular shutdown. However, viable tumor cells were often detected at...tumor sections (Fig. 4). However, viable tumor cells were commonly detected at tumor periphery. Because of the existence of viable peripheral tumor cells

  17. Potential dosimetric benefits of adaptive tumor tracking over the internal target volume concept for stereotactic body radiation therapy of pancreatic cancer.

    Science.gov (United States)

    Karava, Konstantina; Ehrbar, Stefanie; Riesterer, Oliver; Roesch, Johannes; Glatz, Stefan; Klöck, Stephan; Guckenberger, Matthias; Tanadini-Lang, Stephanie

    2017-11-09

    Radiotherapy for pancreatic cancer has two major challenges: (I) the tumor is adjacent to several critical organs and, (II) the mobility of both, the tumor and its surrounding organs at risk (OARs). A treatment planning study simulating stereotactic body radiation therapy (SBRT) for pancreatic tumors with both the internal target volume (ITV) concept and the tumor tracking approach was performed. The two respiratory motion-management techniques were compared in terms of doses to the target volume and organs at risk. Two volumetric-modulated arc therapy (VMAT) treatment plans (5 × 5 Gy) were created for each of the 12 previously treated pancreatic cancer patients, one using the ITV concept and one the tumor tracking approach. To better evaluate the overall dose delivered to the moving tumor volume, 4D dose calculations were performed on four-dimensional computed tomography (4DCT) scans. The resulting planning target volume (PTV) size for each technique was analyzed. Target and OAR dose parameters were reported and analyzed for both 3D and 4D dose calculation. Tumor motion ranged from 1.3 to 11.2 mm. Tracking led to a reduction of PTV size (max. 39.2%) accompanied with significant better tumor coverage (p<0.05, paired Wilcoxon signed rank test) both in 3D and 4D dose calculations and improved organ at risk sparing. Especially for duodenum, stomach and liver, the mean dose was significantly reduced (p<0.05) with tracking for 3D and 4D dose calculations. By using an adaptive tumor tracking approach for respiratory-induced pancreatic motion management, a significant reduction in PTV size can be achieved, which subsequently facilitates treatment planning, and improves organ dose sparing. The dosimetric benefit of tumor tracking is organ and patient-specific.

  18. Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging

    Directory of Open Access Journals (Sweden)

    Estrada Giovani

    2010-03-01

    Full Text Available Abstract Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB, a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical

  19. Intracellular delivery of nanomaterials for sub-cellular imaging and tracking of biomolecules

    Science.gov (United States)

    Medepalli, Krishna Kiran

    Nanomaterials have many intriguing applications in biology and medicine. Unique properties such as enhanced electrical properties, increased chemical reactivity and resistance to degradation, novel optical properties and comparable size to that of biological systems have led to their use in various biomedical applications. The most important applications of nanomaterials for medicine are in drug delivery and imaging. This research focuses on utilizing the biocompatibility of single walled Carbon nanotubes (SWCNTs) and optical properties colloidal quantum dots (QDs) for cellular drug delivery and imaging of biomolecules. The first part of this research deals with single walled carbon nanotubes which are excellent candidates for targeted drug delivery applications due their unique structural and functional properties. However, prior to their use in therapeutics, their biocompatibility needs to be thoroughly investigated. The objectives of this research were to establish the biocompatibility of SWCNTs and demonstrate their use as drug delivery carriers into cells. Blood, a living tissue, is chosen as the biological system as it contains various cells which can potentially interact with SWCNTs during the delivery mechanism. The interactions of these cells in the blood (specifically white blood cells or leukocytes) with the SWCNTs provide vital information regarding the immune response of the host to the nanotubes. This research investigates the immune response of white blood cells due to SWCNTs via (a) direct interaction---presence of nanotubes in the blood and, (b) indirect interaction---presentation of nanotubes by antigen-presenting-cells to white blood cells. These two interactions recreate the innate and adaptive immune responses occurring in the body to any foreign substance. SWCNTs are functionalized with single stranded DNA (ss-DNA), which serves as a dispersant of nanotubes as well as a backbone for further attachment of other biomolecules of interest

  20. Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration.

    Science.gov (United States)

    Chertok, Beata; David, Allan E; Yang, Victor C

    2010-08-01

    This study aimed to examine the applicability of polyethyleneimine (PEI)-modified magnetic nanoparticles (GPEI) as a potential vascular drug/gene carrier to brain tumors. In vitro, GPEI exhibited high cell association and low cell toxicity--properties which are highly desirable for intracellular drug/gene delivery. In addition, a high saturation magnetization of 93 emu/g Fe was expected to facilitate magnetic targeting of GPEI to brain tumor lesions. However, following intravenous administration, GPEI could not be magnetically accumulated in tumors of rats harboring orthotopic 9L-gliosarcomas due to its poor pharmacokinetic properties, reflected by a negligibly low plasma AUC of 12 +/- 3 microg Fe/ml min. To improve "passive" GPEI presentation to brain tumor vasculature for subsequent "active" magnetic capture, we examined the intra-carotid route as an alternative for nanoparticle administration. Intra-carotid administration in conjunction with magnetic targeting resulted in 30-fold (p=0.002) increase in tumor entrapment of GPEI compared to that seen with intravenous administration. In addition, magnetic accumulation of cationic GPEI (zeta-potential = + 37.2 mV) in tumor lesions was 5.2-fold higher (p=0.004) than that achieved with slightly anionic G100 (zeta-potential= -12 mV) following intra-carotid administration, while no significant accumulation difference was detected between the two types of nanoparticles in the contra-lateral brain (p=0.187). These promising results warrant further investigation of GPEI as a potential cell-permeable, magnetically-responsive platform for brain tumor delivery of drugs and genes. 2010 Elsevier Ltd. All rights reserved.

  1. Capability verification of the beam delivery system in the superficially-placed tumor therapy terminal at HIRFL

    International Nuclear Information System (INIS)

    Dai Zhongying; Li Qiang; Xiao Guoqing; Jin Xiaodong; Yan Zheng; Chinese Academy of Sciences, Beijing

    2007-01-01

    The passive beam delivery system in the superficially-placed tumor therapy terminal at Heavy Ion Research Facility in Lanzhou (HIRFL), which includes two orthogonal dipole magnets as scanning system, a motor-driven energy degrader as range-shifter, series of ridge filters as range modulator and a multileaf collimator, is introduced in detail. The capacities of its important components and the whole system have been verified experimentally. The tests of the ridge filter for extending Bragg peak and the range shifter for energy adjustment show both work well. To examine the passive beam delivery system, a beam shaping experiment were carried out, simulating a three-dimensional (3D) conformal irradiation to a tumor. The encouraging experimental result confirms that 3D layer-stacking conformal irradiation can be performed by means of the passive system. The validation of the beam delivery system establishes a substantial basis for upcoming clinical trial for superficially-placed tumors with heavy ions in the therapy terminal at HIRFL. (authors)

  2. Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer.

    Science.gov (United States)

    Ota, Shinichi; Geschwind, Jean-Francois H; Buijs, Manon; Wijlemans, Joost W; Kwak, Byung Kook; Ganapathy-Kanniappan, Shanmugasundaram

    2013-06-01

    Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer.

  3. Supporting Data for Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs

    Directory of Open Access Journals (Sweden)

    Guowei Wu

    2016-06-01

    Full Text Available Although nanoparticulate drug delivery systems (NDDSs can preferentially accumulate in tumors, active targeting by targeting ligands (e.g. monoclonal antibody is necessary for increasing its targeting efficacy in vivo. We conjugated mAb198.3 on the SiO2@AuNP system surface to make it obtain active targeting efficacy. The FAT1 targeting capability of SiO2@AuNP system is the first issue to be solved. Thus, flow cytometry analysis was attempted to demonstrate that the SiO2@AuNP system could bind to native FAT1 molecules on the surface of Colo205 cells. Also, together with the drug release behavior study of self-decomposable SiO2 NPs, the continuous morphological evolution needed to be clarified. Therefore, to characterize the morphological evolution in vitro, we analyzed the morphology of inner self-decomposable NPs in different time intervals using transmission electron microscopy (TEM. A more comprehensive analysis of this data may be obtained from the article “Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs” in Biomaterials.

  4. Murine bone marrow-derived mesenchymal stem cells as vehicles for interleukin-12 gene delivery into Ewing sarcoma tumors.

    Science.gov (United States)

    Duan, Xiaoping; Guan, Hui; Cao, Ying; Kleinerman, Eugenie S

    2009-01-01

    This study evaluated the therapeutic efficacy of interleukin 12 (IL-12) gene therapy in Ewing sarcoma and whether murine mesenchymal stem cells (MSCs) could serve as vehicles for IL-12 gene delivery. MSCs were isolated from murine bone marrow cells. Cells were phenotyped using flow cytometry. Cultured MSCs differentiated into osteocytes and adipocytes using the appropriate media. Freshly isolated MSCs were transfected with adenoviral vectors containing either the beta-galactosidase (Ad:beta-gal) or the IL-12 (Ad:IL-12) gene. Expression of IL-12 was confirmed using reverse transcription polymerase chain reaction. Mice with TC71 Ewing sarcoma tumors were then treated intravenously with MSCs transfected with Ad:beta-gal or Ad:IL-12. Tumors were measured and analyzed by immunohistochemical analysis for expression of IL-12 protein. Expression of both p35 and p40 IL-12 subunits was demonstrated in MSCs transfected in vitro with Ad:IL-12. IL-12 expression was seen in tumors from mice treated with MSCs transfected with Ad:IL-12. Tumor growth was also significantly inhibited compared with that in mice treated with MSCs transfected with Ad:beta-gal. MSCs can be transfected with the IL-12 gene. These transfected cells localize to tumors after intravenous injection and induce local IL-12 protein production and the regression of established tumors. Copyright (c) 2008 American Cancer Society.

  5. Solar concentrator with integrated tracking and light delivery system with collimation

    Science.gov (United States)

    Maxey, Lonnie Curt

    2015-06-09

    A solar light distribution system includes a solar light concentrator that is affixed externally to a light transfer tube. Solar light waves are processed by the concentrator into a collimated beam of light, which is then transferred through a light receiving port and into the light transfer tube. A reflector directs the collimated beam of light through the tube to a light distribution port. The interior surface of the light transfer tube is highly reflective so that the light transfers through the tube with minimal losses. An interchangeable luminaire is attached to the light distribution port and distributes light inside of a structure. A sun tracking device rotates the concentrator and the light transfer tube to optimize the receiving of solar light by the concentrator throughout the day. The system provides interior lighting, uses only renewable energy sources, and releases no carbon dioxide emissions into the atmosphere.

  6. Solar concentrator with integrated tracking and light delivery system with summation

    Science.gov (United States)

    Maxey, Lonnie Curt

    2015-05-05

    A solar light distribution system includes a solar light concentrator that is affixed externally to a light transfer tube. Solar light waves are processed by the concentrator into a collimated beam of light, which is then transferred through a light receiving port and into the light transfer tube. A reflector redirects the collimated beam of light through the tube to a light distribution port. The interior surface of the light transfer tube is highly reflective so that the light transfers through the tube with minimal losses. An interchangeable luminaire is attached to the light distribution port and provides light inside of a structure. A sun tracking device rotates the concentrator and the light transfer tube to optimize the receiving of solar light by the concentrator throughout the day. The system provides interior lighting that uses only renewable energy sources, and releases no carbon dioxide emissions into the atmosphere.

  7. Tracking of [{sup 18}F]FDG-labeled natural killer cells to HER2/neu-positive tumors

    Energy Technology Data Exchange (ETDEWEB)

    Meier, Reinhard [Department of Radiology, University of California San Francisco (United States)], E-mail: reinhardt.meier@gmail.com; Piert, Morand [Department of Radiology, Division of Nuclear Medicine, University of Michigan (United States); Piontek, Guido; Rudelius, Martina [Institute of Pathology, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Oostendorp, Robert A. [3rd Department of Internal Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Senekowitsch-Schmidtke, Reingard [Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Henning, Tobias D. [Department of Radiology, University of California San Francisco (United States); Wels, Winfried S.; Uherek, Christoph [Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt am Main (Germany); Rummeny, Ernst J. [Department of Radiology, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Daldrup-Link, Heike E. [Department of Radiology, University of California San Francisco (United States)

    2008-07-15

    Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [{sup 18}F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [{sup 18}F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [{sup 18}F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [{sup 18}F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10{sup 6} [{sup 18}F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10{sup 6} NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [{sup 18}F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography.

  8. Tracking of [18F]FDG-labeled natural killer cells to HER2/neu-positive tumors

    International Nuclear Information System (INIS)

    Meier, Reinhard; Piert, Morand; Piontek, Guido; Rudelius, Martina; Oostendorp, Robert A.; Senekowitsch-Schmidtke, Reingard; Henning, Tobias D.; Wels, Winfried S.; Uherek, Christoph; Rummeny, Ernst J.; Daldrup-Link, Heike E.

    2008-01-01

    Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [ 18 F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [ 18 F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [ 18 F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [ 18 F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10 6 [ 18 F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10 6 NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [ 18 F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography

  9. Clinical Accuracy of the Respiratory Tumor Tracking System of the CyberKnife: Assessment by Analysis of Log Files

    International Nuclear Information System (INIS)

    Hoogeman, Mischa; Prevost, Jean-Briac; Nuyttens, Joost; Poell, Johan; Levendag, Peter; Heijmen, Ben

    2009-01-01

    Purpose: To quantify the clinical accuracy of the respiratory motion tracking system of the CyberKnife treatment device. Methods and Materials: Data in log files of 44 lung cancer patients treated with tumor tracking were analyzed. Errors in the correlation model, which relates the internal target motion with the external breathing motion, were quantified. The correlation model error was compared with the geometric error obtained when no respiratory tracking was used. Errors in the prediction method were calculated by subtracting the predicted position from the actual measured position after 192.5 ms (the time lag to prediction in our current system). The prediction error was also measured for a time lag of 115 ms and a new prediction method. Results: The mean correlation model errors were less than 0.3 mm. Standard deviations describing intrafraction variations around the whole-fraction mean error were 0.2 to 1.9 mm for cranio-caudal, 0.1 to 1.9 mm for left-right, and 0.2 to 2.5 mm for anterior-posterior directions. Without the use of respiratory tracking, these variations would have been 0.2 to 8.1 mm, 0.2 to 5.5 mm, and 0.2 to 4.4 mm. The overall mean prediction error was small (0.0 ± 0.0 mm) for all directions. The intrafraction standard deviation ranged from 0.0 to 2.9 mm for a time delay of 192.5 ms but was halved by using the new prediction method. Conclusions: Analyses of the log files of real clinical cases have shown that the geometric error caused by respiratory motion is substantially reduced by the application of respiratory motion tracking.

  10. Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis.

    Science.gov (United States)

    Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

    Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis.

  11. Intrafractional Baseline Shift or Drift of Lung Tumor Motion During Gated Radiation Therapy With a Real-Time Tumor-Tracking System

    International Nuclear Information System (INIS)

    Takao, Seishin; Miyamoto, Naoki; Matsuura, Taeko; Onimaru, Rikiya; Katoh, Norio; Inoue, Tetsuya; Sutherland, Kenneth Lee; Suzuki, Ryusuke; Shirato, Hiroki; Shimizu, Shinichi

    2016-01-01

    Purpose: To investigate the frequency and amplitude of baseline shift or drift (shift/drift) of lung tumors in stereotactic body radiation therapy (SBRT), using a real-time tumor-tracking radiation therapy (RTRT) system. Methods and Materials: Sixty-eight patients with peripheral lung tumors were treated with SBRT using the RTRT system. One of the fiducial markers implanted near the tumor was used for the real-time monitoring of the intrafractional tumor motion every 0.033 seconds by the RTRT system. When baseline shift/drift is determined by the system, the position of the treatment couch is adjusted to compensate for the shift/drift. Therefore, the changes in the couch position correspond to the baseline shift/drift in the tumor motion. The frequency and amount of adjustment to the couch positions in the left-right (LR), cranio-caudal (CC), and antero-posterior (AP) directions have been analyzed for 335 fractions administered to 68 patients. Results: The average change in position of the treatment couch during the treatment time was 0.45 ± 2.23 mm (mean ± standard deviation), −1.65 ± 5.95 mm, and 1.50 ± 2.54 mm in the LR, CC, and AP directions, respectively. Overall the baseline shift/drift occurs toward the cranial and posterior directions. The incidence of baseline shift/drift exceeding 3 mm was 6.0%, 15.5%, 14.0%, and 42.1% for the LR, CC, AP, and for the square-root of sum of 3 directions, respectively, within 10 minutes of the start of treatment, and 23.0%, 37.6%, 32.5%, and 71.6% within 30 minutes. Conclusions: Real-time monitoring and frequent adjustments of the couch position and/or adding appropriate margins are suggested to be essential to compensate for possible underdosages due to baseline shift/drift in SBRT for lung cancers.

  12. Image-guided, targeted and triggered drug delivery to tumors using polymer-based microbubbles.

    NARCIS (Netherlands)

    Fokong, S.; Theek, B.; Koczera, P.; Appold, L.; Resch-Genger, U.; van Zandvoort, M.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria

    2012-01-01

    Abstract Microbubbles (MB) are routinely used contrast agents for functional and molecular ultrasound (US) imaging. In addition, they have been attracting more and more attention for drug delivery purposes, enabling e.g. US-mediated drug delivery across biological barriers and US-induced triggered

  13. Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells.

    Science.gov (United States)

    Maran, Avudaiappan; Dadsetan, Mahrokh; Buenz, Colleen M; Shogren, Kristen L; Lu, Lichun; Yaszemski, Michael J

    2013-09-01

    Osteosarcoma is a bone tumor that affects children and young adults. 2-Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2-ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma. Copyright © 2012 Wiley Periodicals, Inc.

  14. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

    Science.gov (United States)

    Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

    2015-03-01

    Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used.

  15. The in vivo study on the radiobiologic effect of prolonged delivery time to tumor control in C57BL mice implanted with Lewis lung cancer

    Directory of Open Access Journals (Sweden)

    Zhu Guo-Pei

    2011-01-01

    Full Text Available Abstract Background High-precision radiation therapy techniques such as IMRT or sterotactic radiosurgery, delivers more complex treatment fields than conventional techniques. The increased complexity causes longer dose delivery times for each fraction. The purpose of this work is to explore the radiobiologic effect of prolonged fraction delivery time on tumor response and survival in vivo. Methods 1-cm-diameter Lewis lung cancer tumors growing in the legs of C57BL mice were used. To evaluate effect of dose delivery prolongation, 18 Gy was divided into different subfractions. 48 mice were randomized into 6 groups: the normal control group, the single fraction with 18 Gy group, the two subfractions with 30 min interval group, the seven subfractions with 5 min interval group, the two subfractions with 60 min interval group and the seven subfractions with 10 min interval group. The tumor growth tendency, the tumor growth delay and the mice survival time were analyzed. Results The tumor growth delay of groups with prolonged delivery time was shorter than the group with single fraction of 18 Gy (P 0.05. Compared to the group with single fraction of 18 Gy, the groups with prolonged delivery time shorten the mice survival time while there was no significant difference between the groups with prolonged delivery time 30 min and the groups with prolonged delivery time 60 min. Conclusions The prolonged delivery time with same radiation dose shorten the tumor growth delay and survival time in the mice implanted with Lewis lung cancer. The anti-tumor effect decreased with elongation of the total interfractional time.

  16. Direct visualization of electroporation-assisted in vivo gene delivery to tumors using intravital microscopy – spatial and time dependent distribution

    Directory of Open Access Journals (Sweden)

    Dachs Gabi U

    2004-11-01

    Full Text Available Abstract Background Electroporation is currently receiving much attention as a way to increase drug and DNA delivery. Recent studies demonstrated the feasibility of electrogene therapy using a range of therapeutic genes for the treatment of experimental tumors. However, the transfection efficiency of electroporation-assisted DNA delivery is still low compared to viral methods and there is a clear need to optimize this approach. In order to optimize treatment, knowledge about spatial and time dependency of gene expression following delivery is of utmost importance in order to improve gene delivery. Intravital microscopy of tumors growing in dorsal skin fold window chambers is a useful method for monitoring gene transfection, since it allows non-invasive dynamic monitoring of gene expression in tumors in a live animal. Methods Intravital microscopy was used to monitor real time spatial distribution of the green fluorescent protein (GFP and time dependence of transfection efficiency in syngeneic P22 rat tumor model. DNA alone, liposome-DNA complexes and electroporation-assisted DNA delivery using two different sets of electric pulse parameters were compared. Results Electroporation-assisted DNA delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz was superior to other methods and resulted in 22% increase in fluorescence intensity in the tumors up to 6 days post-transfection, compared to the non-transfected area in granulation tissue. Functional GFP was detected within 5 h after transfection. Cells expressing GFP were detected throughout the tumor, but not in the surrounding tissue that was not exposed to electric pulses. Conclusions Intravital microscopy was demonstrated to be a suitable method for monitoring time and spatial distribution of gene expression in experimental tumors and provided evidence that electroporation-assisted gene delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz is an effective method, resulting in early onset and homogenous

  17. Direct visualization of electroporation-assisted in vivo gene delivery to tumors using intravital microscopy – spatial and time dependent distribution

    International Nuclear Information System (INIS)

    Cemazar, Maja; Wilson, Ian; Dachs, Gabi U; Tozer, Gillian M; Sersa, Gregor

    2004-01-01

    Electroporation is currently receiving much attention as a way to increase drug and DNA delivery. Recent studies demonstrated the feasibility of electrogene therapy using a range of therapeutic genes for the treatment of experimental tumors. However, the transfection efficiency of electroporation-assisted DNA delivery is still low compared to viral methods and there is a clear need to optimize this approach. In order to optimize treatment, knowledge about spatial and time dependency of gene expression following delivery is of utmost importance in order to improve gene delivery. Intravital microscopy of tumors growing in dorsal skin fold window chambers is a useful method for monitoring gene transfection, since it allows non-invasive dynamic monitoring of gene expression in tumors in a live animal. Intravital microscopy was used to monitor real time spatial distribution of the green fluorescent protein (GFP) and time dependence of transfection efficiency in syngeneic P22 rat tumor model. DNA alone, liposome-DNA complexes and electroporation-assisted DNA delivery using two different sets of electric pulse parameters were compared. Electroporation-assisted DNA delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz was superior to other methods and resulted in 22% increase in fluorescence intensity in the tumors up to 6 days post-transfection, compared to the non-transfected area in granulation tissue. Functional GFP was detected within 5 h after transfection. Cells expressing GFP were detected throughout the tumor, but not in the surrounding tissue that was not exposed to electric pulses. Intravital microscopy was demonstrated to be a suitable method for monitoring time and spatial distribution of gene expression in experimental tumors and provided evidence that electroporation-assisted gene delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz is an effective method, resulting in early onset and homogenous distribution of gene expression in the syngeneic P22 rat tumor model

  18. Tracking the rise in popularity of electronic nicotine delivery systems (electronic cigarettes) using search query surveillance.

    Science.gov (United States)

    Ayers, John W; Ribisl, Kurt M; Brownstein, John S

    2011-04-01

    Public interest in electronic nicotine delivery systems (ENDS) is undocumented. By monitoring search queries, ENDS popularity and correlates of their popularity were assessed in Australia, Canada, the United Kingdom (UK), and the U.S. English-language Google searches conducted from January 2008 through September 2010 were compared to snus, nicotine replacement therapy (NRT), and Chantix® or Champix®. Searches for each week were scaled to the highest weekly search proportion (100), with lower values indicating the relative search proportion compared to the highest-proportion week (e.g., 50=50% of the highest observed proportion). Analyses were performed in 2010. From July 2008 through February 2010, ENDS searches increased in all nations studied except Australia, there an increase occurred more recently. By September 2010, ENDS searches were several-hundred-fold greater than searches for smoking alternatives in the UK and U.S., and were rivaling alternatives in Australia and Canada. Across nations, ENDS searches were highest in the U.S., followed by similar search intensity in Canada and the UK, with Australia having the fewest ENDS searches. Stronger tobacco control, created by clean indoor air laws, cigarette taxes, and anti-smoking populations, were associated with consistently higher levels of ENDS searches. The online popularity of ENDS has surpassed that of snus and NRTs, which have been on the market for far longer, and is quickly outpacing Chantix or Champix. In part, the association between ENDS's popularity and stronger tobacco control suggests ENDS are used to bypass, or quit in response to, smoking restrictions. Search query surveillance is a valuable, real-time, free, and public method to evaluate the diffusion of new health products. This method may be generalized to other behavioral, biological, informational, or psychological outcomes manifested on search engines. Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc

  19. Dosimetric perturbation due to scattered rays released by a gold marker used for tumor tracking in external radiotherapy

    International Nuclear Information System (INIS)

    Habara, Kosaku; Furukawa, Takashi; Shimozato, Tomohiro; Obata, Yasunori; Aoyama, Yuichi; Kawanami, Ryota; Hayashi, Naoki; Yasui, Keisuke; Matsuura, Kanji

    2011-01-01

    Image-guided radiation therapy using a gold marker-based tumor tracking technique provides precise patient setup and monitoring. However, the marker consists of high-Z material, and the resulting scattered rays tend to have adverse effects on the dose distribution of radiotherapy. The purpose of this study was to evaluate the dosimetric perturbation due to the use of a gold marker for radiotherapy in the lungs. The relative dose distributions were compared with film measurement, Monte Carlo simulation, and XiO calculation with the multi grid superposition algorithm using two types of virtual lung phantoms, which were composed of tough water phantoms, tough lung phantoms, cork boards, and a 2.0-mm-diameter gold ball. No dose increase and decrease in the vicinity of the gold ball was seen in the XiO calculations, although it was seen in the film measurements and the Monte Carlo simulation. The dose perturbation due to a gold marker cannot be evaluated using XiO calculation with the superposition algorithm when the tumor is near a gold marker (especially within 0.5 cm). To rule out the presence of such dose perturbations due to a gold marker, the distance between the gold marker and the tumor must therefore be greater than 0.5 cm. (author)

  20. Quantitative tracking of tumor cells in phase-contrast microscopy exploiting halo artifact pattern

    Science.gov (United States)

    Kang, Mi-Sun; Song, Soo-Min; Lee, Hana; Kim, Myoung-Hee

    2012-03-01

    Tumor cell morphology is closely related to its invasiveness characteristics and migratory behaviors. An invasive tumor cell has a highly irregular shape, whereas a spherical cell is non-metastatic. Thus, quantitative analysis of cell features is crucial to determine tumor malignancy or to test the efficacy of anticancer treatment. We use phase-contrast microscopy to analyze single cell morphology and to monitor its change because it enables observation of long-term activity of living cells without photobleaching and phototoxicity, which is common in other fluorescence-labeled microscopy. Despite this advantage, there are image-level drawbacks to phase-contrast microscopy, such as local light effect and contrast interference ring, among others. Thus, we first applied a local filter to compensate for non-uniform illumination. Then, we used intensity distribution information to detect the cell boundary. In phase-contrast microscopy images, the cell normally appears as a dark region surrounded by a bright halo. As the halo artifact around the cell body is minimal and has an asymmetric diffusion pattern, we calculated the cross-sectional plane that intersected the center of each cell and was orthogonal to the first principal axis. Then, we extracted the dark cell region by level set. However, a dense population of cultured cells still rendered single-cell analysis difficult. Finally, we measured roundness and size to classify tumor cells into malignant and benign groups. We validated segmentation accuracy by comparing our findings with manually obtained results.

  1. Tumor pHe-triggered charge-reversal and redox-responsive nanoparticles for docetaxel delivery in hepatocellular carcinoma treatment

    Science.gov (United States)

    Chen, Fengqian; Zhang, Jinming; Wang, Lu; Wang, Yitao; Chen, Meiwan

    2015-09-01

    The insufficient cellular uptake of nanocarriers and their slow drug release have become major obstacles for achieving satisfactory anticancer outcomes in nano-medicine therapy. Because of the slightly acidic extracellular environment (pHe ~ 6.5) and a higher glutathione (GSH) concentration (approximately 10 mM) in tumor tissue/cells, we firstly designed a novel d-α-tocopheryl polyethylene glycol 1000-poly(β-amino ester) block copolymer containing disulfide linkages (TPSS). TPSS nanoparticles (NPs) with pH- and redox-sensitive behaviors were developed for on-demand delivery of docetaxel (DTX) in hepatocellular carcinoma. DTX/TPSS NPs exhibited sensitive surface charge reversal from -47.6 +/- 2.5 mV to +22.5 +/- 3.2 mV when the pH decreased from 7.4 to 6.5, to simulate the pHe. Meanwhile, anabatic drug release of DTX/TPSS NPs was observed in PBS buffer (pH 6.5, 10 mM GSH). Due to the synergism between the pHe-triggered charge reversal and the redox-triggered drug release, enhanced drug uptake and anticancer efficacy were observed in HepG2 and SMMC 7721 cells treated with DTX/TPSS NPs. The positively charged NPs exhibited a stronger inhibitory effect on cell proliferation, promoted cell cycle arrest in the G2/M phase, and increased the rate of apoptosis. More importantly, based on the higher tumor accumulation of TPSS vehicles in vivo, a significant suppression of tumor growth, but without side-effects, was observed when DTX/TPSS NPs were injected intravenously into HepG2 xenograft tumor-bearing mice. Collectively, these results demonstrate that the newly developed dual-functional TPSS copolymer may be utilized as a drug delivery system for anticancer therapy.The insufficient cellular uptake of nanocarriers and their slow drug release have become major obstacles for achieving satisfactory anticancer outcomes in nano-medicine therapy. Because of the slightly acidic extracellular environment (pHe ~ 6.5) and a higher glutathione (GSH) concentration (approximately 10 m

  2. Gene silencing in primary and metastatic tumors by small interfering RNA delivery in mice: quantitative analysis using melanoma cells expressing firefly and sea pansy luciferases.

    Science.gov (United States)

    Takahashi, Yuki; Nishikawa, Makiya; Kobayashi, Naoki; Takakura, Yoshinobu

    2005-07-20

    Silencing of oncogenes or other genes contributing to tumor malignancy or progression by RNA interference (RNAi) offers a promising approach to treating tumor patients. To achieve RNAi-based tumor therapy, a small interfering RNA (siRNA) or siRNA-expressing vector needs to be delivered to tumor cells, but little information about its in vivo delivery has been reported. In this study, we examined whether the expression of the target gene in tumor cells can be suppressed by the delivery of RNAi effectors to primary and metastatic tumor cells. To quantitatively evaluate the RNAi effects in tumor cells, mouse melanoma B16-BL6 cells were stably transfected with both firefly (a model target gene) and sea pansy (an internal standard gene) luciferase genes to obtain B16-BL6/dual Luc cells. The target gene expression in subcutaneous primary tumors of B16-BL6/dual Luc cells was significantly suppressed by direct injection of the RNAi effectors followed by electroporation. The expression in metastatic hepatic tumors was also significantly reduced by an intravenous injection of either RNAi effector by the hydrodynamics-based procedure. These results indicate that the both RNAi effectors have a potential to silence target gene in tumor cells in vivo when successfully delivered to tumor cells.

  3. The effects of tumor motion on planning and delivery of respiratory-gated IMRT

    International Nuclear Information System (INIS)

    Hugo, Geoffrey D.; Agazaryan, Nzhde; Solberg, Timothy D.

    2003-01-01

    The purpose of this study is to investigate the effects of object motion on the planning and delivery of IMRT. Two phantoms containing objects were imaged using CT under a variety of motion conditions. The effects of object motion on axial CT acquisition with and without gating were assessed qualitatively and quantitatively. Measurements of effective slice width and position for the CT scans were made. Mutual information image fusion was adapted for use as a quantitative measure of object deformation in CT images. IMRT plans were generated on the CT scans of the moving and gated object images. These plans were delivered with motion, with and without gating, and the delivery error between the moving deliveries and a nonmoving delivery was assessed using a scalable vector-based index. Motion during CT acquisition produces motion artifact, object deformation, and object mispositioning, which can be substantially reduced with gating. Objects that vary in cross section in the direction of motion exhibit the most deformation in CT images. Mutual information provides a useful quantitative estimate of object deformation. The delivery of IMRT in the presence of target motion significantly alters the delivered dose distribution in relation to the planned distribution. The utilization of gating for IMRT treatment, including imaging, planning, and delivery, significantly reduces the errors introduced by object motion

  4. A Bayesian approach to real-time 3D tumor localization via monoscopic x-ray imaging during treatment delivery

    International Nuclear Information System (INIS)

    Li, Ruijiang; Fahimian, Benjamin P.; Xing, Lei

    2011-01-01

    Purpose: Monoscopic x-ray imaging with on-board kV devices is an attractive approach for real-time image guidance in modern radiation therapy such as VMAT or IMRT, but it falls short in providing reliable information along the direction of imaging x-ray. By effectively taking consideration of projection data at prior times and/or angles through a Bayesian formalism, the authors develop an algorithm for real-time and full 3D tumor localization with a single x-ray imager during treatment delivery. Methods: First, a prior probability density function is constructed using the 2D tumor locations on the projection images acquired during patient setup. Whenever an x-ray image is acquired during the treatment delivery, the corresponding 2D tumor location on the imager is used to update the likelihood function. The unresolved third dimension is obtained by maximizing the posterior probability distribution. The algorithm can also be used in a retrospective fashion when all the projection images during the treatment delivery are used for 3D localization purposes. The algorithm does not involve complex optimization of any model parameter and therefore can be used in a ''plug-and-play'' fashion. The authors validated the algorithm using (1) simulated 3D linear and elliptic motion and (2) 3D tumor motion trajectories of a lung and a pancreas patient reproduced by a physical phantom. Continuous kV images were acquired over a full gantry rotation with the Varian TrueBeam on-board imaging system. Three scenarios were considered: fluoroscopic setup, cone beam CT setup, and retrospective analysis. Results: For the simulation study, the RMS 3D localization error is 1.2 and 2.4 mm for the linear and elliptic motions, respectively. For the phantom experiments, the 3D localization error is < 1 mm on average and < 1.5 mm at 95th percentile in the lung and pancreas cases for all three scenarios. The difference in 3D localization error for different scenarios is small and is not

  5. Evaluation of RGD-targeted albumin carriers for specific delivery of auristatin E to tumor blood vessels.

    Science.gov (United States)

    Temming, Kai; Meyer, Damon L; Zabinski, Roger; Dijkers, Eli C F; Poelstra, Klaas; Molema, Grietje; Kok, Robbert J

    2006-01-01

    Induction of apoptosis in endothelial cells is considered an attractive strategy to therapeutically interfere with a solid tumor's blood supply. In the present paper, we constructed cytotoxic conjugates that specifically target angiogenic endothelial cells, thus preventing typical side effects of apoptosis-inducing drugs. For this purpose, we conjugated the potent antimitotic agent monomethyl-auristatin-E (MMAE) via a lysosomal cleavable linker to human serum albumin (HSA) and further equipped this drug-albumin conjugate with cyclic c(RGDfK) peptides for multivalent interaction with alphavbeta3-integrin. The RGD-peptides were conjugated via either an extended poly(ethylene glycol) linker or a short alkyl linker. The resulting drug-targeting conjugates RGDPEG-MMAE-HSA and RGD-MMAE-HSA demonstrated high binding affinity and specificity for alphavbeta3-integrin expressing human umbilical vein endothelial cells (HUVEC). Both types of conjugates were internalized by endothelial cells and killed the target cells at low nM concentrations. Furthermore, we observed RGD-dependent binding of the conjugates to C26 carcinoma. Upon i.v. administration to C26-tumor bearing mice, both drug-targeting conjugates displayed excellent tumor homing properties. Our results demonstrate that RGD-modified albumins are suitable carriers for cell selective intracellular delivery of cytotoxic compounds, and further studies will be conducted to assess the antivascular and tumor inhibitory potential of RGDPEG-MMAE-HSA and RGD-MMAE-HSA.

  6. Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3-Bromopyruvate: A Biodistribution and Survival Study

    Science.gov (United States)

    Vali, Mustafa; Vossen, Josephina A.; Buijs, Manon; Engles, James M.; Liapi, Eleni; Ventura, Veronica Prieto; Khwaja, Afsheen; Acha-Ngwodo, Obele; Shanmugasundaram, Ganapathy; Syed, Labiq; Wahl, Richard L.; Geschwind, Jean-Francois H.

    2009-01-01

    The aim of this study was to determine the biodistribution and tumor targeting ability of 14C-labeled 3-bromopyruvate ([14C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [14C]3-BrPA on tumor and healthy tissue glucose metabolism by determining 18F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [14C]3-BrPA i.a., 1.75 mM [14C]3-BrPA i.v., 20 mM [14C]3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM [14C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [14C]3-BrPA was 1.8 ± 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of [14C]3-BrPA was 0.03 ± 0.01% ID/g. After i.a. administration of [14C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [14C]3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit. PMID:18591216

  7. Development of a real-time internal and external marker tracking system for particle therapy: a phantom study using patient tumor trajectory data.

    Science.gov (United States)

    Cho, Junsang; Cheon, Wonjoong; Ahn, Sanghee; Jung, Hyunuk; Sheen, Heesoon; Park, Hee Chul; Han, Youngyih

    2017-09-01

    Target motion-induced uncertainty in particle therapy is more complicated than that in X-ray therapy, requiring more accurate motion management. Therefore, a hybrid motion-tracking system that can track internal tumor motion and as well as an external surrogate of tumor motion was developed. Recently, many correlation tests between internal and external markers in X-ray therapy have been developed; however, the accuracy of such internal/external marker tracking systems, especially in particle therapy, has not yet been sufficiently tested. In this article, the process of installing an in-house hybrid internal/external motion-tracking system is described and the accuracy level of tracking system was acquired. Our results demonstrated that the developed in-house external/internal combined tracking system has submillimeter accuracy, and can be clinically used as a particle therapy system as well as a simulation system for moving tumor treatment. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  8. Development of the SyncTraX FX4 version real-time tumor tracking system for radiation therapy

    International Nuclear Information System (INIS)

    Ishiyama, Tomoharu; Torigoe, Yui; Nagae, Koudai; Kajiki, Shunsuke; Sano, Takayuki

    2017-01-01

    Based on the current SyncTraX that was developed jointly with Hokkaido University, we have developed the SyncTraX FX4 version, which features not only tumor tracking but also patient positioning. The SyncTraX FX4 version is configured with four fixed x-ray tubes an detectors and eliminated the rail that is used to move the x-ray tube and detector as in the current SyncTraX. This development simplifies limitations on facility construction. We also adopted a distortion free flat panel detector instead of a color I.I., and the additional patient positioning feature will enable the SyncTraX FX4 version to become more widely applied in clinical cases. (author)

  9. NIR fluorescent chitosan-based nanoparticles for tracking and delivery of cancer therapeutic molecule in living systems

    Science.gov (United States)

    Suarato, Giulia; Chin, Amanda; Meng, Yizhi

    2013-03-01

    Tumor metastasis is associated with the epithelial-to-mesenchymal transition (EMT), in which cells lose their polarized phenotype to acquire the asymmetry and motility of mesenchymal cells. Among the many molecular determinants for EMT is bone morphogenetic protein-7 (BMP-7), a critical regulator of skeletal tissue formation and kidney development. Current treatments for metastatic cancer primarily involve surgery and chemotherapy, both with considerable side effects. Therefore the goal of our research is to evaluate the ability of BMP-7 to reverse EMT using a delivery system based on glycol chitosan nanoparticles (GCNP), naturally biodegradable. The GCNP are labeled with Cy5.5, a near infrared (NIR) excitable dye that enables non-invasive imaging in living systems. The chitosan shell provides affinity for the cell surface and protection from intracellular enzymes during transport. Preliminary data show that Cy5.5-GCNP vehicles were successfully delivered to murine preosteoblast (MC3T3-E1), rat osteosarcoma (ROS) 17/2.8 and human embryonic kidney (HEK293) cells. Release kinetics using a model protein (BSA) and BMP-7, and the stability of the protein nano-cargo are currently being evaluated. Cell morphology will be examined with immunofluorescence microscopy.

  10. Ultrasound-Mediated Drug/Gene Delivery in Solid Tumor Treatment

    Directory of Open Access Journals (Sweden)

    Yufeng Zhou

    2013-01-01

    Full Text Available Ultrasound is an emerging modality for drug delivery in chemotherapy. This paper reviews this novel technology by first introducing the designs and characteristics of three classes of drug/gene vehicles, microbubble (including nanoemulsion, liposomes, and micelles. In comparison to conventional free drug, the targeted drug-release and delivery through vessel wall and interstitial space to cancerous cells can be activated and enhanced under certain sonication conditions. In the acoustic field, there are several reactions of these drug vehicles, including hyperthermia, bubble cavitation, sonoporation, and sonodynamics, whose physical properties are illustrated for better understanding of this approach. In vitro and in vivo results are summarized, and future directions are discussed. Altogether, ultrasound-mediated drug/gene delivery under imaging guidance provides a promising option in cancer treatment with enhanced agent release and site specificity and reduced toxicity.

  11. Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Wang Q

    2015-07-01

    Full Text Available Qingbing Wang,1,2 Jianfeng Li,3 Sai An,3 Yi Chen,1 Chen Jiang,3 Xiaolin Wang1,2 1Department of Interventional Radiology, Zhongshan Hospital, Fudan University, 2Shanghai Institute of Medical Imaging, 3Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China Background: Gene therapy is a very promising technology for treatment of pancreatic ductal adenocarcinoma (PDAC. However, its application has been limited by the abundant stromal response in the tumor microenvironment. The aim of this study was to prepare a dendrimer-based gene-free loading vector with high permeability in the tumor stroma and explore an imaging-guided local gene delivery strategy for PDAC to promote the efficiency of targeted gene delivery.Methods: The experimental protocol was approved by the animal ethics committee of Zhongshan Hospital, Fudan University. Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd chelates. DNA plasmids were loaded with these nanocarriers via electrostatic interaction. The cellular uptake and loaded gene expression were examined in MIA PaCa-2 cell lines in vitro. Permeability of the nanoparticles in the tumor stroma and transfected gene distribution in vivo were studied using a magnetic resonance imaging-guided delivery strategy in an orthotopic nude mouse model of PDAC.Results: The nanocarriers were synthesized with a dendrigraft poly-L-lysine to polyethylene glycol to DTPA ratio of 1:3.4:8.3 and a mean diameter of 110.9±7.7 nm. The luciferases were strictly expressed in the tumor, and the luminescence intensity in mice treated by Gd-DPT/plasmid luciferase (1.04×104±9.75×102 p/s/cm2/sr was significantly (P<0.05 higher than in those treated with Gd-DTPA (9.56×102±6.15×10 p/s/cm2/sr and Gd-DP (5.75×103± 7.45×102 p/s/cm2/sr

  12. A simple reduction-sensitive micelles co-delivery of paclitaxel and dasatinib to overcome tumor multidrug resistance

    Directory of Open Access Journals (Sweden)

    Li J

    2017-11-01

    Full Text Available Jun Li,1,* Ruitong Xu,2,* Xiao Lu,3 Jing He,1 Shidai Jin1 1Department of Medical Oncology, 2Department of General Practice, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 3Department of Medical Oncology, Changshu No 1 People’s Hospital, Changshu, People’s Republic of China *These authors contributed equally to this work Abstract: Multidrug resistance (MDR is one of the major obstacles in successful chemotherapy. The combination of chemotherapy drugs and multidrug-resistant reversing agents for treating MDR tumor is a good strategy to overcome MDR. In this work, we prepared the simple redox-responsive micelles based on mPEG-SS-C18 as a co-delivery system to load the paclitaxel (PTX and dasatinib (DAS for treatment of MCF-7/ADR cells. The co-loaded micelles had a good dispersity and a spherical shape with a uniform size distribution, and they could quickly disassemble and rapidly release drugs under the reduction environment. Compared with MCF-7 cells, the DAS and PTX co-loaded redox-sensitive micelle (SS-PDNPs showed stronger cytotoxicity and a more improving intracellular drug concentration than other drug formulations in MCF-7/ADR cells. In summary, the results suggested that the simple co-delivery micelles of PTX and DAS possessed significant potential to overcome drug resistance in cancer therapy. Keywords: redox responsive, overcoming multidrug resistant, co-delivery, paclitaxel, dasatinib 

  13. Clinical application of fiber tracking technique for neuronavigation in brain tumor surgery

    International Nuclear Information System (INIS)

    Kamada, Kyousuke; Aoki, Shigeki; Masutani, Yoshitaka; Ino, Kenji; Todo, Tomoki; Kawai, Kensuke; Ota, Takahiro; Saito, Nobuhito

    2007-01-01

    Preserving brain functions while maximizing tumor resection is the basic strategy to prolong survival of patients with brain tumors while maintaining their quality of life. In order for better preoperative planning and direct application to intraoperative procedures, we achieved accurate co-registration of diffusion tensor imaging (DTI) -based tractography and anatomical MRI, and imported the combined images to a neuronavigation system (functional neuronavigation). Forty patients with brain lesions adjacent to the corticospinal tract (CST; n=32) and optic radiation (OR; n=8) were studied. During surgery, direct fiber stimulation was used to evoke the motor responses to confirm the accuracy of CST depicted on the functional neuronavigation. Cortical visual evoked potentials (VEPs) with flash stimulation were continuously monitored. In 25 patients, stimulation of the supposed CST led to elicitation of expected motor-evoked potentials. In the seven, stimulation at resection borders more than 1.5 cm apart from the supposed CST showed no motor responses. When the resection reached the OR on the functional neuronavigation, the cortical VEP suddenly diminished in two of 8 patients. Integration of DTI-based tractography information into a traditional neuronavigation system allowed demonstration of spatial relationships between lesions and the CST, leading to avoidance of tract injury during lesion resection. (author)

  14. Hydrolytically degradable polymer micelles for anticancer drug delivery to solid tumors

    Czech Academy of Sciences Publication Activity Database

    Chytil, Petr; Etrych, Tomáš; Kostka, Libor; Ulbrich, Karel

    2012-01-01

    Roč. 213, č. 8 (2012), s. 858-867 ISSN 1022-1352 R&D Projects: GA AV ČR IAAX00500803; GA ČR GAP301/11/0325 Institutional research plan: CEZ:AV0Z40500505 Keywords : HPMA copolymers * drug delivery systems * doxorubicin Subject RIV: EC - Immunology Impact factor: 2.386, year: 2012

  15. MO-FG-BRD-01: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: Introduction and KV Tracking

    International Nuclear Information System (INIS)

    Fahimian, B.

    2015-01-01

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow

  16. MO-FG-BRD-02: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: MV Tracking

    Energy Technology Data Exchange (ETDEWEB)

    Berbeco, R. [Brigham and Women’s Hospital and Dana-Farber Cancer Institute (United States)

    2015-06-15

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow.

  17. MO-FG-BRD-04: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: MR Tracking

    Energy Technology Data Exchange (ETDEWEB)

    Low, D. [University of California Los Angeles: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: MR Tracking (United States)

    2015-06-15

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow.

  18. MO-FG-BRD-03: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: EM Tracking

    Energy Technology Data Exchange (ETDEWEB)

    Keall, P. [University of Sydney (Australia)

    2015-06-15

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow.

  19. MO-FG-BRD-01: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: Introduction and KV Tracking

    Energy Technology Data Exchange (ETDEWEB)

    Fahimian, B. [Stanford University (United States)

    2015-06-15

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow.

  20. MO-FG-BRD-04: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: MR Tracking

    International Nuclear Information System (INIS)

    Low, D.

    2015-01-01

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow

  1. MO-FG-BRD-03: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: EM Tracking

    International Nuclear Information System (INIS)

    Keall, P.

    2015-01-01

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow

  2. MO-FG-BRD-02: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management: MV Tracking

    International Nuclear Information System (INIS)

    Berbeco, R.

    2015-01-01

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow

  3. Synthesis and evaluation of ligand targeting the somatostatin receptor for drug delivery to tumor cell

    Energy Technology Data Exchange (ETDEWEB)

    Lee, So Young; Hong, Young Don; Jung, Sung Hee; Choi, Sun Ju [Radioisotope Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-12-15

    Most of targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells to produce its cytotoxic effect. Either small molecule drugs or monoclonal antibodies are mostly used in targeted therapies. Unfortunately, targeted therapy has a certain degree of unwanted side effect like other cytotoxicity inducing chemotherapies. To overcome and to reduce unwanted side effects during a cancer therapy, recently radiopeptide therapies has got the worlds' attraction for the tumor targeting modalities due to its beneficial effect on less side effect compared to cytotoxic chemotherapies. Among radiopeptide therapies, {sup 177}Lu-DOTATATE is a major modality as an effective one invented so far in treating neuroendocrine tumor (NET) and it has been in clinical trials at least one decade. Although it does have rather effective therapeutic effect on NET, it has less effective in rather large solid tumor. There are many ways to improve or increase therapeutic effect of radiopeptide are a finding the potent small molecules to target the tumor site selectively, or a labeling with radioisotope of emitting high energy, or an improving its biological half-life by introducing different moieties to increase lipophilicity. Present study was focus to increase a biological halflife of radio somatostatin which will target the somatostatin receptor by altering the bifunctional chelator (BFCA) by introducing lipophilic moiety to the somatostatin, which would make the labeled peptide stay longer in the tumor site and thus it can intensify the therapeutic effect on tumor cell itself and around tissues.

  4. Optimizing the Delivery of Short-Lived Alpha Particle-Emitting Isotopes to Solid Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Adams, Gregory P.

    2004-11-24

    The underlying hypothesis of this project was that optimal alpha emitter-based radioimmunotherapy (RAIT) could be achieved by pairing the physical half-life of the radioisotope to the biological half-life of the targeting vehicle. The project had two specific aims. The first aim was to create and optimize the therapeutic efficacy of 211At-SAPS-C6.5 diabody conjugates. The second aim was to develop bispecific-targeting strategies that increase the specificity and efficacy of alpha-emitter-based RAIT. In the performance of the first aim, we created 211At-SAPS-C6.5 diabody conjugates that specifically targeted the HER2 tumor associated antigen. In evaluating these immunoconjugates we determined that they were capable of efficient tumor targeting and therapeutic efficacy of established human tumor xenografts growing in immunodeficient mice. We also determined that therapeutic doses were associated with late renal toxicity, likely due to the role of the kidneys in the systemic elimination o f these agents. We are currently performing more studies focused on better understanding the observed toxicity. In the second aim, we successfully generated bispecific single-chain Fv (bs-scFv) molecules that co-targeted HER2 and HER3 or HER2 and HER4. The in vitro kinetics and in vivo tumor-targeting properties of these molecules were evaluated. These studies revealed that the bs-scFv molecules selectively localized in vitro on tumor cells that expressed both antigens and were capable of effective tumor localization in in vivo studies.

  5. Optimizing the Delivery of Short-Lived Alpha Particle-Emitting Isotopes to Solid Tumors

    International Nuclear Information System (INIS)

    Adams, Gregory P.

    2004-01-01

    The underlying hypothesis of this project was that optimal alpha emitter-based radioimmunotherapy (RAIT) could be achieved by pairing the physical half-life of the radioisotope to the biological half-life of the targeting vehicle. The project had two specific aims. The first aim was to create and optimize the therapeutic efficacy of 211At-SAPS-C6.5 diabody conjugates. The second aim was to develop bispecific-targeting strategies that increase the specificity and efficacy of alpha-emitter-based RAIT. In the performance of the first aim, we created 211At-SAPS-C6.5 diabody conjugates that specifically targeted the HER2 tumor associated antigen. In evaluating these immunoconjugates we determined that they were capable of efficient tumor targeting and therapeutic efficacy of established human tumor xenografts growing in immunodeficient mice. We also determined that therapeutic doses were associated with late renal toxicity, likely due to the role of the kidneys in the systemic elimination o f these agents. We are currently performing more studies focused on better understanding the observed toxicity. In the second aim, we successfully generated bispecific single-chain Fv (bs-scFv) molecules that co-targeted HER2 and HER3 or HER2 and HER4. The in vitro kinetics and in vivo tumor-targeting properties of these molecules were evaluated. These studies revealed that the bs-scFv molecules selectively localized in vitro on tumor cells that expressed both antigens and were capable of effective tumor localization in in vivo studies

  6. Effective experimental tumor therapy with targeted polymer drug delivery systems based on HPMA copolymers.

    Czech Academy of Sciences Publication Activity Database

    Šírová, Milada; Horková, Veronika; Sivák, Ladislav; Etrych, Tomáš; Říhová, Blanka; Studenovský, Martin

    SI (2016), s. 24-24 ISSN 0014-2980. [3rd Meeting of Middle – European Societies for Immunology and Allergology. 01.12.2016-03.12.2016, Budapest ] R&D Projects: GA ČR(CZ) GA14-12742S Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Tumor therapy * polymer drug * HPMA copolymers Subject RIV: EE - Microbiology, Virology

  7. Complement inhibition enables tumor delivery of LCMV glycoprotein pseudotyped viruses in the presence of antiviral antibodies

    Directory of Open Access Journals (Sweden)

    Laura Evgin

    2016-01-01

    Full Text Available The systemic delivery of therapeutic viruses, such as oncolytic viruses or vaccines, is limited by the generation of neutralizing antibodies. While pseudotyping of rhabdoviruses with the lymphocytic choriomeningitis virus glycoprotein has previously allowed for multiple rounds of delivery in mice, this strategy has not translated to other animal models. For the first time, we provide experimental evidence that antibodies generated against the lymphocytic choriomeningitis virus glycoprotein mediate robust complement-dependent viral neutralization via activation of the classical pathway. We show that this phenotype can be capitalized upon to deliver maraba virus pseudotyped with the lymphocytic choriomeningitis virus glycoprotein in a Fischer rat model in the face of neutralizing antibody through the use of complement modulators. This finding changes the understanding of the humoral immune response to arenaviruses, and also describes methodology to deliver viral vectors to their therapeutic sites of action without the interference of neutralizing antibody.

  8. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    Directory of Open Access Journals (Sweden)

    John C. Leach

    2016-03-01

    Full Text Available The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA, was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

  9. Investigation of the change in marker geometry during respiration motion: a preliminary study for dynamic-multi-leaf real-time tumor tracking

    International Nuclear Information System (INIS)

    Yamazaki, Rie; Nishioka, Seiko; Date, Hiroyuki; Shirato, Hiroki; Koike, Takao; Nishioka, Takeshi

    2012-01-01

    The use of stereotactic body radiotherapy (SBRT) is rapidly increasing. Presently, the most accurate method uses fiducial markers implanted near the tumor. A shortcoming of this method is that the beams turn off during the majority of the respiratory cycle, resulting in a prolonged treatment time. Recent advances in collimation technology have enabled continuous irradiation to a moving tumor. However, the lung is a dynamic organ characterized by inhalation exhalation cycles, during which marker/tumor geometry may change (i.e., misalignment), resulting in under-dosing to the tumor. Eight patients with lung cancer who were candidates for stereotactic radiotherapy were examined with 4D high-resolution CT. As a marker surrogate, virtual bronchoscopy using the pulmonary artery (VBPA) was conducted. To detect possible marker/tumor misalignment during the respiration cycle, the distance between the peripheral bronchus, where a marker could be implanted, and the center of gravity of a tumor were calculated for each respiratory phase. When the respiration cycle was divided into 10 phases, the median value was significantly larger for the 30%-70% respiratory phases compared to that for the 10% respiratory phase (P<0.05, Mann–Whitney U-test). These results demonstrate that physiological aspect must be considered when continuous tumor tracking is applied to a moving tumor. To minimize an “additional” internal target volume (ITV) margin, a marker should be placed approximately 2.5 cm from the tumor

  10. Nanodrug-enhanced radiofrequency tumor ablation: effect of micellar or liposomal carrier on drug delivery and treatment efficacy.

    Directory of Open Access Journals (Sweden)

    Marwan Moussa

    Full Text Available To determine the effect of different drug-loaded nanocarriers (micelles and liposomes on delivery and treatment efficacy for radiofrequency ablation (RFA combined with nanodrugs.Fischer 344 rats were used (n = 196. First, single subcutaneous R3230 tumors or normal liver underwent RFA followed by immediate administration of i.v. fluorescent beads (20, 100, and 500 nm, with fluorescent intensity measured at 4-24 hr. Next, to study carrier type on drug efficiency, RFA was combined with micellar (20 nm or liposomal (100 nm preparations of doxorubicin (Dox; targeting HIF-1α or quercetin (Qu; targeting HSP70. Animals received RFA alone, RFA with Lipo-Dox or Mic-Dox (1 mg i.v., 15 min post-RFA, and RFA with Lipo-Qu or Mic-Qu given 24 hr pre- or 15 min post-RFA (0.3 mg i.v.. Tumor coagulation and HIF-1α or HSP70 expression were assessed 24 hr post-RFA. Third, the effect of RFA combined with i.v. Lipo-Dox, Mic-Dox, Lipo-Qu, or Mic-Qu (15 min post-RFA compared to RFA alone on tumor growth and animal endpoint survival was evaluated. Finally, drug uptake was compared between RFA/Lipo-Dox and RFA/Mic-Dox at 4-72 hr.Smaller 20 nm beads had greater deposition and deeper tissue penetration in both tumor (100 nm/500 nm and liver (100 nm (p<0.05. Mic-Dox and Mic-Qu suppressed periablational HIF-1α or HSP70 rim thickness more than liposomal preparations (p<0.05. RFA/Mic-Dox had greater early (4 hr intratumoral doxorubicin, but RFA/Lipo-Dox had progressively higher intratumoral doxorubicin at 24-72 hr post-RFA (p<0.04. No difference in tumor growth and survival was seen between RFA/Lipo-Qu and RFA/Mic-Qu. Yet, RFA/Lipo-Dox led to greater animal endpoint survival compared to RFA/Mic-Dox (p<0.03.With RF ablation, smaller particle micelles have superior penetration and more effective local molecular modulation. However, larger long-circulating liposomal carriers can result in greater intratumoral drug accumulation over time and reduced tumor growth. Accordingly

  11. Novel functionalized nanoparticles for tumor-targeting co-delivery of doxorubicin and siRNA to enhance cancer therapy

    Directory of Open Access Journals (Sweden)

    Xia Y

    2017-12-01

    Full Text Available Yu Xia, Tiantian Xu, Changbing Wang, Yinghua Li, Zhengfang Lin, Mingqi Zhao, Bing Zhu Central Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China Abstract: Human homeobox protein (Nanog is highly expressed in most cancer cells and has gradually emerged as an excellent target in cancer therapy, owing to its regulation of cancer cell proliferation, metastasis and apoptosis. In this study, we prepared tumor-targeting functionalized selenium nanoparticles (RGDfC-SeNPs to load chemotherapeutic doxorubicin (DOX and Nanog siRNA. Herein, RGDfC peptide was used as a tumor-targeting moiety which could specifically bind to αvβ3 integrins overexpressed on various cancer cells. The sizes of RGDfC-SeNPs@DOX nanoparticles (~12 nm were confirmed by both dynamic light scattering and transmission electron microscopy. The chemical structure of RGDfC-SeNPs@DOX was characterized via Fourier-transform infrared spectroscopy. The RGDfC-SeNPs@DOX was compacted with siRNA (anti-Nanog by electrostatic interaction to fabricate the RGDfC-SeNPs@DOX/siRNA complex. The RGDfC-SeNPs@DOX/siRNA complex nanoparticles could efficiently enter into HepG2 cells via clathrin-associated endocytosis, and showed high gene transfection efficiency that resulted in enhanced gene silencing. The in vivo biodistribution experiment indicated that RGDfC-SeNPs@DOX/siRNA nanoparticles were capable of specifically accumulating in the tumor site. Furthermore, treatment with RGDfC-SeNPs@DOX/siRNA resulted in a more significant anticancer activity than the free DOX, RGDfC-SeNPs@DOX or RGDfC-SeNPs/siRNA in vitro and in vivo. In summary, this study shows a novel type of DOX and siRNA co-delivery system, thereby providing an alternative route for cancer treatment. Keywords: nanoparticles, tumor targeting, drug delivery, doxorubicin, Nanog siRNA

  12. Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery

    OpenAIRE

    Seitz, Joshua; Vineberg, Jacob G.; Zuniga, Edison S.; Ojima, Iwao

    2013-01-01

    A long-standing problem of conventional chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Consequently, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, incl...

  13. The development of a 4D treatment planning methodology to simulate the tracking of central lung tumors in an MRI-linac.

    Science.gov (United States)

    Al-Ward, Shahad M; Kim, Anthony; McCann, Claire; Ruschin, Mark; Cheung, Patrick; Sahgal, Arjun; Keller, Brian M

    2018-01-01

    Targeting and tracking of central lung tumors may be feasible on the Elekta MRI-linac (MRL) due to the soft-tissue visualization capabilities of MRI. The purpose of this work is to develop a novel treatment planning methodology to simulate tracking of central lung tumors with the MRL and to quantify the benefits in OAR sparing compared with the ITV approach. Full 4D-CT datasets for five central lung cancer patients were selected to simulate the condition of having 4D-pseudo-CTs derived from 4D-MRI data available on the MRL with real-time tracking capabilities. We used the MRL treatment planning system to generate two plans: (a) with a set of MLC-defined apertures around the target at each phase of the breathing ("4D-MRL" method); (b) with a fixed set of fields encompassing the maximum inhale and exhale of the breathing cycle ("ITV" method). For both plans, dose accumulation was performed onto a reference phase. To further study the potential benefits of a 4D-MRL method, the results were stratified by tumor motion amplitude, OAR-to-tumor proximity, and the relative OAR motion (ROM). With the 4D-MRL method, the reduction in mean doses was up to 3.0 Gy and 1.9 Gy for the heart and the lung. Moreover, the lung's V12.5 Gy was spared by a maximum of 300 cc. Maximum doses to serial organs were reduced by up to 6.1 Gy, 1.5 Gy, and 9.0 Gy for the esophagus, spinal cord, and the trachea, respectively. OAR dose reduction with our method depended on the tumor motion amplitude and the ROM. Some OARs with large ROMs and in close proximity to the tumor benefited from tracking despite small tumor amplitudes. We developed a novel 4D tracking methodology for the MRL for central lung tumors and quantified the potential dosimetric benefits compared with our current ITV approach. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

  14. Folate-decorated chitosan/doxorubicin poly(butyl)cyanoacrylate nanoparticles for tumor-targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Duan Jinghua [Xiangya Hospital, Central South University, Hepatobiliary and Enteric Surgery Research Center (China); Liu Mujun [Central South University, School of Biological Science and Technology (China); Zhang Yangde; Zhao Jinfeng; Pan Yifeng [Xiangya Hospital, Central South University, Hepatobiliary and Enteric Surgery Research Center (China); Yang Xiyun, E-mail: bax_2007@126.com [Central South University, School of Metallurgical Science and Engineering (China)

    2012-03-15

    A novel chitosan coated poly(butyl cyanoacrylate) (PBCA) nanoparticles loaded doxorubicin (DOX) were synthesized and then conjugated with folic acid to produce a folate-targeted drug carrier for tumor-specific drug delivery. Prepared nanoparticles were surface modified by folate for targeting cancer cells, which is confirmed by FTIR spectroscopy and characterized for shape, size, and zeta potential measurements. The size and zeta potential of prepared DOX-PBCA nanoparticles (DOX-PBCA NPs) were almost 174 {+-} 8.23 nm and +23.14 {+-} 4.25 mV, respectively with 46.8 {+-} 3.32% encapsulation capacity. The transmission electron microscopy study revealed that preparation allowed the formation of spherical nanometric and homogeneous. Fluorescent microscopy imaging and flow cytometry analysis revealed that DOX-PBCA NPs were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells. The results demonstrate that folate-conjugated DOX-PBCA NPs drug delivery system could provide increased therapeutic benefit by delivering the encapsulated drug to the folate receptor positive cancer cells.

  15. Tumor Angiogenesis Therapy Using Targeted Delivery of Paclitaxel to the Vasculature of Breast Cancer Metastases

    Directory of Open Access Journals (Sweden)

    Shijun Zhu

    2014-01-01

    Full Text Available Breast cancer aberrantly expresses tissue factor (TF in cancer tissues and cancer vascular endothelial cells (VECs. TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa. We have coupled PTX (paclitaxel, also named Taxol with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p<0.01–0.05 compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis.

  16. Development of Surface-Variable Polymeric Nanoparticles for Drug Delivery to Tumors.

    Science.gov (United States)

    Han, Ning; Pang, Liang; Xu, Jun; Hyun, Hyesun; Park, Jinho; Yeo, Yoon

    2017-05-01

    To develop nanoparticle drug carriers that interact with cells specifically in the mildly acidic tumor microenvironment, we produced polymeric nanoparticles modified with amidated TAT peptide via a simple surface modification method. Two types of core poly(lactic-co-glycolic acid) nanoparticles (NL and NP) were prepared with a phospholipid shell as an optional feature and covered with polydopamine that enabled the conjugation of TAT peptide on the surface. Subsequent treatment with acid anhydrides such as cis-aconitic anhydride (CA) and succinic anhydride (SA) converted amines of lysine residues in TAT peptide to β-carboxylic amides, introducing carboxylic groups that undergo pH-dependent protonation and deprotonation. The nanoparticles modified with amidated TAT peptide (NLpT-CA and NPpT-CA) avoided interactions with LS174T colon cancer cells and J774A.1 macrophages at pH 7.4 but restored the ability to interact with LS174T cells at pH 6.5, delivering paclitaxel efficiently to the cells following a brief contact time. In LS174T tumor-bearing nude mice, NPpT-CA showed less accumulation in the lung than NPpT, reflecting the shielding effect of amidation, but tumor accumulation of NPpT and NPpT-CA was equally minimal. Comparison of particle stability and protein corona formation in media containing sera from different species suggests that NPpT-CA has been activated and opsonized in mouse blood to a greater extent than those in bovine serum-containing medium, thus losing the benefits of pH-sensitivity expected from in vitro experiments.

  17. Maternal and Cord Blood Levels of Serum Amyloid A, C-Reactive Protein, Tumor Necrosis Factor-α, Interleukin -1β, and Interleukin-8 During and After Delivery

    Directory of Open Access Journals (Sweden)

    Luciane Marzzullo Cicarelli

    2005-01-01

    after delivery and try to correlate these proteins with tumor necrosis factor-α, interleukin -1β, and interleukin-8. Acute-phase proteins and cytokines were measured by ELISA in 24 healthy pregnant women undergoing vaginal delivery or Cesarean section. Cord blood samples in addition to maternal blood were collected. SAA and CRP reached the maximum maternal serum levels 24 hours after delivery, while cytokines remained constant over time. SAA and CRP were significantly higher in maternal serum than in newborn's (P<.001 at the moment of delivery. SAA and CRP, regardless of the type of delivery, reproduce the common pattern observed in most inflammatory conditions. Proinflammatory cytokine serum levels do not mirror the increase in SAA and CRP levels.

  18. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Dolores Hernán Pérez de la Ossa

    Full Text Available Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9-Tetrahydrocannabinol (THC and Cannabidiol (CBD - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

  19. Reactor beam calculations to determine optimum delivery of epithermal neutrons for treatment of brain tumors

    International Nuclear Information System (INIS)

    Wheeler, F.J.; Nigg, D.W.; Capala, J.

    1997-01-01

    Studies were performed to assess theoretical tumor control probability (TCP) for brain-tumor treatment with boron neutron capture therapy (BNCT) using epithermal neutron sources from reactors. The existing epithermal-neutron beams at the Brookhaven Medical Research Reactor Facility (BMRR), the Petten High Flux Reactor Facility (HWR) and the Finnish Research Reactor 1 (FIR1) have been analyzed and characterized using common analytical and measurement methods allowing for this inter-comparison. Each of these three facilities is unique and each offers an advantage in some aspect of BNCT, but none of these existing facilities excel in all neutron-beam attributes as related to BNCT. A comparison is therefore also shown for a near-optimum reactor beam which does not currently exist but which would be feasible with existing technology. This hypothetical beam is designated BNCT-1 and has a spectrum similar to the FIR-1, the mono-directionality of the HFR and the intensity of the BMRR. A beam very similar to the BNCT-1 could perhaps be achieved with modification of the BMRR, HFR, or FIR, and could certainly be realized in a new facility with today's technology

  20. CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Single Peripheral Lung Metastases

    Energy Technology Data Exchange (ETDEWEB)

    Snider, James W.; Oermann, Eric K.; Chen, Viola; Rabin, Jennifer; Suy, Simeng; Yu, Xia [Department of Radiation Medicine, Georgetown University Hospital, Washington, DC (United States); Vahdat, Saloomeh [Department of Pathology, Georgetown University Hospital, Washington, DC (United States); Collins, Sean P. [Department of Radiation Medicine, Georgetown University Hospital, Washington, DC (United States); Banovac, Filip [Department of Radiology, Georgetown University Hospital, Washington, DC (United States); Anderson, Eric [Division of Pulmonary, Critical Care and Sleep Medicine, Georgetown University Hospital, Washington, DC (United States); Collins, Brian T., E-mail: collinsb@gunet.georgetown.edu [Department of Radiation Medicine, Georgetown University Hospital, Washington, DC (United States)

    2012-06-29

    Standard treatment for operable patients with single peripheral lung metastases is metastasectomy. We report mature CyberKnife outcomes for high-risk surgical patients with biopsy proven single peripheral lung metastases. Twenty-four patients (median age 73 years) with a mean maximum tumor diameter of 2.5 cm (range, 0.8–4.5 cm) were treated over a 6-year period extending from September 2004 to September 2010 and followed for a minimum of 1 year or until death. A mean dose of 52 Gy (range, 45–60 Gy) was delivered to the prescription isodose line in three fractions over a 3–11 day period (mean, 7 days). At a median follow-up of 20 months, the 2-year Kaplan–Meier local control and overall survival rates were 87 and 50%, respectively. CyberKnife with fiducial tracking is an effective treatment for high-risk surgical patients with single small peripheral lung metastases. Trials comparing CyberKnife with metastasectomy for operable patients are necessary to confirm equivalence.

  1. Ferromagnetic filled carbon nanotubes and nanoparticles: synthesis and lipid-mediated delivery into human tumor cells

    International Nuclear Information System (INIS)

    Moench, I.; Meye, A.; Leonhardt, A.; Kraemer, K.; Kozhuharova, R.; Gemming, T.; Wirth, M.P.; Buechner, B.

    2005-01-01

    We describe the synthesis and the properties of Fe-filled multi-walled carbon nanotubes (MWNTs) and nanoparticles (NP) produced by chemical vapor deposition (CVD). We have employed ferrocene as a starting substance and oxidized Si-wafers as substrates. The magnetic properties and the interaction of the material with bladder cancer cells were determined. After the addition of NP suspensions to cultured cells, no adhesion of the nanoparticles/nanotubes (NT/NP) to the cell membrane and also no cellular uptake were observed. However, the preincubation of the (NT/NP) suspension with cationic lipid caused an efficient delivery of the lipid-nanostructure complexes into the cytoplasm within 2 h after adding to the culture medium

  2. SU-G-BRA-10: Marker Free Lung Tumor Motion Tracking by An Active Contour Model On Cone Beam CT Projections for Stereotactic Body Radiation Therapy of Lung Cancer

    International Nuclear Information System (INIS)

    Chao, M; Yuan, Y; Lo, Y; Wei, J

    2016-01-01

    Purpose: To develop a novel strategy to extract the lung tumor motion from cone beam CT (CBCT) projections by an active contour model with interpolated respiration learned from diaphragm motion. Methods: Tumor tracking on CBCT projections was accomplished with the templates derived from planning CT (pCT). There are three major steps in the proposed algorithm: 1) The pCT was modified to form two CT sets: a tumor removed pCT and a tumor only pCT, the respective digitally reconstructed radiographs DRRtr and DRRto following the same geometry of the CBCT projections were generated correspondingly. 2) The DRRtr was rigidly registered with the CBCT projections on the frame-by-frame basis. Difference images between CBCT projections and the registered DRRtr were generated where the tumor visibility was appreciably enhanced. 3) An active contour method was applied to track the tumor motion on the tumor enhanced projections with DRRto as templates to initialize the tumor tracking while the respiratory motion was compensated for by interpolating the diaphragm motion estimated by our novel constrained linear regression approach. CBCT and pCT from five patients undergoing stereotactic body radiotherapy were included in addition to scans from a Quasar phantom programmed with known motion. Manual tumor tracking was performed on CBCT projections and was compared to the automatic tracking to evaluate the algorithm accuracy. Results: The phantom study showed that the error between the automatic tracking and the ground truth was within 0.2mm. For the patients the discrepancy between the calculation and the manual tracking was between 1.4 and 2.2 mm depending on the location and shape of the lung tumor. Similar patterns were observed in the frequency domain. Conclusion: The new algorithm demonstrated the feasibility to track the lung tumor from noisy CBCT projections, providing a potential solution to better motion management for lung radiation therapy.

  3. SU-G-BRA-10: Marker Free Lung Tumor Motion Tracking by An Active Contour Model On Cone Beam CT Projections for Stereotactic Body Radiation Therapy of Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chao, M; Yuan, Y; Lo, Y [The Mount Sinai Medical Center, New York, NY (United States); Wei, J [City College of New York, New York, NY (United States)

    2016-06-15

    Purpose: To develop a novel strategy to extract the lung tumor motion from cone beam CT (CBCT) projections by an active contour model with interpolated respiration learned from diaphragm motion. Methods: Tumor tracking on CBCT projections was accomplished with the templates derived from planning CT (pCT). There are three major steps in the proposed algorithm: 1) The pCT was modified to form two CT sets: a tumor removed pCT and a tumor only pCT, the respective digitally reconstructed radiographs DRRtr and DRRto following the same geometry of the CBCT projections were generated correspondingly. 2) The DRRtr was rigidly registered with the CBCT projections on the frame-by-frame basis. Difference images between CBCT projections and the registered DRRtr were generated where the tumor visibility was appreciably enhanced. 3) An active contour method was applied to track the tumor motion on the tumor enhanced projections with DRRto as templates to initialize the tumor tracking while the respiratory motion was compensated for by interpolating the diaphragm motion estimated by our novel constrained linear regression approach. CBCT and pCT from five patients undergoing stereotactic body radiotherapy were included in addition to scans from a Quasar phantom programmed with known motion. Manual tumor tracking was performed on CBCT projections and was compared to the automatic tracking to evaluate the algorithm accuracy. Results: The phantom study showed that the error between the automatic tracking and the ground truth was within 0.2mm. For the patients the discrepancy between the calculation and the manual tracking was between 1.4 and 2.2 mm depending on the location and shape of the lung tumor. Similar patterns were observed in the frequency domain. Conclusion: The new algorithm demonstrated the feasibility to track the lung tumor from noisy CBCT projections, providing a potential solution to better motion management for lung radiation therapy.

  4. Effect of antigen shedding on targeted delivery of immunotoxins in solid tumors from a mathematical model.

    Directory of Open Access Journals (Sweden)

    Youngshang Pak

    Full Text Available Most cancer-specific antigens used as targets of antibody-drug conjugates and immunotoxins are shed from the cell surface (Zhang & Pastan (2008 Clin. Cancer Res. 14: 7981-7986, although at widely varying rates and by different mechanisms (Dello Sbarba & Rovida (2002 Biol. Chem. 383: 69-83. Why many cancer-specific antigens are shed and how the shedding affects delivery efficiency of antibody-based protein drugs are poorly understood questions at present. Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins. However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38, and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules. Here, we improved this model and applied it to both SS1P and another recombinant immunotoxin, LMB-2, which targets CD25. We show that the effect of antigen shedding is influenced by a number of factors including the number of antigen molecules on the cell surface and the endocytosis rate. The high shedding rate of mesothelin is beneficial for SS1P, for which the antigen is large in number and endocytosed rapidly. On the other hand, the slow shedding of CD25 is beneficial for LMB-2, for which the antigen is small in number and endocytosed slowly.

  5. Tumor-directed gene therapy in mice using a composite nonviral gene delivery system consisting of the piggyBac transposon and polyethylenimine

    International Nuclear Information System (INIS)

    Kang, Yu; Zhang, Xiaoyan; Jiang, Wei; Wu, Chaoqun; Chen, Chunmei; Zheng, Yufang; Gu, Jianren; Xu, Congjian

    2009-01-01

    Compared with viral vectors, nonviral vectors are less immunogenic, more stable, safer and easier to replication for application in cancer gene therapy. However, nonviral gene delivery system has not been extensively used because of the low transfection efficiency and the short transgene expression, especially in vivo. It is desirable to develop a nonviral gene delivery system that can support stable genomic integration and persistent gene expression in vivo. Here, we used a composite nonviral gene delivery system consisting of the piggyBac (PB) transposon and polyethylenimine (PEI) for long-term transgene expression in mouse ovarian tumors. A recombinant plasmid PB [Act-RFP, HSV-tk] encoding both the herpes simplex thymidine kinase (HSV-tk) and the monomeric red fluorescent protein (mRFP1) under PB transposon elements was constructed. This plasmid and the PBase plasmid were injected into ovarian cancer tumor xenografts in mice by in vivo PEI system. The antitumor effects of HSV-tk/ganciclovir (GCV) system were observed after intraperitoneal injection of GCV. Histological analysis and TUNEL assay were performed on the cryostat sections of the tumor tissue. Plasmid construction was confirmed by PCR analysis combined with restrictive enzyme digestion. mRFP1 expression could be visualized three weeks after the last transfection of pPB/TK under fluorescence microscopy. After GCV admission, the tumor volume of PB/TK group was significantly reduced and the tumor inhibitory rate was 81.96% contrasted against the 43.07% in the TK group. Histological analysis showed that there were extensive necrosis and lymphocytes infiltration in the tumor tissue of the PB/TK group but limited in the tissue of control group. TUNEL assays suggested that the transfected cells were undergoing apoptosis after GCV admission in vivo. Our results show that the nonviral gene delivery system coupling PB transposon with PEI can be used as an efficient tool for gene therapy in ovarian cancer

  6. Evaluation of the Effectiveness of the Stereotactic Body Frame in Reducing Respiratory Intrafractional Organ Motion Using the Real-Time Tumor-Tracking Radiotherapy System

    International Nuclear Information System (INIS)

    Bengua, Gerard; Ishikawa, Masayori; Sutherland, Kenneth; Horita, Kenji; Yamazaki, Rie; Fujita, Katsuhisa; Onimaru, Rikiya; Katoh, Noriwo; Inoue, Tetsuya; Onodera, Shunsuke; Shirato, Hiroki

    2010-01-01

    Purpose: To evaluate the effectiveness of the stereotactic body frame (SBF), with or without a diaphragm press or a breathing cycle monitoring device (Abches), in controlling the range of lung tumor motion, by tracking the real-time position of fiducial markers. Methods and Materials: The trajectories of gold markers in the lung were tracked with the real-time tumor-tracking radiotherapy system. The SBF was used for patient immobilization and the diaphragm press and Abches were used to actively control breathing and for self-controlled respiration, respectively. Tracking was performed in five setups, with and without immobilization and respiration control. The results were evaluated using the effective range, which was defined as the range that includes 95% of all the recorded marker positions in each setup. Results: The SBF, with or without a diaphragm press or Abches, did not yield effective ranges of marker motion which were significantly different from setups that did not use these materials. The differences in the effective marker ranges in the upper lobes for all the patient setups were less than 1mm. Larger effective ranges were obtained for the markers in the middle or lower lobes. Conclusion: The effectiveness of controlling respiratory-induced organ motion by using the SBF+diaphragm press or SBF + Abches patient setups were highly dependent on the individual patient reaction to the use of these materials and the location of the markers. They may be considered for lung tumors in the lower lobes, but are not necessary for tumors in the upper lobes.

  7. Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

    Directory of Open Access Journals (Sweden)

    Brody LP

    2017-09-01

    Full Text Available Leigh P Brody,1,* Meliz Sahuri-Arisoylu,1,* James R Parkinson,1 Harry G Parkes,2 Po Wah So,3 Nabil Hajji,4 E Louise Thomas,1 Gary S Frost,5 Andrew D Miller,6,* Jimmy D Bell1,* 1Department of Life Sciences, Faculty of Science and Technology, University of Westminster, 2CR-UK Clinical MR Research Group, Institute of Cancer Research, Sutton, Surrey, 3Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 4Department of Medicine, Division of Experimental Medicine, Centre for Pharmacology & Therapeutics, Toxicology Unit, Imperial College London, 5Faculty of Medicine, Nutrition and Dietetic Research Group, Division of Diabetes, Endocrinology and Metabolism, Department of Investigative Medicine, Imperial College London, Hammersmith Hospital, 6Institute of Pharmaceutical Science, King’s College London, London, UK *These authors contributed equally to this work Abstract: Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN. We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53-/-. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo. Keywords: lipid-based nanoparticles, liposomes

  8. A motion-compensated image filter for low-dose fluoroscopy in a real-time tumor-tracking radiotherapy system

    International Nuclear Information System (INIS)

    Miyamoto, Naoki; Ishikawa, Masayori; Sutherland, Kenneth

    2015-01-01

    In the real-time tumor-tracking radiotherapy system, a surrogate fiducial marker inserted in or near the tumor is detected by fluoroscopy to realize respiratory-gated radiotherapy. The imaging dose caused by fluoroscopy should be minimized. In this work, an image processing technique is proposed for tracing a moving marker in low-dose imaging. The proposed tracking technique is a combination of a motion-compensated recursive filter and template pattern matching. The proposed image filter can reduce motion artifacts resulting from the recursive process based on the determination of the region of interest for the next frame according to the current marker position in the fluoroscopic images. The effectiveness of the proposed technique and the expected clinical benefit were examined by phantom experimental studies with actual tumor trajectories generated from clinical patient data. It was demonstrated that the marker motion could be traced in low-dose imaging by applying the proposed algorithm with acceptable registration error and high pattern recognition score in all trajectories, although some trajectories were not able to be tracked with the conventional spatial filters or without image filters. The positional accuracy is expected to be kept within ±2 mm. The total computation time required to determine the marker position is a few milliseconds. The proposed image processing technique is applicable for imaging dose reduction. (author)

  9. Impact of sampling interval in training data acquisition on intrafractional predictive accuracy of indirect dynamic tumor-tracking radiotherapy.

    Science.gov (United States)

    Mukumoto, Nobutaka; Nakamura, Mitsuhiro; Akimoto, Mami; Miyabe, Yuki; Yokota, Kenji; Matsuo, Yukinori; Mizowaki, Takashi; Hiraoka, Masahiro

    2017-08-01

    To explore the effect of sampling interval of training data acquisition on the intrafractional prediction error of surrogate signal-based dynamic tumor-tracking using a gimbal-mounted linac. Twenty pairs of respiratory motions were acquired from 20 patients (ten lung, five liver, and five pancreatic cancer patients) who underwent dynamic tumor-tracking with the Vero4DRT. First, respiratory motions were acquired as training data for an initial construction of the prediction model before the irradiation. Next, additional respiratory motions were acquired for an update of the prediction model due to the change of the respiratory pattern during the irradiation. The time elapsed prior to the second acquisition of the respiratory motion was 12.6 ± 3.1 min. A four-axis moving phantom reproduced patients' three dimensional (3D) target motions and one dimensional surrogate motions. To predict the future internal target motion from the external surrogate motion, prediction models were constructed by minimizing residual prediction errors for training data acquired at 80 and 320 ms sampling intervals for 20 s, and at 500, 1,000, and 2,000 ms sampling intervals for 60 s using orthogonal kV x-ray imaging systems. The accuracies of prediction models trained with various sampling intervals were estimated based on training data with each sampling interval during the training process. The intrafractional prediction errors for various prediction models were then calculated on intrafractional monitoring images taken for 30 s at the constant sampling interval of a 500 ms fairly to evaluate the prediction accuracy for the same motion pattern. In addition, the first respiratory motion was used for the training and the second respiratory motion was used for the evaluation of the intrafractional prediction errors for the changed respiratory motion to evaluate the robustness of the prediction models. The training error of the prediction model was 1.7 ± 0.7 mm in 3D for all sampling

  10. SU-G-JeP1-01: A Combination of Real Time Electromagnetic Localization and Tracking with Cone Beam Computed Tomography in Stereotactic Radiosurgery for Brain Tumors

    International Nuclear Information System (INIS)

    Muralidhar, K Raja; Pangam, Suresh; Ponaganti, Srinivas; Krishna, Jayarama; Sujana, Kolla V; Komanduri, Priya K

    2016-01-01

    Purpose: 1. online verification of patient position during treatment using calypso electromagnetic localization and tracking system. 2. Verification and comparison of positional accuracy between cone beam computed tomography and calypso system. 3. Presenting the advantage of continuation localization in Stereotactic radiosurgery treatments. Methods: Ten brain tumor cases were taken for this study. Patients with head mask were under gone Computed Tomography (CT). Before scanning, mask was cut on the fore head area to keep surface beacons on the skin. Slice thickness of 0.65 mm were taken for this study. x, y, z coordinates of these beacons in TPS were entered into tracking station. Varian True Beam accelerator, equipped with On Board Imager was used to take Cone beam Computed Tomography (CBCT) to localize the patient. Simultaneously Surface beacons were used to localize and track the patient throughout the treatment. The localization values were compared in both systems. For localization CBCT considered as reference. Tracking was done throughout the treatment using Calypso tracking system using electromagnetic array. This array was in tracking position during imaging and treatment. Flattening Filter free beams of 6MV photons along with Volumetric Modulated Arc Therapy was used for the treatment. The patient movement was observed throughout the treatment ranging from 2 min to 4 min. Results: The average variation observed between calypso system and CBCT localization was less than 0.5 mm. These variations were due to manual errors while keeping beacon on the patient. Less than 0.05 cm intra-fraction motion was observed throughout the treatment with the help of continuous tracking. Conclusion: Calypso target localization system is one of the finest tools to perform radiosurgery in combination with CBCT. This non radiographic method of tracking is a real beneficial method to treat patients confidently while observing real-time motion information of the patient.

  11. SU-G-JeP1-01: A Combination of Real Time Electromagnetic Localization and Tracking with Cone Beam Computed Tomography in Stereotactic Radiosurgery for Brain Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Muralidhar, K Raja; Pangam, Suresh; Ponaganti, Srinivas; Krishna, Jayarama; Sujana, Kolla V; Komanduri, Priya K [American Oncology Institute, Hyderabad, Telangana (India)

    2016-06-15

    Purpose: 1. online verification of patient position during treatment using calypso electromagnetic localization and tracking system. 2. Verification and comparison of positional accuracy between cone beam computed tomography and calypso system. 3. Presenting the advantage of continuation localization in Stereotactic radiosurgery treatments. Methods: Ten brain tumor cases were taken for this study. Patients with head mask were under gone Computed Tomography (CT). Before scanning, mask was cut on the fore head area to keep surface beacons on the skin. Slice thickness of 0.65 mm were taken for this study. x, y, z coordinates of these beacons in TPS were entered into tracking station. Varian True Beam accelerator, equipped with On Board Imager was used to take Cone beam Computed Tomography (CBCT) to localize the patient. Simultaneously Surface beacons were used to localize and track the patient throughout the treatment. The localization values were compared in both systems. For localization CBCT considered as reference. Tracking was done throughout the treatment using Calypso tracking system using electromagnetic array. This array was in tracking position during imaging and treatment. Flattening Filter free beams of 6MV photons along with Volumetric Modulated Arc Therapy was used for the treatment. The patient movement was observed throughout the treatment ranging from 2 min to 4 min. Results: The average variation observed between calypso system and CBCT localization was less than 0.5 mm. These variations were due to manual errors while keeping beacon on the patient. Less than 0.05 cm intra-fraction motion was observed throughout the treatment with the help of continuous tracking. Conclusion: Calypso target localization system is one of the finest tools to perform radiosurgery in combination with CBCT. This non radiographic method of tracking is a real beneficial method to treat patients confidently while observing real-time motion information of the patient.

  12. On the suitability of Elekta’s Agility 160 MLC for tracked radiation delivery: closed-loop machine performance

    International Nuclear Information System (INIS)

    Glitzner, M; Crijns, S P M; De Senneville, B Denis; Lagendijk, J J W; Raaymakers, B W

    2015-01-01

    For motion adaptive radiotherapy, dynamic multileaf collimator tracking can be employed to reduce treatment margins by steering the beam according to the organ motion. The Elekta Agility 160 MLC has hitherto not been evaluated for its tracking suitability. Both dosimetric performance and latency are key figures and need to be assessed generically, independent of the used motion sensor. In this paper, we propose the use of harmonic functions directly fed to the MLC to determine its latency during continuous motion. Furthermore, a control variable is extracted from a camera system and fed to the MLC. Using this setup, film dosimetry and subsequent γ statistics are performed, evaluating the response when tracking (MRI)-based physiologic motion in a closed-loop. The delay attributed to the MLC itself was shown to be a minor contributor to the overall feedback chain as compared to the impact of imaging components such as MRI sequences. Delay showed a linear phase behaviour of the MLC employed in continuously dynamic applications, which enables a general MLC-characterization. Using the exemplary feedback chain, dosimetry showed a vast increase in pass rate employing γ statistics. In this early stage, the tracking performance of the Agility using the test bench yielded promising results, making the technique eligible for translation to tracking using clinical imaging modalities. (paper)

  13. SU-E-J-150: Impact of Intrafractional Prostate Motion On the Accuracy and Efficiency of Prostate SBRT Delivery: A Retrospective Analysis of Prostate Tracking Log Files

    Energy Technology Data Exchange (ETDEWEB)

    Xiang, H; Hirsch, A; Willins, J; Kachnic, J [Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States); Boston Medical Center and Boston University School of Medicine, Boston, MA (United States); Qureshi, M; Katz, M; Nicholas, B; Keohan, S [Boston Medical Center and Boston University School of Medicine, Boston, MA (United States); De Armas, R [Massachusetts Institute of Technology, Cambridge, MA (United States); Lu, H; Efstathiou, J; Zietman, A [Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)

    2014-06-01

    Purpose: To measure intrafractional prostate motion by time-based stereotactic x-ray imaging and investigate the impact on the accuracy and efficiency of prostate SBRT delivery. Methods: Prostate tracking log files with 1,892 x-ray image registrations from 18 SBRT fractions for 6 patients were retrospectively analyzed. Patient setup and beam delivery sessions were reviewed to identify extended periods of large prostate motion that caused delays in setup or interruptions in beam delivery. The 6D prostate motions were compared to the clinically used PTV margin of 3–5 mm (3 mm posterior, 5 mm all other directions), a hypothetical PTV margin of 2–3 mm (2 mm posterior, 3 mm all other directions), and the rotation correction limits (roll ±2°, pitch ±5° and yaw ±3°) of CyberKnife to quantify beam delivery accuracy. Results: Significant incidents of treatment start delay and beam delivery interruption were observed, mostly related to large pitch rotations of ≥±5°. Optimal setup time of 5–15 minutes was recorded in 61% of the fractions, and optimal beam delivery time of 30–40 minutes in 67% of the fractions. At a default imaging interval of 15 seconds, the percentage of prostate motion beyond PTV margin of 3–5 mm varied among patients, with a mean at 12.8% (range 0.0%–31.1%); and the percentage beyond PTV margin of 2–3 mm was at a mean of 36.0% (range 3.3%–83.1%). These timely detected offsets were all corrected real-time by the robotic manipulator or by operator intervention at the time of treatment interruptions. Conclusion: The durations of patient setup and beam delivery were directly affected by the occurrence of large prostate motion. Frequent imaging of down to 15 second interval is necessary for certain patients. Techniques for reducing prostate motion, such as using endorectal balloon, can be considered to assure consistently higher accuracy and efficiency of prostate SBRT delivery.

  14. SU-E-J-150: Impact of Intrafractional Prostate Motion On the Accuracy and Efficiency of Prostate SBRT Delivery: A Retrospective Analysis of Prostate Tracking Log Files

    International Nuclear Information System (INIS)

    Xiang, H; Hirsch, A; Willins, J; Kachnic, J; Qureshi, M; Katz, M; Nicholas, B; Keohan, S; De Armas, R; Lu, H; Efstathiou, J; Zietman, A

    2014-01-01

    Purpose: To measure intrafractional prostate motion by time-based stereotactic x-ray imaging and investigate the impact on the accuracy and efficiency of prostate SBRT delivery. Methods: Prostate tracking log files with 1,892 x-ray image registrations from 18 SBRT fractions for 6 patients were retrospectively analyzed. Patient setup and beam delivery sessions were reviewed to identify extended periods of large prostate motion that caused delays in setup or interruptions in beam delivery. The 6D prostate motions were compared to the clinically used PTV margin of 3–5 mm (3 mm posterior, 5 mm all other directions), a hypothetical PTV margin of 2–3 mm (2 mm posterior, 3 mm all other directions), and the rotation correction limits (roll ±2°, pitch ±5° and yaw ±3°) of CyberKnife to quantify beam delivery accuracy. Results: Significant incidents of treatment start delay and beam delivery interruption were observed, mostly related to large pitch rotations of ≥±5°. Optimal setup time of 5–15 minutes was recorded in 61% of the fractions, and optimal beam delivery time of 30–40 minutes in 67% of the fractions. At a default imaging interval of 15 seconds, the percentage of prostate motion beyond PTV margin of 3–5 mm varied among patients, with a mean at 12.8% (range 0.0%–31.1%); and the percentage beyond PTV margin of 2–3 mm was at a mean of 36.0% (range 3.3%–83.1%). These timely detected offsets were all corrected real-time by the robotic manipulator or by operator intervention at the time of treatment interruptions. Conclusion: The durations of patient setup and beam delivery were directly affected by the occurrence of large prostate motion. Frequent imaging of down to 15 second interval is necessary for certain patients. Techniques for reducing prostate motion, such as using endorectal balloon, can be considered to assure consistently higher accuracy and efficiency of prostate SBRT delivery

  15. Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+ Mice

    Directory of Open Access Journals (Sweden)

    Marcel A. Deken

    2016-12-01

    Full Text Available Current genetically-engineered mouse melanoma models are often based on Tyr::CreERT2-controlled MAPK pathway activation by the BRAFV600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreERT2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in PtenLoxP/LoxP;BrafCA/+ mice lacking the Tyr::CreERT2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in PtenLoxP/LoxP;BrafCA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors in Tyr::CreERT2;PtenLoxP/LoxP;BrafCA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies.

  16. Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment.

    Science.gov (United States)

    Fujii, Hidetaka; Shin-Ya, Masaharu; Takeda, Shigeo; Hashimoto, Yoshihide; Mukai, Sada-atsu; Sawada, Shin-ichi; Adachi, Tetsuya; Akiyoshi, Kazunari; Miki, Tsuneharu; Mazda, Osam

    2014-12-01

    RNAi enables potent and specific gene silencing, potentially offering useful means for treatment of cancers. However, safe and efficient drug delivery systems (DDS) that are appropriate for intra-tumor delivery of siRNA or shRNA have rarely been established, hindering clinical application of RNAi technology to cancer therapy. We have devised hydrogel polymer nanoparticles, or nanogel, and shown its validity as a novel DDS for various molecules. Here we examined the potential of self-assembled nanogel of cholesterol-bearing cycloamylose with spermine group (CH-CA-Spe) to deliver vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) into tumor cells. The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF. Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice. The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production. Therefore, the CH-CA-Spe nanogel may be a feasible DDS for intra-tumor delivery of therapeutic siRNA. The results also suggest that local suppression of VEGF may have a positive impact on systemic immune responses against malignancies. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  17. SU-G-BRA-07: An Innovative Fiducial-Less Tracking Method for Radiation Treatment of Abdominal Tumors by Diaphragm Disparity Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Dick, D; Zhao, W [University of Miami, Coral Gables, Florida (United States); Wu, X [Biophysics Research Institute of America, Miami, Florida (United States)

    2016-06-15

    Purpose: To investigate the feasibility of tracking abdominal tumors without the use of gold fiducial markers Methods: In this simulation study, an abdominal 4DCT dataset, acquired previously and containing 8 phases of the breathing cycle, was used as the testing data. Two sets of DRR images (45 and 135 degrees) were generated for each phase. Three anatomical points along the lung-diaphragm interface on each of the Digital Reconstructed Radiograph(DRR) images were identified by cross-correlation. The gallbladder, which simulates the tumor, was contoured for each phase of the breathing cycle and the corresponding centroid values serve as the measured center of the tumor. A linear model was created to correlate the diaphragm’s disparity of the three identified anatomical points with the center of the tumor. To verify the established linear model, we sequentially removed one phase of the data (i.e., 3 anatomical points and the corresponding tumor center) and created new linear models with the remaining 7 phases. Then we substituted the eliminated phase data (disparities of the 3 anatomical points) into the corresponding model to compare model-generated tumor center and the measured tumor center. Results: The maximum difference between the modeled and the measured centroid values across the 8 phases were 0.72, 0.29 and 0.30 pixels in the x, y and z directions respectively, which yielded a maximum mean-squared-error value of 0.75 pixels. The outcomes of the verification process, by eliminating each phase, produced mean-squared-errors ranging from 0.41 to 1.28 pixels. Conclusion: Gold fiducial markers, requiring surgical procedures to be implanted, are conventionally used in radiation therapy. The present work shows the feasibility of a fiducial-less tracking method for localizing abdominal tumors. Through developed diaphragm disparity analysis, the established linear model was verified with clinically accepted errors. The tracking method in real time under different

  18. Management of three-dimensional intrafraction motion through real-time DMLC tracking

    International Nuclear Information System (INIS)

    Sawant, Amit; Venkat, Raghu; Srivastava, Vikram; Carlson, David; Povzner, Sergey; Cattell, Herb; Keall, Paul

    2008-01-01

    Tumor tracking using a dynamic multileaf collimator (DMLC) represents a promising approach for intrafraction motion management in thoracic and abdominal cancer radiotherapy. In this work, we develop, empirically demonstrate, and characterize a novel 3D tracking algorithm for real-time, conformal, intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT)-based radiation delivery to targets moving in three dimensions. The algorithm obtains real-time information of target location from an independent position monitoring system and dynamically calculates MLC leaf positions to account for changes in target position. Initial studies were performed to evaluate the geometric accuracy of DMLC tracking of 3D target motion. In addition, dosimetric studies were performed on a clinical linac to evaluate the impact of real-time DMLC tracking for conformal, step-and-shoot (S-IMRT), dynamic (D-IMRT), and VMAT deliveries to a moving target. The efficiency of conformal and IMRT delivery in the presence of tracking was determined. Results show that submillimeter geometric accuracy in all three dimensions is achievable with DMLC tracking. Significant dosimetric improvements were observed in the presence of tracking for conformal and IMRT deliveries to moving targets. A gamma index evaluation with a 3%-3 mm criterion showed that deliveries without DMLC tracking exhibit between 1.7 (S-IMRT) and 4.8 (D-IMRT) times more dose points that fail the evaluation compared to corresponding deliveries with tracking. The efficiency of IMRT delivery, as measured in the lab, was observed to be significantly lower in case of tracking target motion perpendicular to MLC leaf travel compared to motion parallel to leaf travel. Nevertheless, these early results indicate that accurate, real-time DMLC tracking of 3D tumor motion is feasible and can potentially result in significant geometric and dosimetric advantages leading to more effective management of intrafraction motion

  19. In Vivo Delivery of miR-34a Sensitizes Lung Tumors to Radiation Through RAD51 Regulation

    Directory of Open Access Journals (Sweden)

    Maria Angelica Cortez

    2015-01-01

    Full Text Available MiR-34a, an important tumor-suppressing microRNA, is downregulated in several types of cancer; loss of its expression has been linked with unfavorable clinical outcomes in non-small-cell lung cancer (NSCLC, among others. MiR-34a represses several key oncogenic proteins, and a synthetic mimic of miR-34a is currently being tested in a cancer trial. However, little is known about the potential role of miR-34a in regulating DNA damage response and repair. Here, we demonstrate that miR-34a directly binds to the 3’ untranslated region of RAD51 and regulates homologous recombination, inhibiting double-strand-break repair in NSCLC cells. We further demonstrate the therapeutic potential of miR-34a delivery in combination with radiotherapy in mouse models of lung cancer. Collectively, our results suggest that administration of miR-34a in combination with radiotherapy may represent a novel strategy for treating NSCLC.

  20. Poly (dopamine) coated superparamagnetic iron oxide nanocluster for noninvasive labeling, tracking, and targeted delivery of adipose tissue-derived stem cells

    Science.gov (United States)

    Liao, Naishun; Wu, Ming; Pan, Fan; Lin, Jiumao; Li, Zuanfang; Zhang, Da; Wang, Yingchao; Zheng, Youshi; Peng, Jun; Liu, Xiaolong; Liu, Jingfeng

    2016-01-01

    Tracking and monitoring of cells in vivo after transplantation can provide crucial information for stem cell therapy. Magnetic resonance imaging (MRI) combined with contrast agents is believed to be an effective and non-invasive technique for cell tracking in living bodies. However, commercial superparamagnetic iron oxide nanoparticles (SPIONs) applied to label cells suffer from shortages such as potential toxicity, low labeling efficiency, and low contrast enhancing. Herein, the adipose tissue-derived stem cells (ADSCs) were efficiently labeled with SPIONs coated with poly (dopamine) (SPIONs cluster@PDA), without affecting their viability, proliferation, apoptosis, surface marker expression, as well as their self-renew ability and multi-differentiation potential. The labeled cells transplanted into the mice through tail intravenous injection exhibited a negative enhancement of the MRI signal in the damaged liver-induced by carbon tetrachloride, and subsequently these homed ADSCs with SPIONs cluster@PDA labeling exhibited excellent repair effects to the damaged liver. Moreover, the enhanced target-homing to tissue of interest and repair effects of SPIONs cluster@PDA-labeled ADSCs could be achieved by use of external magnetic field in the excisional skin wound mice model. Therefore, we provide a facile, safe, noninvasive and sensitive method for external magnetic field targeted delivery and MRI based tracking of transplanted cells in vivo.

  1. Poly (dopamine) coated superparamagnetic iron oxide nanocluster for noninvasive labeling, tracking, and targeted delivery of adipose tissue-derived stem cells.

    Science.gov (United States)

    Liao, Naishun; Wu, Ming; Pan, Fan; Lin, Jiumao; Li, Zuanfang; Zhang, Da; Wang, Yingchao; Zheng, Youshi; Peng, Jun; Liu, Xiaolong; Liu, Jingfeng

    2016-01-05

    Tracking and monitoring of cells in vivo after transplantation can provide crucial information for stem cell therapy. Magnetic resonance imaging (MRI) combined with contrast agents is believed to be an effective and non-invasive technique for cell tracking in living bodies. However, commercial superparamagnetic iron oxide nanoparticles (SPIONs) applied to label cells suffer from shortages such as potential toxicity, low labeling efficiency, and low contrast enhancing. Herein, the adipose tissue-derived stem cells (ADSCs) were efficiently labeled with SPIONs coated with poly (dopamine) (SPIONs cluster@PDA), without affecting their viability, proliferation, apoptosis, surface marker expression, as well as their self-renew ability and multi-differentiation potential. The labeled cells transplanted into the mice through tail intravenous injection exhibited a negative enhancement of the MRI signal in the damaged liver-induced by carbon tetrachloride, and subsequently these homed ADSCs with SPIONs cluster@PDA labeling exhibited excellent repair effects to the damaged liver. Moreover, the enhanced target-homing to tissue of interest and repair effects of SPIONs cluster@PDA-labeled ADSCs could be achieved by use of external magnetic field in the excisional skin wound mice model. Therefore, we provide a facile, safe, noninvasive and sensitive method for external magnetic field targeted delivery and MRI based tracking of transplanted cells in vivo.

  2. Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma.

    Science.gov (United States)

    Liang, Chao; Li, Fangfei; Wang, Luyao; Zhang, Zong-Kang; Wang, Chao; He, Bing; Li, Jie; Chen, Zhihao; Shaikh, Atik Badshah; Liu, Jin; Wu, Xiaohao; Peng, Songlin; Dang, Lei; Guo, Baosheng; He, Xiaojuan; Au, D W T; Lu, Cheng; Zhu, Hailong; Zhang, Bao-Ting; Lu, Aiping; Zhang, Ge

    2017-12-01

    Osteosarcoma (OS) is a highly aggressive pediatric cancer, characterized by frequent lung metastasis and pathologic bone destruction. Vascular endothelial growth factor A (VEGFA), highly expressed in OS, not only contributes to angiogenesis within the tumor microenvironment via paracrine stimulation of vascular endothelial cells, but also acts as an autocrine survival factor for tumor cell themselves, thus making it a promising therapeutic target for OS. CRISPR/Cas9 is a versatile genome editing technology and holds tremendous promise for cancer treatment. However, a major bottleneck to achieve the therapeutic potential of the CRISPR/Cas9 is the lack of in vivo tumor-targeted delivery systems. Here, we screened an OS cell-specific aptamer (LC09) and developed a LC09-functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9. Our results demonstrated that LC09 facilitated selective distribution of CRISPR/Cas9 in both orthotopic OS and lung metastasis, leading to effective VEGFA genome editing in tumor, decreased VEGFA expression and secretion, inhibited orthotopic OS malignancy and lung metastasis, as well as reduced angiogenesis and bone lesion with no detectable toxicity. The delivery system simultaneously restrained autocrine and paracrine VEGFA signaling in tumor cells and could facilitate translating CRISPR-Cas9 into clinical cancer treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Optimum location of external markers using feature selection algorithms for real-time tumor tracking in external-beam radiotherapy: a virtual phantom study.

    Science.gov (United States)

    Nankali, Saber; Torshabi, Ahmad Esmaili; Miandoab, Payam Samadi; Baghizadeh, Amin

    2016-01-08

    In external-beam radiotherapy, using external markers is one of the most reliable tools to predict tumor position, in clinical applications. The main challenge in this approach is tumor motion tracking with highest accuracy that depends heavily on external markers location, and this issue is the objective of this study. Four commercially available feature selection algorithms entitled 1) Correlation-based Feature Selection, 2) Classifier, 3) Principal Components, and 4) Relief were proposed to find optimum location of external markers in combination with two "Genetic" and "Ranker" searching procedures. The performance of these algorithms has been evaluated using four-dimensional extended cardiac-torso anthropomorphic phantom. Six tumors in lung, three tumors in liver, and 49 points on the thorax surface were taken into account to simulate internal and external motions, respectively. The root mean square error of an adaptive neuro-fuzzy inference system (ANFIS) as prediction model was considered as metric for quantitatively evaluating the performance of proposed feature selection algorithms. To do this, the thorax surface region was divided into nine smaller segments and predefined tumors motion was predicted by ANFIS using external motion data of given markers at each small segment, separately. Our comparative results showed that all feature selection algorithms can reasonably select specific external markers from those segments where the root mean square error of the ANFIS model is minimum. Moreover, the performance accuracy of proposed feature selection algorithms was compared, separately. For this, each tumor motion was predicted using motion data of those external markers selected by each feature selection algorithm. Duncan statistical test, followed by F-test, on final results reflected that all proposed feature selection algorithms have the same performance accuracy for lung tumors. But for liver tumors, a correlation-based feature selection algorithm, in

  4. Optimum location of external markers using feature selection algorithms for real‐time tumor tracking in external‐beam radiotherapy: a virtual phantom study

    Science.gov (United States)

    Nankali, Saber; Miandoab, Payam Samadi; Baghizadeh, Amin

    2016-01-01

    In external‐beam radiotherapy, using external markers is one of the most reliable tools to predict tumor position, in clinical applications. The main challenge in this approach is tumor motion tracking with highest accuracy that depends heavily on external markers location, and this issue is the objective of this study. Four commercially available feature selection algorithms entitled 1) Correlation‐based Feature Selection, 2) Classifier, 3) Principal Components, and 4) Relief were proposed to find optimum location of external markers in combination with two “Genetic” and “Ranker” searching procedures. The performance of these algorithms has been evaluated using four‐dimensional extended cardiac‐torso anthropomorphic phantom. Six tumors in lung, three tumors in liver, and 49 points on the thorax surface were taken into account to simulate internal and external motions, respectively. The root mean square error of an adaptive neuro‐fuzzy inference system (ANFIS) as prediction model was considered as metric for quantitatively evaluating the performance of proposed feature selection algorithms. To do this, the thorax surface region was divided into nine smaller segments and predefined tumors motion was predicted by ANFIS using external motion data of given markers at each small segment, separately. Our comparative results showed that all feature selection algorithms can reasonably select specific external markers from those segments where the root mean square error of the ANFIS model is minimum. Moreover, the performance accuracy of proposed feature selection algorithms was compared, separately. For this, each tumor motion was predicted using motion data of those external markers selected by each feature selection algorithm. Duncan statistical test, followed by F‐test, on final results reflected that all proposed feature selection algorithms have the same performance accuracy for lung tumors. But for liver tumors, a correlation‐based feature

  5. Registration accuracy and possible migration of internal fiducial gold marker implanted in prostate and liver treated with real-time tumor-tracking radiation therapy (RTRT)

    International Nuclear Information System (INIS)

    Kitamura, Kei; Shirato, Hiroki; Shimizu, Shinichi; Shinohara, Nobuo; Harabayashi, Toru; Shimizu, Tadashi; Kodama, Yoshihisa; Endo, Hideho; Onimaru, Rikiya; Nishioka, Seiko; Aoyama, Hidefumi; Tsuchiya, Kazuhiko; Miyasaka, Kazuo

    2002-01-01

    Background and purpose: We have developed a linear accelerator synchronized with a fluoroscopic real-time tumor-tracking system to reduce errors due to setup and organ motion. In the real-time tumor-tracking radiation therapy (RTRT) system, the accuracy of tumor tracking depends on the registration of the marker's coordinates. The registration accuracy and possible migration of the internal fiducial gold marker implanted into prostate and liver was investigated. Materials and methods: Internal fiducial gold markers were implanted in 14 patients with prostate cancer and four patients with liver tumors. Computed tomography (CT) was carried out as a part of treatment planning in the 18 patients. A total of 72 follow-up CT scans were taken. We calculated the relative relationship between the coordinates of the center of mass (CM) of the organs and those of the marker. The discrepancy in the CM coordinates during a follow-up CT compared to those recorded during the planning CT was used to study possible marker migration. Results: The standard deviation (SD) of interobserver variations in the CM coordinates was within 2.0 and 0.4 mm for the organ and the marker, respectively, in seven observers. Assuming that organs do not shrink, grow, or rotate, the maximum SD of migration error in each direction was estimated to be less than 2.5 and 2.0 mm for liver and prostate, respectively. There was no correlation between the marker position and the time after implantation. Conclusion: The degree of possible migration of the internal fiducial marker was within the limits of accuracy of the CT measurement. Most of the marker movement can be attributed to the measurement uncertainty, which also influences registration in actual treatment planning. Thus, even with the gold marker and RTRT system, a planning target volume margin should be used to account for registration uncertainty

  6. SU-E-J-240: Development of a Novel 4D MRI Sequence for Real-Time Liver Tumor Tracking During Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhuang, L; Burmeister, J [Department of Oncology, Wayne State Univ School of Medicine, Detroit, MI (United States); Ye, Y [Department of Radiology, Wayne State Univ School of Medicine, Detroit, MI (United States)

    2015-06-15

    Purpose: To develop a Novel 4D MRI Technique that is feasible for realtime liver tumor tracking during radiotherapy. Methods: A volunteer underwent an abdominal 2D fast EPI coronal scan on a 3.0T MRI scanner (Siemens Inc., Germany). An optimal set of parameters was determined based on image quality and scan time. A total of 23 slices were scanned to cover the whole liver in the test scan. For each scan position, the 2D images were retrospectively sorted into multiple phases based on breathing signal extracted from the images. Consequently the 2D slices with same phase numbers were stacked to form one 3D image. Multiple phases of 3D images formed the 4D MRI sequence representing one breathing cycle. Results: The optimal set of scan parameters were: TR= 57ms, TE= 19ms, FOV read= 320mm and flip angle= 30°, which resulted in a total scan time of 14s for 200 frames (FMs) per slice and image resolution of (2.5mm,2.5mm,5.0mm) in three directions. Ten phases of 3D images were generated, each of which had 23 slices. Based on our test scan, only 100FMs were necessary for the phase sorting process which may lower the scan time to 7s/100FMs/slice. For example, only 5 slices/35s are necessary for a 4D MRI scan to cover liver tumor size ≤ 2cm leading to the possibility of tumor trajectory tracking every 35s during treatment. Conclusion: The novel 4D MRI technique we developed can reconstruct a 4D liver MRI sequence representing one breathing cycle (7s/ slice) without an external monitor. This technique can potentially be used for real-time liver tumor tracking during radiotherapy.

  7. MO-FG-BRD-00: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2015-06-15

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow.

  8. MO-FG-BRD-00: Real-Time Imaging and Tracking Techniques for Intrafractional Motion Management

    International Nuclear Information System (INIS)

    2015-01-01

    Intrafraction target motion is a prominent complicating factor in the accurate targeting of radiation within the body. Methods compensating for target motion during treatment, such as gating and dynamic tumor tracking, depend on the delineation of target location as a function of time during delivery. A variety of techniques for target localization have been explored and are under active development; these include beam-level imaging of radio-opaque fiducials, fiducial-less tracking of anatomical landmarks, tracking of electromagnetic transponders, optical imaging of correlated surrogates, and volumetric imaging within treatment delivery. The Joint Imaging and Therapy Symposium will provide an overview of the techniques for real-time imaging and tracking, with special focus on emerging modes of implementation across different modalities. In particular, the symposium will explore developments in 1) Beam-level kilovoltage X-ray imaging techniques, 2) EPID-based megavoltage X-ray tracking, 3) Dynamic tracking using electromagnetic transponders, and 4) MRI-based soft-tissue tracking during radiation delivery. Learning Objectives: Understand the fundamentals of real-time imaging and tracking techniques Learn about emerging techniques in the field of real-time tracking Distinguish between the advantages and disadvantages of different tracking modalities Understand the role of real-time tracking techniques within the clinical delivery work-flow

  9. Folic acid-targeted disulfide-based cross-linking micelle for enhanced drug encapsulation stability and site-specific drug delivery against tumors

    Directory of Open Access Journals (Sweden)

    Zhang Y

    2016-03-01

    Full Text Available Yumin Zhang,1,* Junhui Zhou,2,* Cuihong Yang,1 Weiwei Wang,3 Liping Chu,1 Fan Huang,1 Qiang Liu,1 Liandong Deng,2 Deling Kong,3 Jianfeng Liu,1 Jinjian Liu1 1Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, 2Department of Polymer Science and Technology, School of Chemical Engineering and Technology, Tianjin University, 3Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, People’s Republic of China *These authors contributed equally in this work Abstract: Although the shortcomings of small molecular antitumor drugs were efficiently improved by being entrapped into nanosized vehicles, premature drug release and insufficient tumor targeting demand innovative approaches that boost the stability and tumor responsiveness of drug-loaded nanocarriers. Here, we show the use of the core cross-linking method to generate a micelle with enhanced drug encapsulation ability and sensitivity of drug release in tumor. This kind of micelle could increase curcumin (Cur delivery to HeLa cells in vitro and improve tumor accumulation in vivo. We designed and synthesized the core cross-linked micelle (CCM with polyethylene glycol and folic acid-polyethylene glycol as the hydrophilic units, pyridyldisulfide as the cross-linkable and hydrophobic unit, and disulfide bond as the cross-linker. CCM showed spherical shape with a diameter of 91.2 nm by the characterization of dynamic light scattering and transmission electron microscope. Attributed to the core cross-linking, drug-loaded CCM displayed higher Nile Red or Cur-encapsulated stability and better sensitivity to glutathione than noncross-linked micelle (NCM. Cellular uptake and in vitro antitumor studies proved the enhanced endocytosis and better cytotoxicity of CCM-Cur against

  10. Development of a video image-based QA system for the positional accuracy of dynamic tumor tracking irradiation in the Vero4DRT system

    Energy Technology Data Exchange (ETDEWEB)

    Ebe, Kazuyu, E-mail: nrr24490@nifty.com; Tokuyama, Katsuichi; Baba, Ryuta; Ogihara, Yoshisada; Ichikawa, Kosuke; Toyama, Joji [Joetsu General Hospital, 616 Daido-Fukuda, Joetsu-shi, Niigata 943-8507 (Japan); Sugimoto, Satoru [Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421 (Japan); Utsunomiya, Satoru; Kagamu, Hiroshi; Aoyama, Hidefumi [Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510 (Japan); Court, Laurence [The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009 (United States)

    2015-08-15

    Purpose: To develop and evaluate a new video image-based QA system, including in-house software, that can display a tracking state visually and quantify the positional accuracy of dynamic tumor tracking irradiation in the Vero4DRT system. Methods: Sixteen trajectories in six patients with pulmonary cancer were obtained with the ExacTrac in the Vero4DRT system. Motion data in the cranio–caudal direction (Y direction) were used as the input for a programmable motion table (Quasar). A target phantom was placed on the motion table, which was placed on the 2D ionization chamber array (MatriXX). Then, the 4D modeling procedure was performed on the target phantom during a reproduction of the patient’s tumor motion. A substitute target with the patient’s tumor motion was irradiated with 6-MV x-rays under the surrogate infrared system. The 2D dose images obtained from the MatriXX (33 frames/s; 40 s) were exported to in-house video-image analyzing software. The absolute differences in the Y direction between the center of the exposed target and the center of the exposed field were calculated. Positional errors were observed. The authors’ QA results were compared to 4D modeling function errors and gimbal motion errors obtained from log analyses in the ExacTrac to verify the accuracy of their QA system. The patients’ tumor motions were evaluated in the wave forms, and the peak-to-peak distances were also measured to verify their reproducibility. Results: Thirteen of sixteen trajectories (81.3%) were successfully reproduced with Quasar. The peak-to-peak distances ranged from 2.7 to 29.0 mm. Three trajectories (18.7%) were not successfully reproduced due to the limited motions of the Quasar. Thus, 13 of 16 trajectories were summarized. The mean number of video images used for analysis was 1156. The positional errors (absolute mean difference + 2 standard deviation) ranged from 0.54 to 1.55 mm. The error values differed by less than 1 mm from 4D modeling function errors

  11. Development of a video image-based QA system for the positional accuracy of dynamic tumor tracking irradiation in the Vero4DRT system

    International Nuclear Information System (INIS)

    Ebe, Kazuyu; Tokuyama, Katsuichi; Baba, Ryuta; Ogihara, Yoshisada; Ichikawa, Kosuke; Toyama, Joji; Sugimoto, Satoru; Utsunomiya, Satoru; Kagamu, Hiroshi; Aoyama, Hidefumi; Court, Laurence

    2015-01-01

    Purpose: To develop and evaluate a new video image-based QA system, including in-house software, that can display a tracking state visually and quantify the positional accuracy of dynamic tumor tracking irradiation in the Vero4DRT system. Methods: Sixteen trajectories in six patients with pulmonary cancer were obtained with the ExacTrac in the Vero4DRT system. Motion data in the cranio–caudal direction (Y direction) were used as the input for a programmable motion table (Quasar). A target phantom was placed on the motion table, which was placed on the 2D ionization chamber array (MatriXX). Then, the 4D modeling procedure was performed on the target phantom during a reproduction of the patient’s tumor motion. A substitute target with the patient’s tumor motion was irradiated with 6-MV x-rays under the surrogate infrared system. The 2D dose images obtained from the MatriXX (33 frames/s; 40 s) were exported to in-house video-image analyzing software. The absolute differences in the Y direction between the center of the exposed target and the center of the exposed field were calculated. Positional errors were observed. The authors’ QA results were compared to 4D modeling function errors and gimbal motion errors obtained from log analyses in the ExacTrac to verify the accuracy of their QA system. The patients’ tumor motions were evaluated in the wave forms, and the peak-to-peak distances were also measured to verify their reproducibility. Results: Thirteen of sixteen trajectories (81.3%) were successfully reproduced with Quasar. The peak-to-peak distances ranged from 2.7 to 29.0 mm. Three trajectories (18.7%) were not successfully reproduced due to the limited motions of the Quasar. Thus, 13 of 16 trajectories were summarized. The mean number of video images used for analysis was 1156. The positional errors (absolute mean difference + 2 standard deviation) ranged from 0.54 to 1.55 mm. The error values differed by less than 1 mm from 4D modeling function errors

  12. An effective intracellular delivery system of monoclonal antibody for treatment of tumors: erythrocyte membrane-coated self-associated antibody nanoparticles

    Science.gov (United States)

    Gao, Lipeng; Han, Lin; Ding, Xiaoling; Xu, Jiaojiao; Wang, Jing; Zhu, Jianzhong; Lu, Weiyue; Sun, Jihong; Yu, Lei; Yan, Zhiqiang; Wang, Yiting

    2017-08-01

    Antibody-based drugs have attracted much attention for their targeting ability, high efficacy and low toxicity. But it is difficult for those intrabodies, a kind of antibody whose targets are intracellular biomarkers, to become effective drugs due to the lack of intracellular delivery strategy and their short circulation time in blood. Human telomerase reverse transcriptase (hTERT), an important biomarker for tumors, is expressed only in cytoplasm instead of on cell membrane. In this study, the anti-hTERT blocking monoclonal antibody (mAb), as the model intrabody, was used to prepare nanoparticles (NPs), followed by the encapsulation of erythrocyte membrane (EM), to obtain the EM-coated anti-hTERT mAb NPs delivery system. The final NPs showed a z-average hydrodynamic diameter of about 197.3 nm. The in vitro cellular uptake by HeLa cells confirmed that compared with free anti-hTERT mAb, the EM-coated anti-hTERT mAb NPs exhibited a significantly increased uptake by tumor cells. Besides, the pharmacokinetic study confirmed that the EM encapsulation can remarkably prolong the circulation time and increase the area under curve (AUC) of NPs in blood. The EM-coated anti-hTERT mAb NPs exhibited a remarkably decreased uptake by macrophages than uncoated NPs, which may be responsible for the prolonged circulation time and increased AUC. Furthermore, the frozen section of tumor tissue was performed and proved that the EM-coated anti-hTERT mAb NPs can be more effectively accumulated in tumor tissues than the free mAb and uncoated NPs. In summary, this study indicated that EM-coated anti-hTERT mAb NPs are an effective delivery system for the long circulation and intracellular delivery of an intrabody, and make it possible for the intracellular biomarkers to become the potential targets of drugs.

  13. Hepatic Intra-arterial Delivery of a "Trojan-horses" Gene Therapy: A Pilot Study on Rabbit VX2 Hepatic Tumor Model.

    Science.gov (United States)

    Pellerin, Olivier; Amara, Ikram; Sapoval, Marc; Méachi, Tchao; Déan, Carole; Beaune, Philippe; de Waziers, Isabelle

    2018-01-01

    Gene-directed enzyme prodrug therapy (GDEPT) is a "Trojan-horses" suicide gene therapy that consists of tumor-targeted gene delivery (vectorized by mesenchymal stem cells MSCs) encoding an enzyme that converts a harmless prodrug into cytotoxic metabolites in situ. Then, cytotoxic metabolites passively diffuse in the neighboring tumor cells and kill them (bystander effect). The goal of our study was to assess the feasibility and efficacy of intra-arterial administration of MSCs transduced with an optimized gene (MSC-CYP2B6TM-RED) followed by intravenous administration of cyclophosphamide (CPA) into the VX2 rabbit liver tumor. Nine rabbits with a VX2 liver tumor were randomly assigned into three groups: Control group A (one rabbit) free of any treatment; Control group B (two rabbits) receiving intravenous injection of cyclophosphamide at day 3 and CPA at day 14; and Group C (six rabbits) receiving the GDEPT treatment, consisting of successive intra-arterial injection of transduced-MSCs at days 0 (n = 6) and 11 (n = 3), followed by injection of CPA at days 3 (n = 6) and 14 (n = 3). The tumor response was assessed by ultrasound scan every 7 days and histopathological analysis at sacrifice (D25). There was a significant difference in the tumor volume between control groups (A + B) and group C at D7: 38/19 cm 3 (p = 0.024); D11: 51/20 cm 3 (p = 0.024), and D25: 121/37 cm 3 (p = 0.048). Tumor necrosis was significantly greater and metastatic spread was lower for rabbits who received GDEPT (78% of total tumor surface) than for control animals (A + B) (22% of total tumor surface (p = 0.006). Intra-arterial delivery of transduced-MSCs is feasible and, after CPA injection, resulted in 78% tumor necrosis (p = 0.006) and less metastasis in a VX2 liver tumor model.

  14. Delivery of kinesin spindle protein targeting siRNA in solid lipid nanoparticles to cellular models of tumor vasculature

    International Nuclear Information System (INIS)

    Ying, Bo; Campbell, Robert B.

    2014-01-01

    Highlights: • siRNA-lipid nanoparticles are solid particles not lipid bilayers with aqueous core. • High, but not low, PEG content can prevent nanoparticle encapsulation of siRNA. • PEG reduces cellular toxicity of cationic nanoparticles in vitro. • PEG reduces zeta potential while improving gene silencing of siRNA nanoparticles. • Kinesin spindle protein can be an effective target for tumor vascular targeting. - Abstract: The ideal siRNA delivery system should selectively deliver the construct to the target cell, avoid enzymatic degradation, and evade uptake by phagocytes. In the present study, we evaluated the importance of polyethylene glycol (PEG) on lipid-based carrier systems for encapsulating, and delivering, siRNA to tumor vessels using cellular models. Lipid nanoparticles containing different percentage of PEG were evaluated based on their physical chemical properties, density compared to water, siRNA encapsulation, toxicity, targeting efficiency and gene silencing in vitro. siRNA can be efficiently loaded into lipid nanoparticles (LNPs) when DOTAP is included in the formulation mixture. However, the total amount encapsulated decreased with increase in PEG content. In the presence of siRNA, the final formulations contained a mixed population of particles based on density. The major population which contains the majority of siRNA exhibited a density of 4% glucose, and the minor fraction associated with a decreased amount of siRNA had a density less than PBS. The inclusion of 10 mol% PEG resulted in a greater amount of siRNA associated with the minor fraction. Finally, when kinesin spindle protein (KSP) siRNA was encapsulated in lipid nanoparticles containing a modest amount of PEG, the proliferation of endothelial cells was inhibited due to the efficient knock down of KSP mRNA. The presence of siRNA resulted in the formation of solid lipid nanoparticles when prepared using the thin film and hydration method. LNPs with a relatively modest amount of

  15. Multileaf Collimator Tracking Improves Dose Delivery for Prostate Cancer Radiation Therapy: Results of the First Clinical Trial

    DEFF Research Database (Denmark)

    Colvill, Emma; Booth, Jeremy T; O'Brien, Ricky T

    2015-01-01

    was tested for each dose-volume value via analysis of variance using the F test. RESULTS: Of the 513 fractions delivered, 475 (93%) were suitable for analysis. The mean difference and standard deviation between the planned and treated MLC tracking doses and the planned and without-MLC tracking doses for all...... 475 fractions were, respectively, PTV D99% -0.8% ± 1.1% versus -2.1% ± 2.7%; CTV D99% -0.6% ± 0.8% versus -0.6% ± 1.1%; rectum V65% 1.6% ± 7.9% versus -1.2% ± 18%; and bladder V65% 0.5% ± 4.4% versus -0.0% ± 9.2% (P

  16. Acridine Orange/exosomes increase the delivery and the effectiveness of Acridine Orange in human melanoma cells: A new prototype for theranostics of tumors.

    Science.gov (United States)

    Iessi, Elisabetta; Logozzi, Mariantonia; Lugini, Luana; Azzarito, Tommaso; Federici, Cristina; Spugnini, Enrico Pierluigi; Mizzoni, Davide; Di Raimo, Rossella; Angelini, Daniela F; Battistini, Luca; Cecchetti, Serena; Fais, Stefano

    2017-12-01

    Specifically targeted drug delivery systems with low immunogenicity and toxicity are deemed to increase efficacy of cancer chemotherapy. Acridine Orange (AO) is an acidophilic dye with a strong tumoricidal action following excitation with a light source at 466 nm. However, to date the clinical use of AO is limited by the potential side effects elicited by systemic administration. The endogenous nanocarrier exosomes have been recently introduced as a natural delivery system for therapeutic molecules. In this article, we show the outcome of the administration to human melanoma cells of AO charged Exosomes (Exo-AO), in both monolayer and spheroid models. The results showed an extended drug delivery time of Exo-AO to melanoma cells as compared to the free AO, improving the cytotoxicity of AO. This study shows that Exo-AO have a great potential for a real exploitation as a new theranostic approach against tumors based on AO delivered through the exosomes.

  17. Functionalized graphene oxide mediated adriamycin delivery and miR-21 gene silencing to overcome tumor multidrug resistance in vitro.

    Directory of Open Access Journals (Sweden)

    Feng Zhi

    Full Text Available Multidrug resistance (MDR is a major impediment to successful cancer chemotherapy. Co-delivery of novel MDR-reversing agents and anticancer drugs to cancer cells holds great promise for cancer treatment. MicroRNA-21 (miR-21 overexpression is associated with the development and progression of MDR in breast cancer, and it is emerging as a novel and promising MDR-reversing target. In this study, a multifunctional nanocomplex, composed of polyethylenimine (PEI/poly(sodium 4-styrenesulfonates (PSS/graphene oxide (GO and termed PPG, was prepared using the layer-by-layer assembly method to evaluate the reversal effects of PPG as a carrier for adriamycin (ADR along with miR-21 targeted siRNA (anti-miR-21 in cancer drug resistance. ADR was firstly loaded onto the PPG surface (PPGADR by physical mixing and anti-miR-21 was sequentially loaded onto PPGADR through electric absorption to form (anti-miR-21PPGADR. Cell experiments showed that PPG significantly enhanced the accumulation of ADR in MCF-7/ADR cells (an ADR resistant breast cancer cell line and exhibited much higher cytotoxicity than free ADR, suggesting that PPG could effectively reverse ADR resistance of MCF-7/ADR. Furthermore, the enhanced therapeutic efficacy of PPG could be correlated with effective silencing of miR-21 and with increased accumulation of ADR in drug-resistant tumor cells. The endocytosis study confirmed that PPG could effectively carry drug molecules into cells via the caveolae and clathrin-mediated endocytosis pathways. These results suggest that this PPG could be a potential and efficient non-viral vector for reversing MDR, and the strategy of combining anticancer drugs with miRNA therapy to overcome MDR could be an attractive approach in cancer treatment.

  18. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    International Nuclear Information System (INIS)

    Daldrup-Link, Heike E.; Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J.; Rudelius, Martina; Piontek, Guido; Schlegel, Juergen; Piert, Morand; Uherek, Christoph; Wels, Winfried

    2005-01-01

    agents, and the accumulation of these labeled cells in murine tumors can be monitored in vivo with MR imaging. This MR cell tracking technique may be applied to monitor NK-cell based immunotherapies in patients in order to assess the presence and extent of NK-cell tumor accumulations and, thus, to determine therapy response early and non-invasively. (orig.)

  19. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Daldrup-Link, Heike E. [UCSF Medical Center, Department of Radiology, San Francisco, CA (United States); Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J. [Technical University Munich, Department of Radiology, Munich (Germany); Rudelius, Martina; Piontek, Guido; Schlegel, Juergen [Technical University Munich, Institute of Pathology, Division of Neuropathology, Munich (Germany); Piert, Morand [Technical University Munich, Department of Nuclear Medicine, Munich (Germany); Uherek, Christoph; Wels, Winfried [University of Frankfurt, Georg Speyer House, Frankfurt (Germany)

    2005-01-01

    labeled with clinically applicable iron-oxide contrast agents, and the accumulation of these labeled cells in murine tumors can be monitored in vivo with MR imaging. This MR cell tracking technique may be applied to monitor NK-cell based immunotherapies in patients in order to assess the presence and extent of NK-cell tumor accumulations and, thus, to determine therapy response early and non-invasively. (orig.)

  20. Reducing Dose Uncertainty for Spot-Scanning Proton Beam Therapy of Moving Tumors by Optimizing the Spot Delivery Sequence

    International Nuclear Information System (INIS)

    Li, Heng; Zhu, X. Ronald; Zhang, Xiaodong

    2015-01-01

    Purpose: To develop and validate a novel delivery strategy for reducing the respiratory motion–induced dose uncertainty of spot-scanning proton therapy. Methods and Materials: The spot delivery sequence was optimized to reduce dose uncertainty. The effectiveness of the delivery sequence optimization was evaluated using measurements and patient simulation. One hundred ninety-one 2-dimensional measurements using different delivery sequences of a single-layer uniform pattern were obtained with a detector array on a 1-dimensional moving platform. Intensity modulated proton therapy plans were generated for 10 lung cancer patients, and dose uncertainties for different delivery sequences were evaluated by simulation. Results: Without delivery sequence optimization, the maximum absolute dose error can be up to 97.2% in a single measurement, whereas the optimized delivery sequence results in a maximum absolute dose error of ≤11.8%. In patient simulation, the optimized delivery sequence reduces the mean of fractional maximum absolute dose error compared with the regular delivery sequence by 3.3% to 10.6% (32.5-68.0% relative reduction) for different patients. Conclusions: Optimizing the delivery sequence can reduce dose uncertainty due to respiratory motion in spot-scanning proton therapy, assuming the 4-dimensional CT is a true representation of the patients' breathing patterns.

  1. Self-assembled nanoparticles based on the c(RGDfk peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy

    Directory of Open Access Journals (Sweden)

    Liu L

    2014-07-01

    Full Text Available Li Liu,1 Xiaoxia Liu,1 Qian Xu,1 Ping Wu,2 Xialin Zuo,3 Jingjing Zhang,1 Houliang Deng,1 Zhuomin Wu,1 Aimin Ji1 1Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmacy, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu, People’s Republic of China; 3Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, People’s Republic of China Abstract: The clinical application of small interfering RNA (siRNA has been restricted by their poor intracellular uptake, low serum stability, and inability to target specific cells. During the last several decades, a great deal of effort has been devoted to exploring materials for siRNA delivery. In this study, biodegradable, tumor-targeted, self-assembled peptide nanoparticles consisting of cyclo(Arg–Gly–Asp–d–Phe–Lys-8–amino–3,6–dioxaoctanoic acid–β–maleimidopropionic acid (hereafter referred to as RPM were found to be an effective siRNA carrier both in vitro and in vivo. The nanoparticles were characterized based on transmission electron microscopy, circular dichroism spectra, and dynamic light scattering. In vitro analyses showed that the RPM/VEGFR2-siRNA exhibited negligible cytotoxicity and induced effective gene silencing. Delivery of the RPM/VEGFR2 (zebrafish-siRNA into zebrafish embryos resulted in inhibition of neovascularization. Administration of RPM/VEGFR2 (mouse-siRNA to tumor-bearing nude mice led to a significant inhibition of tumor growth, a marked reduction of vessels, and a downregulation of VEGFR2 (messenger RNA and protein in tumor tissue. Furthermore, the levels of IFN-α, IFN-γ, IL-12, and IL-6 in mouse serum, assayed via enzyme-linked immunosorbent assay, did not indicate any immunogenicity of the RPM/VEGFR2

  2. An NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles for tumor targeted drug delivery in vitro and in vivo

    Science.gov (United States)

    Gayam, Srivardhan Reddy; Venkatesan, Parthiban; Sung, Yi-Ming; Sung, Shuo-Yuan; Hu, Shang-Hsiu; Hsu, Hsin-Yun; Wu, Shu-Pao

    2016-06-01

    The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this smart biocompatible carrier system showed obvious uptake and consequent release of the drug in tumor cells, could selectively induce the tumor cell death and enhance the capability of inhibition of tumor growth in vivo. The controlled drug delivery system demonstrated its use as a potential theranostic material.The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this

  3. Smart pH- and reduction-dual-responsive folate-PEG-coated polymeric lipid vesicles for tumor-triggered targeted drug delivery

    Science.gov (United States)

    Wang, Sheng; Wang, Hanjie; Liu, Zhongyun; Wang, Liangliang; Wang, Xiaomin; Su, Lin; Chang, Jin

    2014-06-01

    To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a nano-sized structure (~50 nm) with a PEG coating. The in vitro DOX release profiles showed that the FPPLVs achieved a triggered drug release in response to acidic pH and reducing environments due to the cleavage of hydrazone bonds and disulfide bonds. It has also been demonstrated by an in vitro cellular uptake study that the FPPLVs lose their PEG coating as well as expose the folate in acidic conditions, which allows them to efficiently enter tumor cells through ligand-receptor interactions. In vitro cytotoxicity measurements also confirmed that FPPLVs exhibited pronounced antitumor activity against HeLa cells. These results suggest that FPPLVs are promising carriers for smart antitumor drug delivery applications.To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a

  4. In vivo Brain Delivery of v-myc Overproduced Human Neural Stem Cells via the Intranasal Pathway: Tumor Characteristics in the Lung of a Nude Mouse

    Directory of Open Access Journals (Sweden)

    Eun Seong Lee

    2015-01-01

    Full Text Available We aimed to monitor the successful brain delivery of stem cells via the intranasal route and to observe the long-term consequence of the immortalized human neural stem cells in the lungs of a nude mouse model. Stably immortalized HB1.F3 human neural stem cells with firefly luciferase gene (F3-effluc were intranasally delivered to BALB/c nude mice. Bioluminescence images were serially acquired until 41 days in vivo and at 4 hours and 41 days ex vivo after intranasal delivery. Lungs were evaluated by histopathology. After intranasal delivery of F3-effluc cells, the intense in vivo signals were detected in the nasal area, migrated toward the brain areas at 4 hours (4 of 13, 30.8%, and gradually decreased for 2 days. The brain signals were confirmed by ex vivo imaging (2 of 4, 50%. In the mice with initial lung signals (4 of 9, 44.4%, the lung signals disappeared for 5 days but reappeared 2 weeks later. The intense lung signals were confirmed to originate from the tumors in the lungs formed by F3-effluc cells by ex vivo imaging and histopathology. We propose that intranasal delivery of immortalized stem cells should be monitored for their successful delivery to the brain and their tumorigenicity longitudinally.

  5. Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells During Prostate Cancer Metastasis

    Science.gov (United States)

    Ruscetti, Marcus; Quach, Bill; Dadashian, Eman L.; Mulholland, David J.; Wu, Hong

    2015-01-01

    The epithelial-mesenchymal transition (EMT) has been postulated as a mechanism by which cancer cells acquire the invasive and stem-like traits necessary for distant metastasis. However, direct in vivo evidence for the role of EMT in the formation of cancer stem-like cells (CSC) and the metastatic cascade remains lacking. Here we report the first isolation and characterization of mesenchymal and EMT tumor cells, which harbor both epithelial and mesenchymal characteristics, in an autochthonous murine model of prostate cancer. By crossing the established Pb-Cre+/−;PtenL/L;KrasG12D/+ prostate cancer model with a vimentin-GFP reporter strain, generating CPKV mice, we were able to isolate epithelial, EMT and mesenchymal cancer cells based on expression of vimentin and EpCAM. CPKV mice (but not mice with Pten deletion alone) exhibited expansion of cells with EMT (EpCAM+/Vim-GFP+) and mesenchymal (EpCAM−/Vim-GFP+) characteristics at the primary tumor site and in circulation. These EMT and mesenchymal tumor cells displayed enhanced stemness and invasive character compared to epithelial tumor cells. Moreover, they displayed an enriched tumor-initiating capacity and could regenerate epithelial glandular structures in vivo, indicative of epithelia-mesenchyme plasticity. Interestingly, while mesenchymal tumor cells could persist in circulation and survive in the lung following intravenous injection, only epithelial and EMT tumor cells could form macrometastases. Our work extends the evidence that mesenchymal and epithelial states in cancer cells contribute differentially to their capacities for tumor initiation and metastatic seeding, respectively, and that EMT tumor cells exist with plasticity that can contribute to multiple stages of the metastatic cascade. PMID:25948589

  6. Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life

    Directory of Open Access Journals (Sweden)

    Glen Daniel

    2009-05-01

    Full Text Available Abstract Background The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas. Methods Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadolinium-diethyltriaminepentaacetic acid (Gd-DTPA, a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1st bolus of Gd-DTPA over the first hour, and then re-imaged with a 2nd bolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods. Results The decrease in systemic blood pressure correlated with the known metabolic stability of the bradykinin B2 receptor agonist infused. Metabolically stable bradykinin B2 agonists, methionine-lysine-bradykinin and labradimil, had differential effects on the transvascular flow rate of Gd-DTPA across the blood-brain tumor barrier. Both methionine

  7. A phase I/II study on stereotactic body radiotherapy with real-time tumor tracking using CyberKnife based on the Monte Carlo algorithm for lung tumors.

    Science.gov (United States)

    Iwata, Hiromitsu; Ishikura, Satoshi; Murai, Taro; Iwabuchi, Michio; Inoue, Mitsuhiro; Tatewaki, Koshi; Ohta, Seiji; Yokota, Naoki; Shibamoto, Yuta

    2017-08-01

    In this phase I/II study, we assessed the safety and initial efficacy of stereotactic body radiotherapy (SBRT) for lung tumors with real-time tumor tracking using CyberKnife based on the Monte Carlo algorithm. Study subjects had histologically confirmed primary non-small-cell lung cancer staged as T1a-T2aN0M0 and pulmonary oligometastasis. The primary endpoint was the incidence of Grade ≥3 radiation pneumonitis (RP) within 180 days of the start of SBRT. The secondary endpoint was local control and overall survival rates. Five patients were initially enrolled at level 1 [50 Gy/4 fractions (Fr)]; during the observation period, level 0 (45 Gy/4 Fr) was opened. The dose was escalated to the next level when grade ≥3 RP was observed in 0 out of 5 or 1 out of 10 patients. Virtual quality assurance planning was performed for 60 Gy/4 Fr; however, dose constraints for the organs at risk did not appear to be within acceptable ranges. Therefore, level 2 (55 Gy/4 Fr) was regarded as the upper limit. After the recommended dose (RD) was established, 15 additional patients were enrolled at the RD. The prescribed dose was normalized at the 95% volume border of the planning target volume based on the Monte Carlo algorithm. Between September 2011 and September 2015, 40 patients (primary 30; metastasis 10) were enrolled. Five patients were enrolled at level 0, 15 at level 1, and 20 at level 2. Only one grade 3 RP was observed at level 1. Two-year local control and overall survival rates were 98 and 81%, respectively. The RD was 55 Gy/4 Fr. SBRT with real-time tumor tracking using CyberKnife based on the Monte Carlo algorithm was tolerated well and appeared to be effective for solitary lung tumors.

  8. Combined Effect of Surface Nano-Topography and Delivery of Therapeutics on the Adhesion of Tumor Cells on Porous Silicon Substrates

    KAUST Repository

    De Vitis, S.

    2016-02-23

    Porous silicon is a nano material in which pores with different sizes, densities and depths are infiltrated in conventional silicon imparting it augmented properties including biodegradability, biocompatibility, photoluminescence. Here, we realized porous silicon substrates in which the pore size and the fractal dimension were varied over a significant range. We loaded the described substrates with a PtCl(O, O′ − acac)(DMSO) antitumor drug and determined its release profile as a function of pore size over time up to 15 days. We observed that the efficacy of delivery augments with the pore size moving from small (∼ 8nm, efficiency of delivery ∼ 0.2) to large (∼ 55nm, efficiency of delivery ∼ 0.7). Then, we verified the adhesion of MCF-7 breast cancer cells on the described substrates with and without the administration of the antitumor drug. This permitted to decouple and understand the coincidental effects of nano-topography and a controlled dosage of drugs on cell adhesion and growth. While large pore sizes guarantee elevated drug dosages, large fractal dimensions boost cell adhesion on a surface. For the particular case of tumor cells and the delivery of an anti-tumor drug, substrates with a small fractal dimension and large pore size hamper cell growth. The competition between nano-topography and a controlled dosage of drugs may either accelerate or block the adhesion of cells on a nanostructured surface, for applications in tissue engineering, regenerative medicine, personalized lab-on-a-chips, and the rational design of implantable drug delivery systems.

  9. Thermo-sensitive liposomes loaded with doxorubicin and lysine modified single-walled carbon nanotubes as tumor-targeting drug delivery system.

    Science.gov (United States)

    Zhu, Xiali; Xie, Yingxia; Zhang, Yingjie; Huang, Heqing; Huang, Shengnan; Hou, Lin; Zhang, Huijuan; Li, Zhi; Shi, Jinjin; Zhang, Zhenzhong

    2014-11-01

    This report focuses on the thermo-sensitive liposomes loaded with doxorubicin and lysine-modified single-walled carbon nanotube drug delivery system, which was designed to enhance the anti-tumor effect and reduce the side effects of doxorubicin. Doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes was prepared by reverse-phase evaporation method, the mean particle size was 232.0 ± 5.6 nm, and drug entrapment efficiency was 86.5 ± 3.7%. The drug release test showed that doxorubicin released more quickly at 42℃ than at 37℃. Compared with free doxorubicin, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes could efficiently cross the cell membranes and afford higher anti-tumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) cells in vitro. For in vivo experiments, the relative tumor volumes of the sarcomaia 180-bearing mice in thermo-sensitive liposomes group and doxorubicin group were significantly smaller than those of N.S. group. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced the tumor growth inhibition both on SMMC-7721 cells and the sarcomaia 180-bearing mice. The quality of life such as body weight, mental state, food and water intake of sarcomaia 180 tumor-bearing mice treated with doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes were much higher than those treated with doxorubicin. In conclusion, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes combined with near-infrared laser irradiation at 808 nm may potentially provide viable clinical strategies for targeting delivery of anti-cancer drugs. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  10. Stereotactic radiotherapy for lung cancer: Non-invasive real-time tumor tracking; Radiotherapie stereotaxique de carcinomes bronchiques primitifs: suivi non invasif de la cible en temps reel

    Energy Technology Data Exchange (ETDEWEB)

    Bibault, J.E.; Prevost, B.; Mirabel, X.; Lacornerie, T.; Dubus, F.; Lartigau, E. [Departement universitaire de radiotherapie, universite Lille 2, CyberKnife Nord-Ouest, centre Oscar-Lambret, 59 - Lille (France); Dansin, E. [Departement d' oncologie generale, centre Oscar-Lambret, 59 - Lille (France)

    2010-12-15

    Purpose: Stereotactic radiation therapy using the CyberKnife{sup R} has been introduced in France in 2006. Two treatment modalities are currently available: the first one (Synchrony{sup R}) is a real-time fiducial-based target tracking system, while the other (Xsight Lung Tracking [XLT] System{sup R}) is completely fiducial-free. Patients and methods: Sixty-eight patients were treated for a pulmonary tumor between June 2007 and November 2009. Since august 2008, the XLT System{sup R} was used for 26 patients. We report the necessary conditions for the XLT System (position, laterality and size of the tumor), the toxicity and outcome of this treatment. Results: Twenty-two patients were analyzed. Median follow-up was 6 months (min = 3; max = 16). Local control rate was 100%. The main toxicity was grade grade 1 pulmonary alveolitis (27%). No grade 3 or 4 toxicities were reported. Conclusion: The high local control rate and low toxicity obtained with the CyberKnife{sup R} XLT System{sup R} suggest that such treatment is an alternative for inoperable patients. (authors)

  11. The pattern recognition molecule deleted in malignant brain tumors 1 (DMBT1) and synthetic mimics inhibit liposomal nucleic acid delivery

    DEFF Research Database (Denmark)

    Lund Hansen, Pernille; Blaich, Stephanie; End, Caroline

    2011-01-01

    Liposomal nucleic acid delivery is a preferred option for therapeutic settings. The cellular pattern recognition molecule DMBT1, secreted at high levels in various diseases, and synthetic mimics efficiently inhibit liposomal nucleic acid delivery to human cells. These findings may have relevance...

  12. HoxD10 gene delivery using adenovirus/adeno-associate hybrid virus inhibits the proliferation and tumorigenicity of GH4 pituitary lactotrope tumor cells

    International Nuclear Information System (INIS)

    Cho, Mi Ae; Yashar, Parham; Kim, Suk Kyoung; Noh, Taewoong; Gillam, Mary P.; Lee, Eun Jig; Jameson, J. Larry

    2008-01-01

    Prolactinoma is one of the most common types of pituitary adenoma. It has been reported that a variety of growth factors and cytokines regulating cell growth and angiogenesis play an important role in the growth of prolactinoma. HoxD10 has been shown to impair endothelial cell migration, block angiogenesis, and maintain a differentiated phenotype of cells. We investigated whether HoxD10 gene delivery could inhibit the growth of prolactinoma. Rat GH4 lactotrope tumor cells were infected with adenovirus/adeno-associated virus (Ad/AAV) hybrid vectors carrying the mouse HoxD10 gene (Hyb-HoxD10) or the β-galactosidase gene (Hyb-Gal). Hyb-HoxD10 expression inhibited GH4 cell proliferation in vitro. The expression of FGF-2 and cyclin D2 was inhibited in GH4 cells infected with Hyb-HoxD10. GH4 cells transduced with Hyb-HoxD10 did not form tumors in nude mice. These results indicate that the delivery of HoxD10 could potentially inhibit the growth of PRL-secreting tumors. This approach may be a useful tool for targeted therapy of prolactinoma and other neoplasms

  13. CNR considerations for rapid real-time MRI tumor tracking in radiotherapy hybrid devices: Effects of B{sub 0} field strength

    Energy Technology Data Exchange (ETDEWEB)

    Wachowicz, K., E-mail: keith.wachowicz@albertahealthservices.ca; De Zanche, N.; Yip, E. [Division of Medical Physics, Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2 (Canada); Volotovskyy, V. [Cross Cancer Institute, Alberta Health Services, 11560 University Avenue, Edmonton, Alberta T6G 1Z2 (Canada); Fallone, B. G. [Department of Medical Physics, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada and Departments of Oncology and Physics, University of Alberta, 11560 University Avenue, Edmonton, Alberta T6G 1Z2 (Canada)

    2016-08-15

    Purpose: This work examines the subject of contrast-to-noise ratio (CNR), specifically between tumor and tissue background, and its dependence on the MRI field strength, B{sub 0}. This examination is motivated by the recent interest and developments in MRI/radiotherapy hybrids where real-time imaging can be used to guide treatment beams. The ability to distinguish a tumor from background tissue is of primary importance in this field, and this work seeks to elucidate the complex relationship between the CNR and B{sub 0} that is too often assumed to be purely linear. Methods: Experimentally based models of B{sub 0}-dependant relaxation for various tumor and normal tissues from the literature were used in conjunction with signal equations for MR sequences suitable for rapid real-time imaging to develop field-dependent predictions for CNR. These CNR models were developed for liver, lung, breast, glioma, and kidney tumors for spoiled gradient-echo, balanced steady-state free precession (bSSFP), and single-shot half-Fourier fast spin echo sequences. Results: Due to the pattern in which the relaxation properties of tissues are found to vary over B{sub 0} field (specifically the T{sub 1} time), there was always an improved CNR at lower fields compared to linear dependency. Further, in some tumor sites, the CNR at lower fields was found to be comparable to, or sometimes higher than those at higher fields (i.e., bSSFP CNR for glioma, kidney, and liver tumors). Conclusions: In terms of CNR, lower B{sub 0} fields have been shown to perform as well or better than higher fields for some tumor sites due to superior T{sub 1} contrast. In other sites this effect was less pronounced, reversing the CNR advantage. This complex relationship between CNR and B{sub 0} reveals both low and high magnetic fields as viable options for tumor tracking in MRI/radiotherapy hybrids.

  14. Tumor-targeting magnetic lipoplex delivery of short hairpin RNA suppresses IGF-1R overexpression of lung adenocarcinoma A549 cells in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chunmao; Ding, Chao; Kong, Minjian [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China); Dong, Aiqiang, E-mail: dr_dongaiqiang@sina.com [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China); Qian, Jianfang; Jiang, Daming; Shen, Zhonghua [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China)

    2011-07-08

    Highlights: {yields} We compared lipofection with magnetofection about difference of transfection efficiency on delivery a therapeutic gene in vitro and in vivo. {yields} We investigated the difference of shRNA induced by magnetofection and lipofection into A549 cell and subcutaneous tumor to knockdown IGF-1R overexpressed in A549 cell and A549 tumor. {yields} We investigated in vivo shRNA silenced IGF-1R overexpression 24, 48, and 72 h after shRNA intravenous injection into tumor-bearing mice by way of magnetofection and lipofection. {yields} Our results showed that magnetofection could achieve therapeutic gene targeted delivery into special site, which contributed to targeted gene therapy of lung cancers. -- Abstract: Liposomal magnetofection potentiates gene transfection by applying a magnetic field to concentrate magnetic lipoplexes onto target cells. Magnetic lipoplexes are self-assembling ternary complexes of cationic lipids with plasmid DNA associated with superparamagnetic iron oxide nanoparticles (SPIONs). Type1insulin-like growth factor receptor (IGF-1R), an important oncogene, is frequently overexpressed in lung cancer and mediates cancer cell proliferation and tumor growth. In this study, we evaluated the transfection efficiency (percentage of transfected cells) and therapeutic potential (potency of IGF-1R knockdown) of liposomal magnetofection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) in A549 cells and in tumor-bearing mice as compared to lipofection using Lipofectamine 2000. Liposomal magnetofection provided a threefold improvement in transgene expression over lipofection and transfected up to 64.1% of A549 cells in vitro. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1 {+-} 6% and by liposomal magnetofection by 85.1 {+-} 3%. In vivo delivery efficiency of the pGFPshIGF-1R plasmid into the tumor was significantly higher in the liposomal magnetofection group than in the

  15. Tumor-targeting magnetic lipoplex delivery of short hairpin RNA suppresses IGF-1R overexpression of lung adenocarcinoma A549 cells in vitro and in vivo

    International Nuclear Information System (INIS)

    Wang, Chunmao; Ding, Chao; Kong, Minjian; Dong, Aiqiang; Qian, Jianfang; Jiang, Daming; Shen, Zhonghua

    2011-01-01

    Highlights: → We compared lipofection with magnetofection about difference of transfection efficiency on delivery a therapeutic gene in vitro and in vivo. → We investigated the difference of shRNA induced by magnetofection and lipofection into A549 cell and subcutaneous tumor to knockdown IGF-1R overexpressed in A549 cell and A549 tumor. → We investigated in vivo shRNA silenced IGF-1R overexpression 24, 48, and 72 h after shRNA intravenous injection into tumor-bearing mice by way of magnetofection and lipofection. → Our results showed that magnetofection could achieve therapeutic gene targeted delivery into special site, which contributed to targeted gene therapy of lung cancers. -- Abstract: Liposomal magnetofection potentiates gene transfection by applying a magnetic field to concentrate magnetic lipoplexes onto target cells. Magnetic lipoplexes are self-assembling ternary complexes of cationic lipids with plasmid DNA associated with superparamagnetic iron oxide nanoparticles (SPIONs). Type1insulin-like growth factor receptor (IGF-1R), an important oncogene, is frequently overexpressed in lung cancer and mediates cancer cell proliferation and tumor growth. In this study, we evaluated the transfection efficiency (percentage of transfected cells) and therapeutic potential (potency of IGF-1R knockdown) of liposomal magnetofection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) in A549 cells and in tumor-bearing mice as compared to lipofection using Lipofectamine 2000. Liposomal magnetofection provided a threefold improvement in transgene expression over lipofection and transfected up to 64.1% of A549 cells in vitro. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1 ± 6% and by liposomal magnetofection by 85.1 ± 3%. In vivo delivery efficiency of the pGFPshIGF-1R plasmid into the tumor was significantly higher in the liposomal magnetofection group than in the lipofection group. In vivo IGF-1R

  16. Real-time 2D/3D registration using kV-MV image pairs for tumor motion tracking in image guided radiotherapy.

    Science.gov (United States)

    Furtado, Hugo; Steiner, Elisabeth; Stock, Markus; Georg, Dietmar; Birkfellner, Wolfgang

    2013-10-01

    Intra-fractional respiratory motion during radiotherapy leads to a larger planning target volume (PTV). Real-time tumor motion tracking by two-dimensional (2D)/3D registration using on-board kilo-voltage (kV) imaging can allow for a reduction of the PTV though motion along the imaging beam axis cannot be resolved using only one projection image. We present a retrospective patient study investigating the impact of paired portal mega-voltage (MV) and kV images on registration accuracy. Material and methods. We used data from 10 patients suffering from non-small cell lung cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT) lung treatment. For each patient we acquired a planning computed tomography (CT) and sequences of kV and MV images during treatment. We compared the accuracy of motion tracking in six degrees-of-freedom (DOF) using the anterior-posterior (AP) kV sequence or the sequence of kV-MV image pairs. Results. Motion along cranial-caudal direction could accurately be extracted when using only the kV sequence but in AP direction we obtained large errors. When using kV-MV pairs, the average error was reduced from 2.9 mm to 1.5 mm and the motion along AP was successfully extracted. Mean registration time was 188 ms. Conclusion. Our evaluation shows that using kV-MV image pairs leads to improved motion extraction in six DOF and is suitable for real-time tumor motion tracking with a conventional LINAC.

  17. CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Stage I Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Viola J.; Oermann, Eric [Department of Radiation Medicine, Georgetown University Hospital, Washington, DC (United States); Vahdat, Saloomeh [Department of Pathology, Georgetown University Hospital, Washington, DC (United States); Rabin, Jennifer; Suy, Simeng; Yu, Xia; Collins, Sean P. [Department of Radiation Medicine, Georgetown University Hospital, Washington, DC (United States); Subramaniam, Deepa [Division of Hematology and Oncology, Georgetown University Hospital, Washington, DC (United States); Banovac, Filip [Department of Radiology, Georgetown University Hospital, Washington, DC (United States); Anderson, Eric [Division of Pulmonary, Critical Care and Sleep Medicine, Georgetown University Hospital, Washington, DC (United States); Collins, Brian T., E-mail: collinsb@gunet.georgetown.edu [Department of Radiation Medicine, Georgetown University Hospital, Washington, DC (United States)

    2012-02-01

    Published data suggests that wedge resection for stage I non-small cell lung cancer (NSCLC) is associated with improved overall survival compared to stereotactic body radiation therapy. We report CyberKnife outcomes for high-risk surgical patients with biopsy-proven stage I NSCLC. PET/CT imaging was completed for staging. Three-to-five gold fiducial markers were implanted in or near tumors to serve as targeting references. Gross tumor volumes (GTVs) were contoured using lung windows; the margins were expanded by 5 mm to establish the planning treatment volume (PTV). Treatment plans were designed using a mean of 156 pencil beams. Doses delivered to the PTV ranged from 42 to 60 Gy in three fractions. The 30 Gy isodose contour extended at least 1 cm from the GTV to eradicate microscopic disease. Treatments were delivered using the CyberKnife system with tumor tracking. Examination and PET/CT imaging occurred at 3 month follow-up intervals. Forty patients (median age 76) with a median maximum tumor diameter of 2.6 cm (range, 1.4–5.0 cm) and a mean post-bronchodilator percent predicted forced expiratory volume in 1 s (FEV1) of 57% (range, 21–111%) were treated. A median dose of 48 Gy was delivered to the PTV over 3–13 days (median, 7 days). The 30 Gy isodose contour extended a mean 1.9 cm from the GTV. At a median 44 months (range, 12–72 months) follow-up, the 3 year Kaplan–Meier locoregional control and overall survival estimates compare favorably with contemporary wedge resection outcomes at 91 and 75%, respectively. CyberKnife is an effective treatment approach for stage I NSCLC that is similar to wedge resection, eradicating tumors with 1–2 cm margins in order to preserve lung function. Prospective randomized trials comparing CyberKnife with wedge resection are necessary to confirm equivalence.

  18. CyberKnife with tumor tracking: An effective alternative to wedge resection for high-risk surgical patients with stage I non-small cell lung cancer (NSCLC

    Directory of Open Access Journals (Sweden)

    Sean eCollins

    2012-02-01

    Full Text Available Published data suggests that wedge resection for stage I NSCLC results in improved overall survival compared to stereotactic body radiation therapy (SBRT. We report CyberKnife outcomes for high-risk surgical patients with biopsy-proven stage I NSCLC. PET/CT imaging was completed for staging. Three-to-five gold fiducial markers were implanted in or near tumors to serve as targeting references. Gross tumor volumes (GTVs were contoured using lung windows; the margins were expanded by 5 mm to establish the planning treatment volume (PTV. Treatment plans were designed using hundreds of pencil beams. Doses delivered to the PTV ranged from 42-60 Gy in 3 fractions. The 30-Gy isodose contour extended at least 1cm from the GTV to eradicate microscopic disease. Treatments were delivered using the CyberKnife system with tumor tracking. Examination and PET/CT imaging occurred at 3-month follow-up intervals. Forty patients (median age 76 with a median maximum tumor diameter of 2.6 cm (range, 1.4-5.0 cm and a mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV1 of 57% (range, 21 - 111% were treated. A mean dose of 50 Gy was delivered to the PTV over 3 to 13 days (median, 7 days. The 30-Gy isodose contour extended a mean 1.9 cm from the GTV. At a median 44 months (range, 12 -72 months follow-up, the 3-year Kaplan-Meier locoregional control and overall survival estimates compare favorably with contemporary wedge resection outcomes at 91% and 75% , respectively. CyberKnife is an effective treatment approach for stage I NSCLC that is similar to wedge resection, eradicating tumors with 1 to 2 cm margins in order to preserve lung function. Prospective randomized trials comparing CyberKnife with wedge resection are necessary to confirm equivalence.

  19. SU-G-BRA-04: Simulation of Errors in Maximal Intensity Projection (MIP)-Based Lung Tumor Internal Target Volumes (ITV) Using Real-Time 2D MRI and Deformable Image Registration Based Lung Tumor Tracking

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, D; Kishan, A; Santhanam, A; Min, Y; O’Connell, D; Lamb, J; Cao, M; Agazaryan, N; Yang, Y; Lee, P; Low, D [University of California, Los Angeles, Ca (United States)

    2016-06-15

    Purpose: To evaluate the effect of inter- and intra-fractional tumor motion on the error in four-dimensional computed tomography (4DCT) maximal intensity projection (MIP)–based lung tumor internal target volumes (ITV), using deformable image registration of real-time 2D-sagital cine-mode MRI acquired during lung SBRT treatments. Methods: Five lung tumor patients underwent free breathing SBRT treatment on the ViewRay, with dose prescribed to PTV (4DCT MIP-based ITV+3–6mm margin). Sagittal slice cine-MR images (3.5×3.5mm pixels) were acquired through the center of the tumor at 4 frames per second throughout the treatments (3–4 fractions of 21–32 minutes duration). Tumor GTVs were contoured on the first frame of the cine and tracked throughout the treatment using off-line optical-flow based deformable registration implemented on a GPU cluster. Pseudo-4DCT MIP-based ITVs were generated from MIPs of the deformed GTV contours limited to short segments of image data. All possible pseudo-4DCT MIP-based ITV volumes were generated with 1s resolution and compared to the ITV volume of the entire treatment course. Varying pseudo-4DCT durations from 10-50s were analyzed. Results: Tumors were covered in their entirety by PTV in the patients analysed here. However, pseudo-4DCT based ITV volumes were observed that were as small as 29% of the entire treatment-ITV, depending on breathing irregularity and the duration of pseudo-4DCT. With an increase in duration of pseudo-4DCT from 10–50s the minimum volume acquired from 95% of all pseudo-4DCTs increased from 62%–81% of the treatment ITV. Conclusion: A 4DCT MIP-based ITV offers a ‘snap-shot’ of breathing motion for the brief period of time the tumor is imaged on a specific day. Real time MRI over prolonged periods of time and over multiple treatment fractions shows that the accuracy of this snap-shot varies according to inter- and intra-fractional tumor motion. Further work is required to investigate the dosimetric

  20. SU-G-BRA-04: Simulation of Errors in Maximal Intensity Projection (MIP)-Based Lung Tumor Internal Target Volumes (ITV) Using Real-Time 2D MRI and Deformable Image Registration Based Lung Tumor Tracking

    International Nuclear Information System (INIS)

    Thomas, D; Kishan, A; Santhanam, A; Min, Y; O’Connell, D; Lamb, J; Cao, M; Agazaryan, N; Yang, Y; Lee, P; Low, D

    2016-01-01

    Purpose: To evaluate the effect of inter- and intra-fractional tumor motion on the error in four-dimensional computed tomography (4DCT) maximal intensity projection (MIP)–based lung tumor internal target volumes (ITV), using deformable image registration of real-time 2D-sagital cine-mode MRI acquired during lung SBRT treatments. Methods: Five lung tumor patients underwent free breathing SBRT treatment on the ViewRay, with dose prescribed to PTV (4DCT MIP-based ITV+3–6mm margin). Sagittal slice cine-MR images (3.5×3.5mm pixels) were acquired through the center of the tumor at 4 frames per second throughout the treatments (3–4 fractions of 21–32 minutes duration). Tumor GTVs were contoured on the first frame of the cine and tracked throughout the treatment using off-line optical-flow based deformable registration implemented on a GPU cluster. Pseudo-4DCT MIP-based ITVs were generated from MIPs of the deformed GTV contours limited to short segments of image data. All possible pseudo-4DCT MIP-based ITV volumes were generated with 1s resolution and compared to the ITV volume of the entire treatment course. Varying pseudo-4DCT durations from 10-50s were analyzed. Results: Tumors were covered in their entirety by PTV in the patients analysed here. However, pseudo-4DCT based ITV volumes were observed that were as small as 29% of the entire treatment-ITV, depending on breathing irregularity and the duration of pseudo-4DCT. With an increase in duration of pseudo-4DCT from 10–50s the minimum volume acquired from 95% of all pseudo-4DCTs increased from 62%–81% of the treatment ITV. Conclusion: A 4DCT MIP-based ITV offers a ‘snap-shot’ of breathing motion for the brief period of time the tumor is imaged on a specific day. Real time MRI over prolonged periods of time and over multiple treatment fractions shows that the accuracy of this snap-shot varies according to inter- and intra-fractional tumor motion. Further work is required to investigate the dosimetric

  1. Wide-field lifetime-based FRET imaging for the assessment of early functional distribution of transferrin-based delivery in breast tumor-bearing small animals

    Science.gov (United States)

    Sinsuebphon, Nattawut; Rudkouskaya, Alena; Barroso, Margarida; Intes, Xavier

    2016-02-01

    Targeted drug delivery is a critical aspect of successful cancer therapy. Assessment of dynamic distribution of the drug provides relative concentration and bioavailability at the target tissue. The most common approach of the assessment is intensity-based imaging, which only provides information about anatomical distribution. Observation of biomolecular interactions can be performed using Förster resonance energy transfer (FRET). Thus, FRET-based imaging can assess functional distribution and provide potential therapeutic outcomes. In this study, we used wide-field lifetime-based FRET imaging for the study of early functional distribution of transferrin delivery in breast cancer tumor models in small animals. Transferrin is a carrier for cancer drug delivery. Its interaction with its receptor is within a few nanometers, which is suitable for FRET. Alexa Fluor® 700 and Alexa Fluor® 750 were conjugated to holo-transferrin which were then administered via tail vein injection to the mice implanted with T47D breast cancer xenografts. Images were continuously acquired for 60 minutes post-injection. The results showed that transferrin was primarily distributed to the liver, the urinary bladder, and the tumor. The cellular uptake of transferrin, which was indicated by the level of FRET, was high in the liver but very low in the urinary bladder. The results also suggested that the fluorescence intensity and FRET signals were independent. The liver showed increasing intensity and increasing FRET during the observation period, while the urinary bladder showed increasing intensity but minimal FRET. Tumors gave varied results corresponding to their FRET progression. These results were relevant to the biomolecular events that occurred in the animals.

  2. Rodlike Supramolecular Nanoassemblies of Degradable Poly(Aspartic Acid) Derivatives and Hydroxyl-Rich Polycations for Effective Delivery of Versatile Tumor-Suppressive ncRNAs.

    Science.gov (United States)

    Song, Hai-Qing; Pan, Wenting; Li, Rui-Quan; Yu, Bingran; Liu, Wenjuan; Yang, Ming; Xu, Fu-Jian

    2018-03-01

    The delivery of tumor-suppressive noncoding RNAs (ncRNAs) including short ncRNAs (i.e., miRNAs) and long ncRNAs (lncRNAs) is put forward to treat tumors. In this work, novel rodlike supramolecular nanoassemblies (CNC @CB[8] @ PGEA) of degradable poly(aspartic acid) (PAsp) derivatives-grafted cellulose nanocrystals (CNCs) and hydroxyl-rich polycations (ethanolamine-functionalized poly(glycidyl methacrylate), PGEA) are proposed via typical cucurbit[8]uril (CB[8])-based host-guest interactions for delivery of different ncRNAs to treat hepatocellular carcinoma (HCC). Spindly CNCs, one kind of natural polysaccharide nanoparticles, possess good biocompatibility and unique physico-chemical properties. PGEA with abundant hydroxyl groups is one promising gene carrier with low cytotoxicity. PAsp can benefit the disassembly and degradability of nanoassemblies within cells. CNC @ CB[8]@PGEA combines the different unique properties of CNC, PGEA, and PAsp. CNC @ CB[8] @ PGEA effectively complexes the expression constructs of miR-101 (plasmid pc3.0-miR-101) and lncRNA MEG3 (plasmid pc3.0-MEG3). CNC @ CB[8] @ PGEA produces much better transfection performances than PGEA-containing assembly units. In addition, the codelivery system of CNC @ CB[8] @ PGEA/(pc3.0-MEG3+pc3.0-miR-101) nanocomplexes demonstrates better efficacy in suppressing HCC than CNC @ CB[8] @ PGEA/pc3.0-MEG3 or CNC @ CB[8] @ PGEA/pc3.0-miR-101 nanocomplexes alone. Such rodlike supramolecular nanoassemblies will provide a promising means to produce efficient delivery vectors of versatile tumor-suppressive nucleic acids. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Dual tumor-targeted poly(lactic-co-glycolic acid–polyethylene glycol–folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery

    Directory of Open Access Journals (Sweden)

    Chen J

    2017-08-01

    Full Text Available Jia Chen,1,2,* Qi Wu,1,* Li Luo,1 Yi Wang,1 Yuan Zhong,1 Han-Bin Dai,1 Da Sun,1,3 Mao-Ling Luo,4 Wei Wu,1 Gui-Xue Wang1 1Key Laboratory for Biorheological Science and Technology, Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College, Chongqing University, Chongqing, 2Institute of Laboratory Animals, Sichuan Academy of Medical Science, Sichuan Provincial People’s Hospital, Chengdu, 3Institute of Life Sciences, Wenzhou University, Wenzhou, 4School of Medicine, Wuhan University, Wuhan, China *These authors contributed equally to this work Abstract: Further specific target-ability development of biodegradable nanocarriers is extremely important to promote their security and efficiency in antitumor drug-delivery applications. In this study, a facilely prepared poly(lactic-co-glycolic acid (PLGA–polyethylene glycol (PEG–folic acid (FA copolymer was able to self-assemble into nanoparticles with favorable hydrodynamic diameters of around 100 nm and negative surface charge in aqueous solution, which was expected to enhance intracellular antitumor drug delivery by advanced dual tumor-target effects, ie, enhanced permeability and retention induced the passive target, and FA mediated the positive target. Fluorescence-activated cell-sorting and confocal laser-scanning microscopy results confirmed that doxorubicin (model drug loaded into PLGA-PEG-FA nanoparticles was able to be delivered efficiently into tumor cells and accumulated at nuclei. In addition, all hemolysis, 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium, and zebrafish-development experiments demonstrated that PLGA-PEG-FA nanoparticles were biocompatible and secure for biomedical applications, even at high polymer concentration (0.1 mg/mL, both in vitro and in vivo. Therefore, PLGA-PEG-FA nanoparticles provide a feasible controlled-release platform for secure and efficient antitumor drug

  4. Doxorubicin-modified magnetic nanoparticles as a drug delivery system for magnetic resonance imaging-monitoring magnet-enhancing tumor chemotherapy.

    Science.gov (United States)

    Liang, Po-Chin; Chen, Yung-Chu; Chiang, Chi-Feng; Mo, Lein-Ray; Wei, Shwu-Yuan; Hsieh, Wen-Yuan; Lin, Win-Li

    2016-01-01

    In this study, we developed functionalized superparamagnetic iron oxide (SPIO) nanoparticles consisting of a magnetic Fe3O4 core and a shell of aqueous stable polyethylene glycol (PEG) conjugated with doxorubicin (Dox) (SPIO-PEG-D) for tumor magnetic resonance imaging (MRI) enhancement and chemotherapy. The size of SPIO nanoparticles was ~10 nm, which was visualized by transmission electron microscope. The hysteresis curve, generated with vibrating-sample magnetometer, showed that SPIO-PEG-D was superparamagnetic with an insignificant hysteresis. The transverse relaxivity (r 2) for SPIO-PEG-D was significantly higher than the longitudinal relaxivity (r 1) (r 2/r 1 >10). The half-life of Dox in blood circulation was prolonged by conjugating Dox on the surface of SPIO with PEG to reduce its degradation. The in vitro experiment showed that SPIO-PEG-D could cause DNA crosslink more serious, resulting in a lower DNA expression and a higher cell apoptosis for HT-29 cancer cells. The Prussian blue staining study showed that the tumors treated with SPIO-PEG-D under a magnetic field had a much higher intratumoral iron density than the tumors treated with SPIO-PEG-D alone. The in vivo MRI study showed that the T2-weighted signal enhancement was stronger for the group under a magnetic field, indicating that it had a better accumulation of SPIO-PEG-D in tumor tissues. In the anticancer efficiency study for SPIO-PEG-D, the results showed that there was a significantly smaller tumor size for the group with a magnetic field than the group without. The in vivo experiments also showed that this drug delivery system combined with a local magnetic field could reduce the side effects of cardiotoxicity and hepatotoxicity. The results showed that the developed SPIO-PEG-D nanoparticles own a great potential for MRI-monitoring magnet-enhancing tumor chemotherapy.

  5. Daily Tracking of Glioblastoma Resection Cavity, Cerebral Edema, and Tumor Volume with MRI-Guided Radiation Therapy.

    Science.gov (United States)

    Mehta, Shahil; Gajjar, Shefali R; Padgett, Kyle R; Asher, David; Stoyanova, Radka; Ford, John C; Mellon, Eric A

    2018-03-19

    Radiation therapy (RT) plays a critical role in the treatment of glioblastoma. Studies of brain imaging during RT for glioblastoma have demonstrated changes in the brain during RT. However, frequent or daily utilization of standalone magnetic resonance imaging (MRI) scans during RT have limited feasibility. The recent release of the tri-cobalt-60 MRI-guided RT (MR-IGRT) device (ViewRay MRIdian, Cleveland, OH) allows for daily brain MRI for the RT setup. Daily MRI of three postoperative patients undergoing RT and temozolomide for glioblastoma over a six-week course allowed for the identification of changes to the cavity, edema, and visible tumor on a daily basis. The volumes and dimensions of the resection cavities, edema, and T2-hyperintense tumor were measured. A general trend of daily decreases in cavity measurements was observed in all patients. For the one patient with edema, a trend of daily increases followed by a trend of daily decreases were observed. These results suggest that daily MRI could be used for onboard resimulation and adaptive RT for future fluctuations in the sizes of brain tumors, cavities, or cystic components. This could improve tumor targeting and reduce RT of healthy brain tissue.

  6. Doxorubicin delivery to 3D multicellular spheroids and tumors based on boronic acid-rich chitosan nanoparticles.

    Science.gov (United States)

    Wang, Xin; Zhen, Xu; Wang, Jing; Zhang, Jialiang; Wu, Wei; Jiang, Xiqun

    2013-06-01

    Boronic acid-rich chitosan-poly(N-3-acrylamidophenylboronic acid) nanoparticles (CS-PAPBA NPs) with the tunable size were successfully prepared by polymerizing N-3-acrylamidophenylboronic acid in the presence of chitosan in an aqueous solution. The CS-PAPBA NPs were then functionalized by a tumor-penetrating peptide iRGD and loading doxorubicin (DOX). The interaction between boronic acid groups of hydrophobic PAPBA and the amino groups of hydrophilic chitosan inside the nanoparticles was examined by solid-state NMR measurement. The size and morphology of nanoparticles were characterized by dynamic light scattering and electron microscopy. The cellular uptake, tumor penetration, biodistribution and antitumor activity of the nanoparticles were evaluated by using three-dimensional (3-D) multicellular spheroids (MCs) as the in vitro model and H22 tumor-bearing mice as the in vivo model. It was found that the iRGD-conjugated nanoparticles significantly improved the efficiency of DOX penetration in MCs, compared with free DOX and non-conjugated nanoparticles, resulting in the efficient cell killing in the MCs. In vivo antitumor activity examination indicated that iRGD-conjugated CS-PAPBA nanoparticles promoted the accumulation of nanoparticles in tumor tissue and enhanced their penetration in tumor areas, both of which improved the efficiency of DOX-loaded nanoparticles in restraining tumor growth and prolonging the life time of H22 tumor-bearing mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Oxaliplatin immuno hybrid nanoparticles for active targeting: an approach for enhanced apoptotic activity and drug delivery to colorectal tumors.

    Science.gov (United States)

    Tummala, Shashank; Gowthamarajan, K; Satish Kumar, M N; Wadhwani, Ashish

    2016-06-01

    Tumor necrosis factor related apoptosis inducing ligand (TRAIL) proved to be a promising new target for colorectal cancer treatment. Elevated expression of TRAIL protein in tumor cells distinguishes it from healthy cells, thereby delivering the drug at the specific site. Here, we formulated oxaliplatin immunohybrid nanoparticles (OIHNPs) to deliver oxaliplatin and anti-TRAIL for colorectal cancer treatment in xenograft tumor models. The polymeric chitosan layer binds to the lipid film with the mixture of phospholipids by an ultra sound method followed by conjugating with thiolated antibody using DSPE-PEG-mal3400, resulting in the formation of OIHNPs. The polymer layer helps in more encapsulation of the drug (71 ± 0.09%) with appreciable particle size (95 ± 0.01 nm), and lipid layer prevents degradation of the drug in serum by preventing nanoparticle aggregation. OIHNPs have shown a 4-fold decrease in the IC50 value compared to oxaliplatin in HT-29 cells by the MTT assay. These immuno-nanoparticles represent the successful uptake and internalization of oxaliplatin in HT-29 cells rather than in MCF-7 cells determined by triple fluorescence method. Apoptotic activity in vitro of OIHNPs was determined by the change in the mitochondria membrane potential that further elevates its anti-tumor property. Furthermore, the conjugated nanoparticles can effectively deliver the drug to the tumor sites, which can be attributed to its ability in reducing tumor mass and tumor volume in xenograft tumor models in vivo along with sustaining its release in vitro. These findings indicated that the oxaliplatin immuno-hybrid nanoparticles would be a promising nano-sized active targeted formulation for colorectal-tumor targeted therapy.

  8. Target tracking using DMLC for volumetric modulated arc therapy: A simulation study

    Energy Technology Data Exchange (ETDEWEB)

    Sun Baozhou; Rangaraj, Dharanipathy; Papiez, Lech; Oddiraju, Swetha; Yang Deshan; Li, H. Harold [Department of Radiation Oncology, School of Medicine, Washington University, 4921 Parkview Place, St. Louis, Missouri 63110 (United States); Department of Radiation Oncology, Southwestern Medical Center, University of Texas, Dallas, Texas 75390 (United States); Department of Radiation Oncology, School of Medicine, Washington University, 4921 Parkview Place, St. Louis, Missouri 63110 (United States)

    2010-12-15

    Purpose: Target tracking using dynamic multileaf collimator (DMLC) is a promising approach for intrafraction motion management in radiation therapy. The purpose of this work is to develop a DMLC tracking algorithm capable of delivering volumetric-modulated arc therapy (VMAT) to the targets that experience two-dimensional (2D) rigid motion in the beam's eye view. Methods: The problem of VMAT delivery to moving targets is formulated as a control problem with constraints. The relationships between gantry speed, gantry acceleration, MLC leaf-velocity, dose rate, and target motion are derived. An iterative search algorithm is developed to find numerical solutions for efficient delivery of a specific VMAT plan to the moving target using 2D DMLC tracking. The delivery of five VMAT lung plans is simulated. The planned and delivered fluence maps in the target-reference frame are calculated and compared. Results: The simulation demonstrates that the 2D tracking algorithm is capable of delivering the VMAT plan to a moving target fast and accurately without violating the machine constraints and the integrity of the treatment plan. The average delivery time is only 29 s longer than that of no-tracking delivery, 101 versus 72 s, respectively. The fluence maps are normalized to 200 MU and the average root-mean-square error between the desired and the delivered fluence is 2.1 MU, compared to 14.8 MU for no-tracking and 3.6 MU for one-dimensional tracking. Conclusions: A locally optimal MLC tracking algorithm for VMAT delivery is proposed, aiming at shortest delivery time while maintaining treatment plan invariant. The inconsequential increase of treatment time due to DMLC tracking is clinically desirable, which makes VMAT with DMLC tracking attractive in treating moving tumors.

  9. SU-G-JeP1-08: Dual Modality Verification for Respiratory Gating Using New Real- Time Tumor Tracking Radiotherapy System

    Energy Technology Data Exchange (ETDEWEB)

    Shiinoki, T; Hanazawa, H; Shibuya, K [Yamaguchi University, Ube, Yamaguchi (Japan); Kawamura, S; Koike, M; Yuasa, Y; Uehara, T; Fujimoto, K [Yamaguchi University Hospital, Ube, Yamaguchi (Japan)

    2016-06-15

    Purpose: The respirato ry gating system combined the TrueBeam and a new real-time tumor-tracking radiotherapy system (RTRT) was installed. The RTRT system consists of two x-ray tubes and color image intensifiers. Using fluoroscopic images, the fiducial marker which was implanted near the tumor was tracked and was used as the internal surrogate for respiratory gating. The purposes of this study was to develop the verification technique of the respiratory gating with the new RTRT using cine electronic portal image device images (EPIDs) of TrueBeam and log files of the RTRT. Methods: A patient who underwent respiratory gated SBRT of the lung using the RTRT were enrolled in this study. For a patient, the log files of three-dimensional coordinate of fiducial marker used as an internal surrogate were acquired using the RTRT. Simultaneously, the cine EPIDs were acquired during respiratory gated radiotherapy. The data acquisition was performed for one field at five sessions during the course of SBRT. The residual motion errors were calculated using the log files (E{sub log}). The fiducial marker used as an internal surrogate into the cine EPIDs was automatically extracted by in-house software based on the template-matching algorithm. The differences between the the marker positions of cine EPIDs and digitally reconstructed radiograph were calculated (E{sub EPID}). Results: Marker detection on EPID using in-house software was influenced by low image contrast. For one field during the course of SBRT, the respiratory gating using the RTRT showed the mean ± S.D. of 95{sup th} percentile E{sub EPID} were 1.3 ± 0.3 mm,1.1 ± 0.5 mm,and those of E{sub log} were 1.5 ± 0.2 mm, 1.1 ± 0.2 mm in LR and SI directions, respectively. Conclusion: We have developed the verification method of respiratory gating combined TrueBeam and new real-time tumor-tracking radiotherapy system using EPIDs and log files.

  10. In vivo human adipose-derived mesenchymal stem cell tracking after intra-articular delivery in a rat osteoarthritis model

    Directory of Open Access Journals (Sweden)

    Meng Li

    2016-11-01

    Full Text Available Abstract Background Human adipose-derived mesenchymal stem cells (haMSCs have shown efficacy in treating osteoarthritis (OA both preclinically and clinically via intra-articular (IA injection. However, understanding the mode of action of the cell therapy has been limited by cell tracking capability and correlation between the pharmacokinetics of the injected cells and the intended pharmacodynamics effect. This study aims to explore methodology and to understand in vivo biodistribution of clinical-grade haMSCs labeled with fluorescent dye and injected into an immunocompetent OA rat model. Methods haMSCs labeled with fluorescent dye were investigated for their proliferation and differentiation capabilities. Labeled cells were used to establish detection threshold of a noninvasive biofluorescent imaging system before the cells (2.5 × 106 were injected into a conventional rat OA model induced by medial meniscectomy for 8 weeks. We attempted to reveal the existence of labeled cells in vivo by imaging and a molecular biomarker approach, and to correlate with the in vivo efficacy and physical presence over a follow-up period up to 10 weeks. Results In vitro proliferation and differentiation of haMSCs were not affected by the labeling of DiD dye. Detection thresholds of the labeled cells in vitro and in vivo were determined to be 104 and 105 cells, respectively. When 2.5 × 106 haMSCs were injected into the joints of a rat OA model, fluorescent signals (or >105 cells lasted for about 10 weeks in the surgical knee joint at the same time as efficacy was observed. Signals in nonsurgical rats only lasted for 4 weeks. The human MSCs were shown to engraft to the rat joint tissues and were proliferative. Human FOXP2 gene was only detected in the knee joint tissue, suggesting limited biodistribution locally to the joints. Conclusions The current study represents the first attempt to correlate cell therapy efficacy on OA with the physical presence

  11. Verification of Accuracy of CyberKnife Tumor-tracking Radiation Therapy Using Patient-specific Lung Phantoms

    International Nuclear Information System (INIS)

    Jung, Jinhong; Song, Si Yeol; Yoon, Sang Min; Kwak, Jungwon; Yoon, KyoungJun; Choi, Wonsik; Jeong, Seong-Yun; Choi, Eun Kyung; Cho, Byungchul

    2015-01-01

    Purpose: To investigate the accuracy of the CyberKnife Xsight Lung Tracking System (XLTS) compared with that of a fiducial-based target tracking system (FTTS) using patient-specific lung phantoms. Methods and Materials: Three-dimensional printing technology was used to make individualized lung phantoms that closely mimicked the lung anatomy of actual patients. Based on planning computed tomographic data from 6 lung cancer patients who underwent stereotactic ablative radiation therapy using the CyberKnife, the volume above a certain Hounsfield unit (HU) was assigned as the structure to be filled uniformly with polylactic acid material by a 3-dimensional printer (3D Edison, Lokit, Korea). We evaluated the discrepancies between the measured and modeled target positions, representing the total tracking error, using 3 log files that were generated during each treatment for both the FTTS and the XLTS. We also analyzed the γ index between the film dose measured under the FTTS and XLTS. Results: The overall mean values and standard deviations of total tracking errors for the FTTS were 0.36 ± 0.39 mm, 0.15 ± 0.64 mm, and 0.15 ± 0.62 mm for the craniocaudal (CC), left–right (LR), and anteroposterior (AP) components, respectively. Those for the XLTS were 0.38 ± 0.54 mm, 0.13 ± 0.18 mm, and 0.14 ± 0.37 mm for the CC, LR, and AP components, respectively. The average of γ passing rates was 100% for the criteria of 3%, 3 mm; 99.6% for the criteria of 2%, 2 mm; and 86.8% for the criteria of 1%, 1 mm. Conclusions: The XLTS has segmentation accuracy comparable with that of the FTTS and small total tracking errors

  12. Verification of Accuracy of CyberKnife Tumor-tracking Radiation Therapy Using Patient-specific Lung Phantoms

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Jinhong [Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul (Korea, Republic of); Song, Si Yeol, E-mail: coocoori@gmail.com [Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Yoon, Sang Min; Kwak, Jungwon; Yoon, KyoungJun [Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Choi, Wonsik [Department of Radiation Oncology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung (Korea, Republic of); Jeong, Seong-Yun [Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Choi, Eun Kyung; Cho, Byungchul [Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2015-07-15

    Purpose: To investigate the accuracy of the CyberKnife Xsight Lung Tracking System (XLTS) compared with that of a fiducial-based target tracking system (FTTS) using patient-specific lung phantoms. Methods and Materials: Three-dimensional printing technology was used to make individualized lung phantoms that closely mimicked the lung anatomy of actual patients. Based on planning computed tomographic data from 6 lung cancer patients who underwent stereotactic ablative radiation therapy using the CyberKnife, the volume above a certain Hounsfield unit (HU) was assigned as the structure to be filled uniformly with polylactic acid material by a 3-dimensional printer (3D Edison, Lokit, Korea). We evaluated the discrepancies between the measured and modeled target positions, representing the total tracking error, using 3 log files that were generated during each treatment for both the FTTS and the XLTS. We also analyzed the γ index between the film dose measured under the FTTS and XLTS. Results: The overall mean values and standard deviations of total tracking errors for the FTTS were 0.36 ± 0.39 mm, 0.15 ± 0.64 mm, and 0.15 ± 0.62 mm for the craniocaudal (CC), left–right (LR), and anteroposterior (AP) components, respectively. Those for the XLTS were 0.38 ± 0.54 mm, 0.13 ± 0.18 mm, and 0.14 ± 0.37 mm for the CC, LR, and AP components, respectively. The average of γ passing rates was 100% for the criteria of 3%, 3 mm; 99.6% for the criteria of 2%, 2 mm; and 86.8% for the criteria of 1%, 1 mm. Conclusions: The XLTS has segmentation accuracy comparable with that of the FTTS and small total tracking errors.

  13. Evaluation of RGD-targeted albumin carriers for specific delivery of auristatin E to tumor blood vessels

    NARCIS (Netherlands)

    Temming, Kai; Meyer, Damon L.; Zabinski, Roger; Dijkers, Eli C. F.; Poelstra, Klaas; Molema, Grietje; Kok, Robbert J.

    2006-01-01

    Induction of apoptosis in endothelial cells is considered an attractive strategy to therapeutically interfere with a solid tumor's blood supply. In the present paper, we constructed cytotoxic conjugates that specifically target angiogenic endothelial cells, thus preventing typical side effects of

  14. Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity.

    Science.gov (United States)

    Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M; Tinder, Teresa L; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J; Mukherjee, Pinku

    2012-11-01

    Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.

  15. Clearance and Biodistribution of Liposomally Encapsulated Nitroxides: A Model for Targeted Delivery of Electron Paramagnetic Resonance Imaging Probes to Tumors

    Science.gov (United States)

    Burks, Scott R.; Legenzov, Eric A.; Rosen, Gerald M.

    2011-01-01

    Electron paramagnetic resonance (EPR) imaging using nitroxides as molecular probes is potentially a powerful tool for the detection and physiological characterization of micrometastatic lesions. Encapsulating nitroxides in anti-HER2 immunoliposomes at high concentrations to take advantage of the “self-quenching” phenomenon of nitroxides allows generation of robust EPR signals in HER2-overexpressing breast tumor cells with minimal background from indifferent tissues or circulating liposomes. We investigated the in vivo pharmacological properties of nitroxides encapsulated in sterically stabilized liposomes designed for long circulation times. We show that circulation times of nitroxides can be extended from hours to days; this increases the proportion of liposomes in circulation to enhance tumor targeting. Furthermore, nitroxides encapsulated in sterically stabilized anti-HER2 immunoliposomes can be delivered to HER2-overexpressing tumors at micromolar concentrations, which should be imageable by EPR. Lastly, after in vivo administration, liposomally encapsulated nitroxide signal also appears in the liver, spleen, and kidneys. Although these organs are spatially distinct and would not hinder tumor imaging in our model, understanding nitroxide signal retention in these organs is essential for further improvements in EPR imaging contrast between tumors and other tissues. These results lay the foundation to use liposomally delivered nitroxides and EPR imaging to visualize tumor cells in vivo. PMID:21737567

  16. Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors

    DEFF Research Database (Denmark)

    Guo, Xiong; Zhao, Zhiyue; Chen, Dawei

    2018-01-01

    Co-delivery of anti-cancer drugs is promising to improve the efficacy of cancer treatment. This study was aiming to investigate the potential of concurrent delivery of resveratrol (RES) and docetaxel (DTX) via polymeric nanocarriers to treat breast cancer. To this end, methoxyl poly(ethylene glycol...... profiles, and enhanced cytotoxicity in vitro against MCF-7 cells. The AUC(0→t) of DTX and RES in mPEG-PDLA micelles after i.v. administration to rats were 3.0-fold and 1.6-fold higher than that of i.v. injections of the individual drugs. These findings indicated that the co-delivery of RES and DTX using m...

  17. Interplay effects in proton scanning for lung: a 4D Monte Carlo study assessing the impact of tumor and beam delivery parameters

    International Nuclear Information System (INIS)

    Dowdell, S; Grassberger, C; Sharp, G C; Paganetti, H

    2013-01-01

    Relative motion between a tumor and a scanning proton beam results in a degradation of the dose distribution (interplay effect). This study investigates the relationship between beam scanning parameters and the interplay effect, with the goal of finding parameters that minimize interplay. 4D Monte Carlo simulations of pencil beam scanning proton therapy treatments were performed using the 4DCT geometry of five lung cancer patients of varying tumor size (50.4–167.1 cc) and motion amplitude (2.9–30.1 mm). Treatments were planned assuming delivery in 35 × 2.5 Gy(RBE) fractions. The spot size, time to change the beam energy (τ es ), time required for magnet settling (τ ss ), initial breathing phase, spot spacing, scanning direction, scanning speed, beam current and patient breathing period were varied for each of the five patients. Simulations were performed for a single fraction and an approximation of conventional fractionation. For the patients considered, the interplay effect could not be predicted using the superior–inferior motion amplitude alone. Larger spot sizes (σ ∼ 9–16 mm) were less susceptible to interplay, giving an equivalent uniform dose (EUD) of 99.0 ± 4.4% (1 standard deviation) in a single fraction compared to 86.1 ± 13.1% for smaller spots (σ ∼ 2–4 mm). The smaller spot sizes gave EUD values as low as 65.3% of the prescription dose in a single fraction. Reducing the spot spacing improved the target dose homogeneity. The initial breathing phase can have a significant effect on the interplay, particularly for shorter delivery times. No clear benefit was evident when scanning either parallel or perpendicular to the predominant axis of motion. Longer breathing periods decreased the EUD. In general, longer delivery times led to lower interplay effects. Conventional fractionation showed significant improvement in terms of interplay, giving a EUD of at least 84.7% and 100.0% of the prescription dose for the small and larger spot sizes

  18. Interplay effects in proton scanning for lung: a 4D Monte Carlo study assessing the impact of tumor and beam delivery parameters.

    Science.gov (United States)

    Dowdell, S; Grassberger, C; Sharp, G C; Paganetti, H

    2013-06-21

    Relative motion between a tumor and a scanning proton beam results in a degradation of the dose distribution (interplay effect). This study investigates the relationship between beam scanning parameters and the interplay effect, with the goal of finding parameters that minimize interplay. 4D Monte Carlo simulations of pencil beam scanning proton therapy treatments were performed using the 4DCT geometry of five lung cancer patients of varying tumor size (50.4-167.1 cc) and motion amplitude (2.9-30.1 mm). Treatments were planned assuming delivery in 35 × 2.5 Gy(RBE) fractions. The spot size, time to change the beam energy (τes), time required for magnet settling (τss), initial breathing phase, spot spacing, scanning direction, scanning speed, beam current and patient breathing period were varied for each of the five patients. Simulations were performed for a single fraction and an approximation of conventional fractionation. For the patients considered, the interplay effect could not be predicted using the superior-inferior motion amplitude alone. Larger spot sizes (σ ~ 9-16 mm) were less susceptible to interplay, giving an equivalent uniform dose (EUD) of 99.0 ± 4.4% (1 standard deviation) in a single fraction compared to 86.1 ± 13.1% for smaller spots (σ ~ 2-4 mm). The smaller spot sizes gave EUD values as low as 65.3% of the prescription dose in a single fraction. Reducing the spot spacing improved the target dose homogeneity. The initial breathing phase can have a significant effect on the interplay, particularly for shorter delivery times. No clear benefit was evident when scanning either parallel or perpendicular to the predominant axis of motion. Longer breathing periods decreased the EUD. In general, longer delivery times led to lower interplay effects. Conventional fractionation showed significant improvement in terms of interplay, giving a EUD of at least 84.7% and 100.0% of the prescription dose for the small and larger spot sizes respectively. The

  19. SU-F-T-321: The Effect of an Electromagnetic Array Used for Patient Localization and Tumor Tracking On OSLD in Vivo Dosimetry

    International Nuclear Information System (INIS)

    Rea, A; Kuruvilla, A; Gill, G; Riegel, A; Klein, E

    2016-01-01

    Purpose: The purpose of this study was to observe the effect of an electromagnetic array used for patient localization and tumor tracking on optically-stimulated luminescent in-vivo dosimetry. Methods: A linear accelerator equipped with four photon energies was used to irradiate optically stimulated luminescent dosimeters (OSLDs) at the respective dmax depths and in the buildup region, with and without the presence of an electromagnetic array used for tumor tracking and patient localization. The OSLDs were placed on solid water slabs under 5 mm bolus and on each face of an octagonal phantom, and irradiated using both static beam and arc geometry, with and without the electromagnetic array under our setup. The electromagnetic array was placed 6 cm above the phantom to coincide with similar distances used during patient treatment. Ionization chamber measurements in a water phantom were also taken initially for comparison with the simple geometry OSLD measurements and published data. Results: Under simple geometry, a negligible change was observed at dmax for all energies when the electromagnetic array was placed over the setup. When measuring at five millimeter depth, increases of 1.3/3.1/16/18% were observed for energies 4X/6X/10X/15X respectively when the electromagnetic array was in place. Measurements using the octagonal phantom yielded scattered results for the lateral and posterior oblique fields, and showed increases in dose to the OSLDs placed on the anterior and lateral anterior faces of the phantom. Conclusion: Placing the electromagnetic array very close to the patient’s surface acts as a beam spoiler in the buildup region (at 5 mm depth), which in turn causes an increase in the measured dose reading of the OSLD. This increase in dose is more pronounced when the OSLD is placed directly underneath the electromagnetic array than off to one side or the other.

  20. Steep Dose-Response Relationship for Stage I Non-Small-Cell Lung Cancer Using Hypofractionated High-Dose Irradiation by Real-Time Tumor-Tracking Radiotherapy

    International Nuclear Information System (INIS)

    Onimaru, Rikiya; Fujino, Masaharu; Yamazaki, Koichi; Onodera, Yuya; Taguchi, Hiroshi; Katoh, Norio; Hommura, Fumihiro; Oizumi, Satoshi; Nishimura, Masaharu; Shirato, Hiroki

    2008-01-01

    Purpose: To investigate the clinical outcomes of patients with pathologically proven, peripherally located, Stage I non-small-cell lung cancer who had undergone stereotactic body radiotherapy using real-time tumor tracking radiotherapy during the developmental period. Methods and Materials: A total of 41 patients (25 with Stage T1 and 16 with Stage T2) were admitted to the study between February 2000 and June 2005. A 5-mm planning target volume margin was added to the clinical target volume determined with computed tomography at the end of the expiratory phase. The gating window ranged from ±2 to 3 mm. The dose fractionation schedule was 40 or 48 Gy in four fractions within 1 week. The dose was prescribed at the center of the planning target volume, giving more than an 80% dose at the planning target volume periphery. Results: For 28 patients treated with 48 Gy in four fractions, the overall actuarial survival rate at 3 years was 82% for those with Stage IA and 32% for those with Stage IB. For patients treated with 40 Gy in four fractions within 1 week, the overall actuarial survival rate at 3 years was 50% for those with Stage IA and 0% for those with Stage IB. A significant difference was found in local control between those with Stage IB who received 40 Gy vs. 48 Gy (p = 0.0015) but not in those with Stage IA (p = 0.5811). No serious radiation morbidity was observed with either dose schedule. Conclusion: The results of our study have shown that 48 Gy in four fractions within 1 week is a safe and effective treatment for peripherally located, Stage IA non-small-cell lung cancer. A steep dose-response curve between 40 and 48 Gy using a daily dose of 12 Gy delivered within 1 week was identified for Stage IB non-small-cell lung cancer in stereotactic body radiotherapy using real-time tumor tracking radiotherapy

  1. Percutaneous biopsy of malignant hepatic tumor in patients with bleeding tendency : usefulness of gelfoam plugging up the biopsy track

    International Nuclear Information System (INIS)

    Yoon, Hye Ran; Kwak, Byung Kook; Choi, Chi Hoon; Park, Yong Ok; Yang, Keun Myeong; Seo, Ja Young; Lee, Shin Hyung; Lee, Chang Joon; Shim, Hyung Jin

    1998-01-01

    To plug the biopsy site in eight patients with coagulopathy who had undergone percutaneous liver biopsy. To this end, gelfoam cartridge was used as a sealant. Materials and Methods: Using an 18G Tru-Cut-type disposable automated biopsy gun(Soo Ho Medi-tech, Seoul, Korea) and under US guidance, eight patients underwent percutaneous liver biopsy. After the gun had fired, the biopsy specimen in the inner stylet was retrieved while the outer cannula was held in place ; the cannula was then used to plug the biopsy tracks with gelfoam, using two or three cartridges. If bleeding occurred, this was controlled by the use of more gelfoam cartridges. Results:Diagnostic target tissue was obtained in seven of the eight patients(87.5%). Hepatocellular carcinoma was diagnosed in five cases and metastatic cancer in two. Profuse bleeding was observed in one patient(12.5%) and resolved by gelfoam plugging. Conclusion: We believe that in patients with coagulopathy who are required to undergo liver biopsy plugging the liver biopsy track with gelfoam cartridge is a simple, safe and useful method

  2. Multiple Delivery of siRNA against Endoglin into Murine Mammary Adenocarcinoma Prevents Angiogenesis and Delays Tumor Growth

    Science.gov (United States)

    Dolinsek, Tanja; Markelc, Bostjan; Sersa, Gregor; Coer, Andrej; Stimac, Monika; Lavrencak, Jaka; Brozic, Andreja; Kranjc, Simona; Cemazar, Maja

    2013-01-01

    Endoglin is a transforming growth factor-β (TGF- β) co-receptor that participates in the activation of a signaling pathway that mediates endothelial cell proliferation and migration in angiogenic tumor vasculature. Therefore, silencing of endoglin expression is an attractive approach for antiangiogenic therapy of tumors. The aim of our study was to evaluate the therapeutic potential of small interfering RNA (siRNA) molecules against endoglin in vitro and in vivo. Therapeutic potential in vitro was assessed in human and murine endothelial cells (HMEC-1, 2H11) by determining endoglin expression level, cell proliferation and tube formation. In vivo, the therapeutic potential of siRNA molecules was evaluated in TS/A mammary adenocarcinoma growing in BALB/c mice. Results of our study showed that siRNA molecules against endoglin have a good antiangiogenic therapeutic potential in vitro, as expression of endoglin mRNA and protein levels in mouse and human microvascular endothelial cells after lipofection were efficiently reduced, which resulted in the inhibition of endothelial cell proliferation and tube formation. In vivo, silencing of endoglin with triple electrotransfer of siRNA molecules into TS/A mammary adenocarcinoma also significantly reduced the mRNA levels, number of tumor blood vessels and the growth of tumors. The obtained results demonstrate that silencing of endoglin is a promising antiangiogenic therapy of tumors that could not be used as single treatment, but as an adjunct to the established cytotoxic treatment approaches. PMID:23593103

  3. Multiple delivery of siRNA against endoglin into murine mammary adenocarcinoma prevents angiogenesis and delays tumor growth.

    Directory of Open Access Journals (Sweden)

    Tanja Dolinsek

    Full Text Available Endoglin is a transforming growth factor-β (TGF- β co-receptor that participates in the activation of a signaling pathway that mediates endothelial cell proliferation and migration in angiogenic tumor vasculature. Therefore, silencing of endoglin expression is an attractive approach for antiangiogenic therapy of tumors. The aim of our study was to evaluate the therapeutic potential of small interfering RNA (siRNA molecules against endoglin in vitro and in vivo. Therapeutic potential in vitro was assessed in human and murine endothelial cells (HMEC-1, 2H11 by determining endoglin expression level, cell proliferation and tube formation. In vivo, the therapeutic potential of siRNA molecules was evaluated in TS/A mammary adenocarcinoma growing in BALB/c mice. Results of our study showed that siRNA molecules against endoglin have a good antiangiogenic therapeutic potential in vitro, as expression of endoglin mRNA and protein levels in mouse and human microvascular endothelial cells after lipofection were efficiently reduced, which resulted in the inhibition of endothelial cell proliferation and tube formation. In vivo, silencing of endoglin with triple electrotransfer of siRNA molecules into TS/A mammary adenocarcinoma also significantly reduced the mRNA levels, number of tumor blood vessels and the growth of tumors. The obtained results demonstrate that silencing of endoglin is a promising antiangiogenic therapy of tumors that could not be used as single treatment, but as an adjunct to the established cytotoxic treatment approaches.

  4. Nanoparticle Delivery of Artesunate Enhances the Anti-tumor Efficiency by Activating Mitochondria-Mediated Cell Apoptosis

    Science.gov (United States)

    Liu, Rui; Yu, Xiwei; Su, Chang; Shi, Yijie; Zhao, Liang

    2017-06-01

    Artemisinin and its derivatives were considered to exert a broad spectrum of anti-cancer activities, and they induced significant anti-cancer effects in tumor cells. Artemisinin and its derivatives could be absorbed quickly, and they were widely distributed, selectively killing tumor cells. Since low concentrations of artesunate primarily depended on oncosis to induce cell death in tumor cells, its anti-tumor effects were undesirable and limited. To obtain better anti-tumor effects, in this study, we took advantage of a new nanotechnology to design novel artesunate-loaded bovine serum albumin nanoparticles to achieve the mitochondrial accumulation of artesunate and induce mitochondrial-mediated apoptosis. The results showed that when compared with free artesunate's reliance on oncotic death, artesunate-loaded bovine serum albumin nanoparticles showed higher cytotoxicity and their significant apoptotic effects were induced through the distribution of artesunate in the mitochondria. This finding indicated that artesunate-loaded bovine serum albumin nanoparticles damaged the mitochondrial integrity and activated mitochondrial-mediated cell apoptosis by upregulating apoptosis-related proteins and facilitating the rapid release of cytochrome C.

  5. Real-time intensity based 2D/3D registration using kV-MV image pairs for tumor motion tracking in image guided radiotherapy

    Science.gov (United States)

    Furtado, H.; Steiner, E.; Stock, M.; Georg, D.; Birkfellner, W.

    2014-03-01

    Intra-fractional respiratorymotion during radiotherapy is one of themain sources of uncertainty in dose application creating the need to extend themargins of the planning target volume (PTV). Real-time tumormotion tracking by 2D/3D registration using on-board kilo-voltage (kV) imaging can lead to a reduction of the PTV. One limitation of this technique when using one projection image, is the inability to resolve motion along the imaging beam axis. We present a retrospective patient study to investigate the impact of paired portal mega-voltage (MV) and kV images, on registration accuracy. We used data from eighteen patients suffering from non small cell lung cancer undergoing regular treatment at our center. For each patient we acquired a planning CT and sequences of kV and MV images during treatment. Our evaluation consisted of comparing the accuracy of motion tracking in 6 degrees-of-freedom(DOF) using the anterior-posterior (AP) kV sequence or the sequence of kV-MV image pairs. We use graphics processing unit rendering for real-time performance. Motion along cranial-caudal direction could accurately be extracted when using only the kV sequence but in AP direction we obtained large errors. When using kV-MV pairs, the average error was reduced from 3.3 mm to 1.8 mm and the motion along AP was successfully extracted. The mean registration time was of 190+/-35ms. Our evaluation shows that using kVMV image pairs leads to improved motion extraction in 6 DOF. Therefore, this approach is suitable for accurate, real-time tumor motion tracking with a conventional LINAC.

  6. Expanding the use of real‐time electromagnetic tracking in radiation oncology

    Science.gov (United States)

    Kupelian, Patrick A.; Willoughby, Twyla R.; Meeks, Sanford L.

    2011-01-01

    In the past 10 years, techniques to improve radiotherapy delivery, such as intensity‐modulated radiation therapy (IMRT), image‐guided radiation therapy (IGRT) for both inter‐ and intrafraction tumor localization, and hypofractionated delivery techniques such as stereotactic body radiation therapy (SBRT), have evolved tremendously. This review article focuses on only one part of that evolution, electromagnetic tracking in radiation therapy. Electromagnetic tracking is still a growing technology in radiation oncology and, as such, the clinical applications are limited, the expense is high, and the reimbursement is insufficient to cover these costs. At the same time, current experience with electromagnetic tracking applied to various clinical tumor sites indicates that the potential benefits of electromagnetic tracking could be significant for patients receiving radiation therapy. Daily use of these tracking systems is minimally invasive and delivers no additional ionizing radiation to the patient, and these systems can provide explicit tumor motion data. Although there are a number of technical and fiscal issues that need to be addressed, electromagnetic tracking systems are expected to play a continued role in improving the precision of radiation delivery. PACS number: 87.63.‐d PMID:22089017

  7. Expanding the use of real-time electromagnetic tracking in radiation oncology.

    Science.gov (United States)

    Shah, Amish P; Kupelian, Patrick A; Willoughby, Twyla R; Meeks, Sanford L

    2011-11-15

    In the past 10 years, techniques to improve radiotherapy delivery, such as intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT) for both inter- and intrafraction tumor localization, and hypofractionated delivery techniques such as stereotactic body radiation therapy (SBRT), have evolved tremendously. This review article focuses on only one part of that evolution, electromagnetic tracking in radiation therapy. Electromagnetic tracking is still a growing technology in radiation oncology and, as such, the clinical applications are limited, the expense is high, and the reimbursement is insufficient to cover these costs. At the same time, current experience with electromagnetic tracking applied to various clinical tumor sites indicates that the potential benefits of electromagnetic tracking could be significant for patients receiving radiation therapy. Daily use of these tracking systems is minimally invasive and delivers no additional ionizing radiation to the patient, and these systems can provide explicit tumor motion data. Although there are a number of technical and fiscal issues that need to be addressed, electromagnetic tracking systems are expected to play a continued role in improving the precision of radiation delivery.

  8. WE-G-BRF-01: Adaptation to Intrafraction Tumor Deformation During Intensity-Modulated Radiotherapy: First Proof-Of-Principle Demonstration

    International Nuclear Information System (INIS)

    Ge, Y; OBrien, R; Shieh, C; Booth, J; Keall, P

    2014-01-01

    Purpose: Intrafraction tumor deformation limits targeting accuracy in radiotherapy and cannot be adapted to by current motion management techniques. This study simulated intrafractional treatment adaptation to tumor deformations using a dynamic Multi-Leaf Collimator (DMLC) tracking system during Intensity-modulated radiation therapy (IMRT) treatment for the first time. Methods: The DMLC tracking system was developed to adapt to the intrafraction tumor deformation by warping the planned beam aperture guided by the calculated deformation vector field (DVF) obtained from deformable image registration (DIR) at the time of treatment delivery. Seven single phantom deformation images up to 10.4 mm deformation and eight tumor system phantom deformation images up to 21.5 mm deformation were acquired and used in tracking simulation. The intrafraction adaptation was simulated at the DMLC tracking software platform, which was able to communicate with the image registration software, reshape the instantaneous IMRT field aperture and log the delivered MLC fields.The deformation adaptation accuracy was evaluated by a geometric target coverage metric defined as the sum of the area incorrectly outside and inside the reference aperture. The incremental deformations were arbitrarily determined to take place equally over the delivery interval. The geometric target coverage of delivery with deformation adaptation was compared against the delivery without adaptation. Results: Intrafraction deformation adaptation during dynamic IMRT plan delivery was simulated for single and system deformable phantoms. For the two particular delivery situations, over the treatment course, deformation adaptation improved the target coverage by 89% for single target deformation and 79% for tumor system deformation compared with no-tracking delivery. Conclusion: This work demonstrated the principle of real-time tumor deformation tracking using a DMLC. This is the first step towards the development of an

  9. Development of PLGA-lipid nanoparticles with covalently conjugated indocyanine green as a versatile nanoplatform for tumor-targeted imaging and drug delivery

    Directory of Open Access Journals (Sweden)

    Xin Y

    2016-11-01

    Full Text Available Yu Xin, Tie Liu, Chenlong Yang Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China Abstract: We have prepared novel poly(d,l-lactide-co-glycolide (PLGA lipid nanoparticles (PNPs that covalently conjugate folic acid (FA and indocyanine green (ICG, in addition to encapsulating resveratrol (RSV (FA-RSV/ICG-PLGA-lipid NPs, abbreviated as FA-RIPNPs; these nanoparticles have been developed for simultaneous targeted delivery of anticancer drug and fluorescence imaging. The FA-RIPNPs, with an average particle size of 92.8±2.1 nm, were prepared by a facile self-assembly-and-nanoprecipitation method, and they showed excellent stability and biocompatibility characteristics. The FA-RIPNPs exhibited an RSV encapsulation efficiency of approximately 65.6%±4.7% and a maximum release ratio of 78.2%±4.1% at pH 5.0 and 37°C. Confocal fluorescence images showed that FA-RIPNPs may facilitate a high cellular uptake via FA receptor-mediated endocytosis. Furthermore, FA-RIPNPs (containing 50 µg/mL RSV induced a 81.4%±2.1% U87 cell inhibition rate via apoptosis, a value that proved to be higher than what has been shown for free RSV (53.1%±1.1%, equivalent RSV concentration. With a formulated polyethylene glycol (PEG shell around the PLGA core, FA-RIPNPs prolonged the blood circulation of both free RSV and ICG, which approximately increased 6.96- and 39.4-fold (t1/2, respectively. Regarding FA-RIPNP use as a near-infrared probe, in vivo fluorescence images indicated a highly efficient accumulation of FA-RIPNPs in the tumor tissue, which proved to be approximately 2.8- and 12.6-fold higher than the RIPNPs and free ICG, respectively. Intravenous injection of FA-RIPNPs into U87 tumor-bearing mice demonstrated the best tumor inhibition effect for all tested drugs, including free RSV and RIPNPs, with no relapse, showing high biocompatibility and with no significant systemic in vivo toxicity over the

  10. Tumor-targeted delivery of IL-2 by NKG2D leads to accumulation of antigen-specific CD8+ T cells in the tumor loci and enhanced anti-tumor effects.

    Directory of Open Access Journals (Sweden)

    Tae Heung Kang

    Full Text Available Interleukin-2 (IL-2 has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7-specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti-tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T-cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci.

  11. Evaluation of a combination tumor treatment using thermo-triggered liposomal drug delivery and carbon ion irradiation.

    Science.gov (United States)

    Kokuryo, Daisuke; Aoki, Ichio; Yuba, Eiji; Kono, Kenji; Aoshima, Sadahito; Kershaw, Jeff; Saga, Tsuneo

    2017-07-01

    The combination of radiotherapy with chemotherapy is one of the most promising strategies for cancer treatment. Here, a novel combination strategy utilizing carbon ion irradiation as a high-linear energy transfer (LET) radiotherapy and a thermo-triggered nanodevice is proposed, and drug accumulation in the tumor and treatment effects are evaluated using magnetic resonance imaging relaxometry and immunohistology (Ki-67, n = 15). The thermo-triggered liposomal anticancer nanodevice was administered into colon-26 tumor-grafted mice, and drug accumulation and efficacy was compared for 6 groups (n = 32) that received or did not receive the radiotherapy and thermo trigger. In vivo quantitative R 1 maps visually demonstrated that the multimodal thermosensitive polymer-modified liposomes (MTPLs) can accumulate in the tumor tissue regardless of whether the region was irradiated by carbon ions or not. The tumor volume after combination treatment with carbon ion irradiation and MTPLs with thermo-triggering was significantly smaller than all the control groups at 8 days after treatment. The proposed strategy of combining high-LET irradiation and the nanodevice provides an effective approach for minimally invasive cancer treatment. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. In-Vivo Detection and Tracking of T Cells in Various Organs in a Melanoma Tumor Model by 19F-Fluorine MRS/MRI.

    Directory of Open Access Journals (Sweden)

    Christine Gonzales

    Full Text Available 19F-MRI and 19F-MRS can identify specific cell types after in-vitro or in-vivo 19F-labeling. Knowledge on the potential to track in-vitro 19F-labeled immune cells in tumor models by 19F-MRI/MRS is scarce.To study 19F-based MR techniques for in-vivo tracking of adoptively transferred immune cells after in-vitro 19F-labeling, i.e. to detect and monitor their migration non-invasively in melanoma-bearing mice.Splenocytes (SP were labeled in-vitro with a perfluorocarbon (PFC and IV-injected into non-tumor bearing mice. In-vitro PFC-labeled ovalbumin (OVA-specific T cells from the T cell receptor-transgenic line OT-1, activated with anti-CD3 and anti-CD28 antibodies (Tact or OVA-peptide pulsed antigen presenting cells (TOVA-act, were injected into B16 OVA melanoma-bearing mice. The distribution of the 19F-labelled donor cells was determined in-vivo by 19F-MRI/MRS. In-vivo 19F-MRI/MRS results were confirmed by ex-vivo 19F-NMR and flow cytometry.SP, Tact, and TOVA-act were successfully PFC-labeled in-vitro yielding 3x1011-1.4x1012 19F-atoms/cell in the 3 groups. Adoptively transferred 19F-labeled SP, TOVA-act, and Tact were detected by coil-localized 19F-MRS in the chest, abdomen, and left flank in most animals (corresponding to lungs, livers, and spleens, respectively, with highest signal-to-noise for SP vs TOVA-act and Tact, p<0.009 for both. SP and Tact were successfully imaged by 19F-MRI (n = 3; liver. These in-vivo data were confirmed by ex-vivo high-resolution 19F-NMR-spectroscopy. By flow cytometric analysis, however, TOVA-act tended to be more abundant versus SP and Tact (liver: p = 0.1313; lungs: p = 0.1073; spleen: p = 0.109. Unlike 19F-MRI/MRS, flow cytometry also identified transferred immune cells (SP, Tact, and TOVA-act in the tumors.SP, Tact, and TOVA-act were successfully PFC-labeled in-vitro and detected in-vivo by non-invasive 19F-MRS/MRI in liver, lung, and spleen. The portion of 19F-labeled T cells in the adoptively transferred cell

  13. Application of neutron capture autoradiography to Boron Delivery seeking techniques for selective accumulation of boron compounds to tumor with intra-arterial administration of boron entrapped water-in-oil-in-water emulsion

    Energy Technology Data Exchange (ETDEWEB)

    Mikado, S. [Physical Science Laboratories, College of Industrial Technology, Nihon University, Chiba (Japan)], E-mail: mikado@cit.nihon-u.ac.jp; Yanagie, H. [Department of Nuclear Engineering and Management, University of Tokyo, Tokyo (Japan); Cooperative Unit of Medicine and Engineering, University of Tokyo Hospital, Tokyo (Japan); Yasuda, N. [Fundamental Technology Center, National Institute of Radiological Sciences, Chiba (Japan); Higashi, S.; Ikushima, I. [Miyakonojyo Metropolitan Hospital, Miyazaki (Japan); Mizumachi, R.; Murata, Y. [Department of Pharmacology, Kumamoto Institute Branch, Mitsubishi Chemical Safety Institute Ltd., Kumamoto (Japan); Morishita, Y. [Department of Human and Molecular Pathology, University of Tokyo, Tokyo (Japan); Nishimura, R. [Faculty of Agriculture, Laboratory of Veterinary Surgery, University of Tokyo (Japan); Shinohara, A. [Department of Humanities, The Graduate School of Seisen University, Tokyo (Japan); Ogura, K. [Physical Science Laboratories, College of Industrial Technology, Nihon University, Chiba (Japan); Sugiyama, H. [Cooperative Unit of Medicine and Engineering, University of Tokyo Hospital, Tokyo (Japan); Iikura, H.; Ando, H. [Japan Atomic Energy Agency, Ibaraki (Japan); Ishimoto, M. [Department of Nuclear Professional School, University of Tokyo (Japan); Takamoto, S. [Cooperative Unit of Medicine and Engineering, University of Tokyo Hospital, Tokyo (Japan); Department of Cardiac Surgery, University of Tokyo Hospital, Tokyo (Japan); Eriguchi, M. [Cooperative Unit of Medicine and Engineering, University of Tokyo Hospital, Tokyo (Japan); Department of Microbiology, Syowa University School of Pharmaceutical Sciences, Tokyo (Japan); Takahashi, H. [Department of Nuclear Engineering and Management, University of Tokyo, Tokyo (Japan); Cooperative Unit of Medicine and Engineering, University of Tokyo Hospital, Tokyo (Japan); Kimura, M. [Department of Physics, Toho University, Chiba (Japan)

    2009-06-21

    It is necessary to accumulate the {sup 10}B atoms selectively to the tumor cells for effective Boron Neutron Capture Therapy (BNCT). In order to achieve an accurate measurement of {sup 10}B accumulations in the biological samples, we employed a technique of neutron capture autoradiography (NCAR) of sliced samples of tumor tissues using CR-39 plastic track detectors. The CR-39 track detectors attached with the biological samples were exposed to thermal neutrons in the thermal column of the JRR3 of Japan Atomic Energy Agency (JAEA). We obtained quantitative NCAR images of the samples for VX-2 tumor in rabbit liver after injection of {sup 10}BSH entrapped water-in-oil-in-water (WOW) emulsion by intra-arterial injection via proper hepatic artery. The {sup 10}B accumulations and distributions in VX-2 tumor and normal liver of rabbit were investigated by means of alpha-track density measurements. In this study, we showed the selective accumulation of {sup 10}B atoms in the VX-2 tumor by intra-arterial injection of {sup 10}B entrapped WOW emulsion until 3 days after injection by using digitized NCAR images (i.e. alpha-track mapping)

  14. Application of neutron capture autoradiography to Boron Delivery seeking techniques for selective accumulation of boron compounds to tumor with intra-arterial administration of boron entrapped water-in-oil-in-water emulsion

    International Nuclear Information System (INIS)

    Mikado, S.; Yanagie, H.; Yasuda, N.; Higashi, S.; Ikushima, I.; Mizumachi, R.; Murata, Y.; Morishita, Y.; Nishimura, R.; Shinohara, A.; Ogura, K.; Sugiyama, H.; Iikura, H.; Ando, H.; Ishimoto, M.; Takamoto, S.; Eriguchi, M.; Takahashi, H.; Kimura, M.

    2009-01-01

    It is necessary to accumulate the 10 B atoms selectively to the tumor cells for effective Boron Neutron Capture Therapy (BNCT). In order to achieve an accurate measurement of 10 B accumulations in the biological samples, we employed a technique of neutron capture autoradiography (NCAR) of sliced samples of tumor tissues using CR-39 plastic track detectors. The CR-39 track detectors attached with the biological samples were exposed to thermal neutrons in the thermal column of the JRR3 of Japan Atomic Energy Agency (JAEA). We obtained quantitative NCAR images of the samples for VX-2 tumor in rabbit liver after injection of 10 BSH entrapped water-in-oil-in-water (WOW) emulsion by intra-arterial injection via proper hepatic artery. The 10 B accumulations and distributions in VX-2 tumor and normal liver of rabbit were investigated by means of alpha-track density measurements. In this study, we showed the selective accumulation of 10 B atoms in the VX-2 tumor by intra-arterial injection of 10 B entrapped WOW emulsion until 3 days after injection by using digitized NCAR images (i.e. alpha-track mapping).

  15. Application of neutron capture autoradiography to Boron Delivery seeking techniques for selective accumulation of boron compounds to tumor with intra-arterial administration of boron entrapped water-in-oil-in-water emulsion

    Science.gov (United States)

    Mikado, S.; Yanagie, H.; Yasuda, N.; Higashi, S.; Ikushima, I.; Mizumachi, R.; Murata, Y.; Morishita, Y.; Nishimura, R.; Shinohara, A.; Ogura, K.; Sugiyama, H.; Iikura, H.; Ando, H.; Ishimoto, M.; Takamoto, S.; Eriguchi, M.; Takahashi, H.; Kimura, M.

    2009-06-01

    It is necessary to accumulate the 10B atoms selectively to the tumor cells for effective Boron Neutron Capture Therapy (BNCT). In order to achieve an accurate measurement of 10B accumulations in the biological samples, we employed a technique of neutron capture autoradiography (NCAR) of sliced samples of tumor tissues using CR-39 plastic track detectors. The CR-39 track detectors attached with the biological samples were exposed to thermal neutrons in the thermal column of the JRR3 of Japan Atomic Energy Agency (JAEA). We obtained quantitative NCAR images of the samples for VX-2 tumor in rabbit liver after injection of 10BSH entrapped water-in-oil-in-water (WOW) emulsion by intra-arterial injection via proper hepatic artery. The 10B accumulations and distributions in VX-2 tumor and normal liver of rabbit were investigated by means of alpha-track density measurements. In this study, we showed the selective accumulation of 10B atoms in the VX-2 tumor by intra-arterial injection of 10B entrapped WOW emulsion until 3 days after injection by using digitized NCAR images (i.e. alpha-track mapping).

  16. Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer

    OpenAIRE

    Wang, Xiaolin; Wang,Qingbing; Li,Jianfeng; An,Sai; Chen,Yi; Jiang,Chen

    2015-01-01

    Qingbing Wang,1,2 Jianfeng Li,3 Sai An,3 Yi Chen,1 Chen Jiang,3 Xiaolin Wang1,2 1Department of Interventional Radiology, Zhongshan Hospital, Fudan University, 2Shanghai Institute of Medical Imaging, 3Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China Background: Gene therapy is a very promising technology for treatment of pancreatic ductal adenocarci...

  17. Anesthesia for cesarean delivery in a patient with large anterior mediastinal tumor presenting as intrathoracic airway compression

    Directory of Open Access Journals (Sweden)

    Yatish Bevinaguddaiah

    2014-01-01

    Full Text Available Anterior mediastinal mass is a rare pathology that presents considerable anesthetic challenges due to cardiopulmonary compromise. We present a case that was referred to us in the third trimester of pregnancy with severe breathlessness and orthopnea. An elective cesarean delivery was performed under combined spinal epidural anesthesia with a favorable outcome. We discuss the perioperative considerations in these patients with a review of the literature.

  18. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Ding Y

    2015-10-01

    Full Text Available Yuan Ding,1,* Dan Sun,1,* Gui-Ling Wang,1 Hong-Ge Yang,1 Hai-Feng Xu,1 Jian-Hua Chen,2 Ying Xie,1,3 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 2School of Medicine, Jianghan University, Wuhan, 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: Cell-penetrating peptides (CPPs as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into

  19. Cytocompatible chitosan-graft-mPEG-based 5-fluorouracil-loaded polymeric nanoparticles for tumor-targeted drug delivery.

    Science.gov (United States)

    Antoniraj, M Gover; Ayyavu, Mahesh; Henry, Linda Jeeva Kumari; Nageshwar Rao, Goutham; Natesan, Subramanian; Sundar, D Sathish; Kandasamy, Ruckmani

    2018-03-01

    Biodegradable materials like chitosan (CH) and methoxy polyethylene glycol (mPEG) are widely being used as drug delivery carriers for various therapeutic applications. In this study, copolymer (CH-g-mPEG) of CH and carboxylic acid terminated mPEG was synthesized by carbodiimide-mediated acid amine reaction. The resultant hydrophilic copolymer was characterized by Fourier transform infrared spectroscopy and 1 H NMR studies, revealing its relevant functional bands and proton peaks, respectively. Blank polymeric nanoparticles (B-PNPs) and 5-fluorouracil loaded polymeric nanoparticles (5-FU-PNPs) were formulated by ionic gelation method. Furthermore, folic acid functionalized FA-PNPs and FA-5-FU-PNPs were prepared for folate receptor-targeted drug delivery. FA-5-FU-PNPs were characterized by particle size, zeta potential, and in vitro drug release studies, resulting in 197.7 nm, +29.9 mv, and sustained drug release of 88% in 24 h, respectively. Cytotoxicity studies were performed for FA-PNPs and FA-5-FU-PNPs in MCF-7 cell line, which exhibited a cell viability of 80 and 41%, respectively. In vitro internalization studies were carried out for 5-FU-PNPs and FA-5-FU-PNPs which demonstrated increased cellular uptake of FA-5-FU-PNPs by receptor-mediated transport. Significant (p drug delivery, thereby influencing better therapeutic effect.

  20. Quantification of the kV X-ray imaging dose during real-time tumor tracking and from three- and four-dimensional cone-beam computed tomography in lung cancer patients using a Monte Carlo simulation.

    Science.gov (United States)

    Nakamura, Mitsuhiro; Ishihara, Yoshitomo; Matsuo, Yukinori; Iizuka, Yusuke; Ueki, Nami; Iramina, Hiraku; Hirashima, Hideaki; Mizowaki, Takashi

    2018-03-01

    Knowledge of the imaging doses delivered to patients and accurate dosimetry of the radiation to organs from various imaging procedures is becoming increasingly important for clinicians. The purposes of this study were to calculate imaging doses delivered to the organs of lung cancer patients during real-time tumor tracking (RTTT) with three-dimensional (3D), and four-dimensional (4D) cone-beam computed tomography (CBCT), using Monte Carlo techniques to simulate kV X-ray dose distributions delivered using the Vero4DRT. Imaging doses from RTTT, 3D-CBCT and 4D-CBCT were calculated with the planning CT images for nine lung cancer patients who underwent stereotactic body radiotherapy (SBRT) with RTTT. With RTTT, imaging doses from correlation modeling and from monitoring of imaging during beam delivery were calculated. With CBCT, doses from 3D-CBCT and 4D-CBCT were also simulated. The doses covering 2-cc volumes (D2cc) in correlation modeling were up to 9.3 cGy for soft tissues and 48.4 cGy for bone. The values from correlation modeling and monitoring were up to 11.0 cGy for soft tissues and 59.8 cGy for bone. Imaging doses in correlation modeling were larger with RTTT. On a single 4D-CBCT, the skin and bone D2cc values were in the ranges of 7.4-10.5 cGy and 33.5-58.1 cGy, respectively. The D2cc from 4D-CBCT was approximately double that from 3D-CBCT. Clinicians should Figure that the imaging dose increases the cumulative doses to organs.

  1. First online real-time evaluation of motion-induced 4D dose errors during radiotherapy delivery

    DEFF Research Database (Denmark)

    Ravkilde, Thomas; Skouboe, Simon; Hansen, Rune

    2018-01-01

    PURPOSE: In radiotherapy, dose deficits caused by tumor motion often far outweigh the discrepancies typically allowed in plan-specific quality assurance (QA). Yet, tumor motion is not usually included in present QA. We here present a novel method for online treatment verification by real......-time motion-including 4D dose reconstruction and dose evaluation and demonstrate its use during stereotactic body radiotherapy (SBRT) delivery with and without MLC tracking. METHODS: Five volumetric modulated arc therapy (VMAT) plans were delivered with and without MLC tracking to a motion stage carrying...... a Delta4 dosimeter. The VMAT plans have previously been used for (non-tracking) liver SBRT with intra-treatment tumor motion recorded by kilovoltage intrafraction monitoring (KIM). The motion stage reproduced the KIM-measured tumor motions in 3D while optical monitoring guided the MLC tracking. Linac...

  2. TU-AB-201-03: A Robot for the Automated Delivery of An Electromagnetic Tracking Sensor for the Localization of Brachytherapy Catheters

    International Nuclear Information System (INIS)

    Don, S; Cormack, R; Viswanathan, A; Damato, A

    2015-01-01

    Purpose: To present a programmable robotic system for the accurate and fast deployment of an electromagnetic (EM) sensor for brachytherapy catheter localization. Methods: A robotic system for deployment of an EM sensor was designed and built. The system was programmed to increment the sensor position at specified time and space intervals. Sensor delivery accuracy was measured in a phantom using the localization of the EM sensor and tested in different environmental conditions. Accuracy was tested by measuring the distance between the physical locations reached by the sensor (measured by the EM tracker) and the intended programmed locations. Results: The system consisted of a stepper motor connected to drive wheels (that grip the cable to move the sensor) and a series of guides to connect to a brachytherapy transfer tube, all controlled by a programmable Arduino microprocessor. The total cost for parts was <$300. The positional accuracy of the sensor location was within 1 mm of the expected position provided by the motorized guide system. Acquisition speed to localize a brachytherapy catheter with 20 cm of active length was 10 seconds. The current design showed some cable slip and warping depending on environment temperature. Conclusion: The use of EM tracking for the localization of brachytherapy catheters has been previously demonstrated. Efficient data acquisition and artifact reduction requires fast and accurate deployment of an EM sensor in consistent, repeatable patterns, which cannot practically be achieved manually. The design of an inexpensive, programmable robot allowing for the precise deployment of stepping patterns was presented, and a prototype was built. Further engineering is necessary to ensure that the device provides efficient independent localization of brachytherapy catheters. This research was funded by the Kaye Family Award

  3. TU-AB-201-03: A Robot for the Automated Delivery of An Electromagnetic Tracking Sensor for the Localization of Brachytherapy Catheters

    Energy Technology Data Exchange (ETDEWEB)

    Don, S; Cormack, R; Viswanathan, A; Damato, A [Dana-Farber Cancer Institute / Brigham and Women’s Hospital, Boston, MA (United States)

    2015-06-15

    Purpose: To present a programmable robotic system for the accurate and fast deployment of an electromagnetic (EM) sensor for brachytherapy catheter localization. Methods: A robotic system for deployment of an EM sensor was designed and built. The system was programmed to increment the sensor position at specified time and space intervals. Sensor delivery accuracy was measured in a phantom using the localization of the EM sensor and tested in different environmental conditions. Accuracy was tested by measuring the distance between the physical locations reached by the sensor (measured by the EM tracker) and the intended programmed locations. Results: The system consisted of a stepper motor connected to drive wheels (that grip the cable to move the sensor) and a series of guides to connect to a brachytherapy transfer tube, all controlled by a programmable Arduino microprocessor. The total cost for parts was <$300. The positional accuracy of the sensor location was within 1 mm of the expected position provided by the motorized guide system. Acquisition speed to localize a brachytherapy catheter with 20 cm of active length was 10 seconds. The current design showed some cable slip and warping depending on environment temperature. Conclusion: The use of EM tracking for the localization of brachytherapy catheters has been previously demonstrated. Efficient data acquisition and artifact reduction requires fast and accurate deployment of an EM sensor in consistent, repeatable patterns, which cannot practically be achieved manually. The design of an inexpensive, programmable robot allowing for the precise deployment of stepping patterns was presented, and a prototype was built. Further engineering is necessary to ensure that the device provides efficient independent localization of brachytherapy catheters. This research was funded by the Kaye Family Award.

  4. Brain Tumor Targeting of Magnetic Nanoparticles for Potential Drug Delivery: Effect of Administration Route and Magnetic Field Topography

    Science.gov (United States)

    Chertok, Beata; David, Allan E.; Yang, Victor C.

    2011-01-01

    Our previous studies demonstrated feasibility of magnetically-mediated retention of iron-oxide nanoparticles in brain tumors after intravascular administration. The purpose of this study was to elucidate strategies for further improvement of this promising approach. In particular, we explored administration of the nanoparticles via a non-occluded carotid artery as a way to increase the passive exposure of tumor vasculature to nanoparticles for subsequent magnetic entrapment. However, aggregation of nanoparticles in the afferent vasculature interfered with tumor targeting. The magnetic setup employed in our experiments was found to generate a relatively uniform magnetic flux density over a broad range, exposing the region of the afferent vasculature to high magnetic force. To overcome this problem, the magnetic setup was modified with a 9-mm diameter cylindrical NdFeB magnet to exhibit steeper magnetic field topography. Six-fold reduction of the magnetic force at the injection site, achieved with this modification, alleviated the aggregation problem under the conditions of intact carotid blood flow. Using this setup, carotid administration was found to present 1.8-fold increase in nanoparticle accumulation in glioma compared to the intravenous route at 350 mT. This increase was found to be in reasonable agreement with the theoretically estimated 1.9-fold advantage of carotid administration, Rd. The developed approach is expected to present an even greater advantage when applied to drug-loaded nanoparticles exhibiting higher values of Rd. PMID:21763736

  5. Real-time tracking of tumor motions and deformations along the leaf travel direction with the aid of a synchronized dynamic MLC leaf sequencer

    International Nuclear Information System (INIS)

    Tacke, Martin; Nill, Simeon; Oelfke, Uwe

    2007-01-01

    Advanced radiotherapeutical techniques like intensity-modulated radiation therapy (IMRT) are based on an accurate knowledge of the location of the radiation target. An accurate dose delivery, therefore, requires a method to account for the inter- and intrafractional target motion and the target deformation occurring during the course of treatment. A method to compensate in real time for changes in the position and shape of the target is the use of a dynamic multileaf collimator (MLC) technique which can be devised to automatically arrange the treatment field according to real-time image information. So far, various approaches proposed for leaf sequencers have had to rely on a priori known target motion data and have aimed to optimize the overall treatment time. Since for a real-time dose delivery the target motion is not known a priori, the velocity range of the leading leaves is restricted by a safety margin to c x v max while the following leaves can travel with an additional maximum speed to compensate for the respective target movements. Another aspect to be considered is the tongue and groove effect. A uniform radiation field can only be achieved if the leaf movements are synchronized. The method presented in this note is the first to combine a synchronizing sequencer and real-time tracking with a dynamic MLC. The newly developed algorithm is capable of online optimizing the leaf velocities by minimizing the overall treatment time while at the same time it synchronizes the leaf trajectories in order to avoid the tongue and groove effect. The simultaneous synchronization is performed with the help of an online-calculated mid-time leaf trajectory which is common for all leaf pairs and which takes into account the real-time target motion and deformation information. (note)

  6. Real-time tracking of tumor motions and deformations along the leaf travel direction with the aid of a synchronized dynamic MLC leaf sequencer.

    Science.gov (United States)

    Tacke, Martin; Nill, Simeon; Oelfke, Uwe

    2007-11-21

    Advanced radiotherapeutical techniques like intensity-modulated radiation therapy (IMRT) are based on an accurate knowledge of the location of the radiation target. An accurate dose delivery, therefore, requires a method to account for the inter- and intrafractional target motion and the target deformation occurring during the course of treatment. A method to compensate in real time for changes in the position and shape of the target is the use of a dynamic multileaf collimator (MLC) technique which can be devised to automatically arrange the treatment field according to real-time image information. So far, various approaches proposed for leaf sequencers have had to rely on a priori known target motion data and have aimed to optimize the overall treatment time. Since for a real-time dose delivery the target motion is not known a priori, the velocity range of the leading leaves is restricted by a safety margin to c x v(max) while the following leaves can travel with an additional maximum speed to compensate for the respective target movements. Another aspect to be considered is the tongue and groove effect. A uniform radiation field can only be achieved if the leaf movements are synchronized. The method presented in this note is the first to combine a synchronizing sequencer and real-time tracking with a dynamic MLC. The newly developed algorithm is capable of online optimizing the leaf velocities by minimizing the overall treatment time while at the same time it synchronizes the leaf trajectories in order to avoid the tongue and groove effect. The simultaneous synchronization is performed with the help of an online-calculated mid-time leaf trajectory which is common for all leaf pairs and which takes into account the real-time target motion and deformation information.

  7. Water-soluble ferrocene complexes (WFCs) functionalized silica nanospheres for WFC delivery in HepG2 tumor therapy.

    Science.gov (United States)

    Yan, Saisai; Hu, Fan; Hong, Xia; Shuai, Qi

    2018-09-01

    Silica-encapsulated nanospheres of water-soluble ferrocene complexes WFCs@SiO 2 and WFCs@SiO 2 @glutaraldehyde (GA) were first synthesized by a facile inverse-microemulsion method. The surface functional groups, particle size, and morphologies of nanospheres were characterized by IR spectra, UV-vis absorption spectra, dynamic light scattering (DLS) and SEM images. Single-crystal X-ray diffraction was used to confirm the molecular structure of free ferrocenyl-pyrazol ligand (L) and three WFCs, namely, [Ni(C 22 H 14 F 6 FeN 4 O 4 )(H 2 O) 4 ] (5a), [Mg(C 22 H 14 F 6 FeN 4 O 4 )(H 2 O) 4 ]·3H 2 O (5b), and [Ba(C 22 H 14 F 6 FeN 4 O 4 )(H 2 O) 3 ] (5c). The electrochemical properties of 5a-5c were explored by cyclic voltammetry. The WFCs-loading capacities of 5a-5c in WFCs@SiO 2 were found to be 38.4, 38.2, and 38.1 μg/mg, respectively. Cell studies under two drug delivery modes (free diffusion and endocytosis) were carried out by MTT cell-survival assays and morphological observation of HepG2 cells. It's interesting that the cytotoxicity of WFCs against HepG2 was increased by applying silica nanocarriers. Compared to WFCs@SiO 2 , the modification of GA on the spherical surface provided not only the better water-dispersity but also additional functional groups for further modification of other pharmacophores. The novel nanocarrier system for WFC delivery present a novel concept-of-proof method to protect varieties of affordable metal-based anticancer agents in physiological conditions and provided experimental basis for future studies focusing on drug delivery of other WFCs. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Biodegradable multiblock polymers based on N-(2-hydroxypropyl)methacrylamide designed as drug carriers for tumor-targeted delivery

    Czech Academy of Sciences Publication Activity Database

    Mužíková, Gabriela; Pola, Robert; Laga, Richard; Pechar, Michal

    2016-01-01

    Roč. 217, č. 15 (2016), s. 1690-1703 ISSN 1022-1352 R&D Projects: GA ČR(CZ) GA14-12742S; GA ČR(CZ) GA16-17207S; GA MŠk(CZ) LO1507; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : biodegradable polymers * click chemistry * drug delivery systems Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.500, year: 2016

  9. Three-Dimensional Intrafractional Motion of Breast During Tangential Breast Irradiation Monitored With High-Sampling Frequency Using a Real-Time Tumor-Tracking Radiotherapy System

    International Nuclear Information System (INIS)

    Kinoshita, Rumiko; Shimizu, Shinichi; Taguchi, Hiroshi; Katoh, Norio; Fujino, Masaharu; Onimaru, Rikiya; Aoyama, Hidefumi; Katoh, Fumi; Omatsu, Tokuhiko; Ishikawa, Masayori; Shirato, Hiroki

    2008-01-01

    Purpose: To evaluate the three-dimensional intrafraction motion of the breast during tangential breast irradiation using a real-time tracking radiotherapy (RT) system with a high-sampling frequency. Methods and Materials: A total of 17 patients with breast cancer who had received breast conservation RT were included in this study. A 2.0-mm gold marker was placed on the skin near the nipple of the breast for RT. A fluoroscopic real-time tumor-tracking RT system was used to monitor the marker. The range of motion of each patient was calculated in three directions. Results: The mean ± standard deviation of the range of respiratory motion was 1.0 ± 0.6 mm (median, 0.9; 95% confidence interval [CI] of the marker position, 0.4-2.6), 1.3 ± 0.5 mm (median, 1.1; 95% CI, 0.5-2.5), and 2.6 ± 1.4 (median, 2.3; 95% CI, 1.0-6.9) for the right-left, craniocaudal, and anteroposterior direction, respectively. No correlation was found between the range of motion and the body mass index or respiratory function. The mean ± standard deviation of the absolute value of the baseline shift in the right-left, craniocaudal, and anteroposterior direction was 0.2 ± 0.2 mm (range, 0.0-0.8 mm), 0.3 ± 0.2 mm (range, 0.0-0.7 mm), and 0.8 ± 0.7 mm (range, 0.1-1.8 mm), respectively. Conclusion: Both the range of motion and the baseline shift were within a few millimeters in each direction. As long as the conventional wedge-pair technique and the proper immobilization are used, the intrafraction three-dimensional change in the breast surface did not much influence the dose distribution

  10. Three-dimensional intrafractional movement of prostate measured during real-time tumor-tracking radiotherapy in supine and prone treatment positions

    International Nuclear Information System (INIS)

    Kitamura, Kei; Shirato, Hiroki; Seppenwoolde, Yvette; Onimaru, Rikiya; Oda, Makoto; Fujita, Katsuhisa; Shimizu, Shinichi; Shinohara, Nobuo; Harabayashi, Toru; Miyasaka, Kazuo

    2002-01-01

    Purpose: To quantify three-dimensional (3D) movement of the prostate gland with the patient in the supine and prone positions and to analyze the movement frequency for each treatment position. Methods and Materials: The real-time tumor-tracking radiotherapy (RTRT) system was developed to identify the 3D position of a 2-mm gold marker implanted in the prostate 30 times/s using two sets of fluoroscopic images. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within the region of the planned coordinates relative to the isocenter. Ten patients with prostate cancer treated with RTRT were the subjects of this study. The coordinates of the gold marker were recorded every 0.033 s during RTRT in the supine treatment position for 2 min. The patient was then moved to the prone position, and the marker was tracked for 2 min to acquire data regarding movement in this position. Measurements were taken 5 times for each patient (once a week); a total of 50 sets for the 10 patients was analyzed. The raw data from the RTRT system were filtered to reduce system noise, and the amplitude of movement was then calculated. The discrete Fourier transform of the unfiltered data was performed for the frequency analysis of prostate movement. Results: No apparent difference in movement was found among individuals. The amplitude of 3D movement was 0.1-2.7 mm in the supine and 0.4-24 mm in the prone positions. The amplitude in the supine position was statistically smaller in all directions than that in the prone position (p < 0.0001). The amplitude in the craniocaudal and AP directions was larger than in the left-right direction in the prone position (p < 0.0001). No characteristic movement frequency was detected in the supine position. The respiratory frequency was detected for all patients regarding movement in the craniocaudal and AP directions in the prone position. The results of the frequency analysis suggest that prostate movement is

  11. Protein-gold clusters-capped mesoporous silica nanoparticles for high drug loading, autonomous gemcitabine/doxorubicin co-delivery, and in-vivo tumor imaging

    KAUST Repository

    Croissant, Jonas G.; Zhang, Dingyuan; Alsaiari, Shahad K.; Lu, Jie; Deng, Lin; Tamanoi, Fuyuhiko; Zink, Jeffrey I.; Khashab, Niveen M.

    2016-01-01

    Functional nanocarriers capable of transporting high drug contents without premature leakage and to controllably deliver several drugs are needed for better cancer treatments. To address this clinical need, gold cluster bovine serum albumin (AuNC@BSA) nanogates were engineered on mesoporous silica nanoparticles (MSN) for high drug loadings and co-delivery of two different anticancer drugs. The first drug, gemcitabine (GEM, 40 wt%), was loaded in positively-charged ammonium-functionalized MSN (MSN-NH3+). The second drug, doxorubicin (DOX, 32 wt%), was bound with negatively-charged AuNC@BSA electrostatically-attached onto MSN-NH3+, affording highly loaded pH-responsive MSN-AuNC@BSA nanocarriers. The co-delivery of DOX and GEM was achieved for the first time via an inorganic nanocarrier, possessing a zero-premature leakage behavior as well as drug loading capacities seven times higher than polymersome NPs. Besides, unlike the majority of strategies used to cap the pores of MSN, AuNC@BSA nanogates are biotools and were applied for targeted red nuclear staining and in-vivo tumor imaging. The straightforward non-covalent combination of MSN and gold-protein cluster bioconjugates thus leads to a simple, yet multifunctional nanotheranostic for the next generation of cancer treatments.

  12. Protein-gold clusters-capped mesoporous silica nanoparticles for high drug loading, autonomous gemcitabine/doxorubicin co-delivery, and in-vivo tumor imaging

    KAUST Repository

    Croissant, Jonas G.

    2016-03-23

    Functional nanocarriers capable of transporting high drug contents without premature leakage and to controllably deliver several drugs are needed for better cancer treatments. To address this clinical need, gold cluster bovine serum albumin (AuNC@BSA) nanogates were engineered on mesoporous silica nanoparticles (MSN) for high drug loadings and co-delivery of two different anticancer drugs. The first drug, gemcitabine (GEM, 40 wt%), was loaded in positively-charged ammonium-functionalized MSN (MSN-NH3+). The second drug, doxorubicin (DOX, 32 wt%), was bound with negatively-charged AuNC@BSA electrostatically-attached onto MSN-NH3+, affording highly loaded pH-responsive MSN-AuNC@BSA nanocarriers. The co-delivery of DOX and GEM was achieved for the first time via an inorganic nanocarrier, possessing a zero-premature leakage behavior as well as drug loading capacities seven times higher than polymersome NPs. Besides, unlike the majority of strategies used to cap the pores of MSN, AuNC@BSA nanogates are biotools and were applied for targeted red nuclear staining and in-vivo tumor imaging. The straightforward non-covalent combination of MSN and gold-protein cluster bioconjugates thus leads to a simple, yet multifunctional nanotheranostic for the next generation of cancer treatments.

  13. Polyethylene glycol-conjugated chondroitin sulfate A derivative nanoparticles for tumor-targeted delivery of anticancer drugs.

    Science.gov (United States)

    Lee, Jae-Young; Park, Ju-Hwan; Lee, Jeong-Jun; Lee, Song Yi; Chung, Suk-Jae; Cho, Hyun-Jong; Kim, Dae-Duk

    2016-10-20

    Polyethylene glycol (PEG)-decorated chondroitin sulfate A-deoxycholic acid (CSD) nanoparticles (NPs) were fabricated for the selective delivery of doxorubicin (DOX) to ovarian cancer. CSD-PEG was synthesized via amide bond formation between the NH2 group of methoxypolyethylene glycol amine and the COOH group of CSD. CSD-PEG/DOX NPs with a 247nm mean diameter, negative zeta potential, and >90% drug encapsulation efficiency were prepared. Sustained and pH-dependent DOX release profiles from CSD-PEG NPs were observed in dissolution tests. Endocytosis of NPs by SKOV-3 cells (CD44 receptor-positive human ovarian cancer cells), based on the CSA-CD44 receptor interaction, was determined by flow cytometry and confocal laser scanning microscopy (CLSM) studies. PEGylation of NPs also resulted in reduced drug clearance (CL) in vivo and improved relative bioavailability, compared to non-PEGylated NPs, as determined by the pharmacokinetic study performed after intravenous administration in rats. Developed CSD-PEG NPs can be a promising delivery vehicle for the therapy of CD44 receptor-expressing ovarian cancers. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment.

    Science.gov (United States)

    Pan, Changqie; Liu, Yuqing; Zhou, Minyu; Wang, Wensheng; Shi, Min; Xing, Malcolm; Liao, Wangjun

    2018-01-01

    A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@ IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR)-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical ( 1 H nuclear magnetic resonance) and physical (morphology and super-magnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer.

  15. Comprehensive study of the drug delivery properties of poly(l-lactide)-poly(ethylene glycol) nanoparticles in rats and tumor-bearing mice.

    Science.gov (United States)

    Shalgunov, Vladimir; Zaytseva-Zotova, Daria; Zintchenko, Arkadi; Levada, Tatiana; Shilov, Yuri; Andreyev, Dmitry; Dzhumashev, Dzhangar; Metelkin, Evgeny; Urusova, Alexandra; Demin, Oleg; McDonnell, Kevin; Troiano, Greg; Zale, Stephen; Safarovа, Elmira

    2017-09-10

    Nanoparticles made of polylactide-poly(ethylene glycol) block-copolymer (PLA-PEG) are promising vehicles for drug delivery due to their biodegradability and controllable payload release. However, published data on the drug delivery properties of PLA-PEG nanoparticles are heterogeneous in terms of nanoparticle characteristics and mostly refer to low injected doses (a few mg nanoparticles per kg body weight). We have performed a comprehensive study of the biodistribution of nanoparticle formulations based on PLA-PEG nanoparticles of ~100nm size at injected doses of 30 to 140mg/kg body weight in healthy rats and nude tumor-bearing mice. Nanoparticle formulations differed by surface PEG coverage and by release kinetics of the encapsulated model active pharmaceutical ingredient (API). Increase in PEG coverage prolonged nanoparticle circulation half-life up to ~20h in rats and ~10h in mice and decreased retention in liver, spleen and lungs. Circulation half-life of the encapsulated API grew monotonously as the release rate slowed down. Plasma and tissue pharmacokinetics was dose-linear for inactive nanoparticles, but markedly dose-dependent for the model therapeutic formulation, presumably because of the toxic effects of released API. A mathematical model of API distribution calibrated on the data for inactive nanoparticles and conventional API form correctly predicted the distribution of the model therapeutic formulation at the lowest investigated dose, but for higher doses the toxic action of the released API had to be explicitly modelled. Our results provide a coherent illustration of the ability of controllable-release PLA-PEG nanoparticles to serve as an effective drug delivery platform to alter API biodistribution. They also underscore the importance of physiological effects of released drug in determining the biodistribution of therapeutic drug formulations at doses approaching tolerability limits. Copyright © 2017 The Authors. Published by Elsevier B.V. All

  16. Overcoming cellular and tissue barriers to improve liposomal drug delivery

    Science.gov (United States)

    Kohli, Aditya G.

    Forty years of liposome research have demonstrated that the anti-tumor efficacy of liposomal therapies is, in part, driven by three parameters: 1) liposome formulation and lipid biophysics, 2) accumulation and distribution in the tumor, and 3) release of the payload at the site of interest. This thesis outlines three studies that improve on each of these delivery steps. In the first study, we engineer a novel class of zwitterlipids with an inverted headgroup architecture that have remarkable biophysical properties and may be useful for drug delivery applications. After intravenous administration, liposomes accumulate in the tumor by the enhanced permeability and retention effect. However, the tumor stroma often limits liposome efficacy by preventing distribution into the tumor. In the second study, we demonstrate that depletion of hyaluronan in the tumor stroma improves the distribution and efficacy of DoxilRTM in murine 4T1 tumors. Once a liposome has distributed to the therapeutic site, it must release its payload over the correct timescale. Few facile methods exist to quantify the release of liposome therapeutics in vivo. In the third study, we outline and validate a simple, robust, and quantitative method for tracking the rate and extent of release of liposome contents in vivo. This tool should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals. This work highlights aspects of liposome behavior that have prevented successful clinical translation and proposes alternative approaches to improve liposome drug delivery.

  17. Tumor-targeting magnetic lipoplex delivery of short hairpin RNA suppresses IGF-1R overexpression of lung adenocarcinoma A549 cells in vitro and in vivo.

    Science.gov (United States)

    Wang, Chunmao; Ding, Chao; Kong, Minjian; Dong, Aiqiang; Qian, Jianfang; Jiang, Daming; Shen, Zhonghua

    2011-07-08

    Liposomal magnetofection potentiates gene transfection by applying a magnetic field to concentrate magnetic lipoplexes onto target cells. Magnetic lipoplexes are self-assembling ternary complexes of cationic lipids with plasmid DNA associated with superparamagnetic iron oxide nanoparticles (SPIONs). Type1 insulin-like growth factor receptor (IGF-1R), an important oncogene, is frequently overexpressed in lung cancer and mediates cancer cell proliferation and tumor growth. In this study, we evaluated the transfection efficiency (percentage of transfected cells) and therapeutic potential (potency of IGF-1R knockdown) of liposomal magnetofection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) in A549 cells and in tumor-bearing mice as compared to lipofection using Lipofectamine 2000. Liposomal magnetofection provided a threefold improvement in transgene expression over lipofection and transfected up to 64.1% of A549 cells in vitro. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1±6% and by liposomal magnetofection by 85.1±3%. In vivo delivery efficiency of the pGFPshIGF-1R plasmid into the tumor was significantly higher in the liposomal magnetofection group than in the lipofection group. In vivo IGF-1R specific-shRNA by lipofection inhibited IGF-1R protein by an average of 43.8±5.3%; that by liposomal magnetofection inhibited IGF-1R protein by 43.4±5.7%, 56.3±9.6%, and 72.2±6.8%, at 24, 48, and 72 h, respectively, after pGFPshIGF-1R injection. Our findings indicate that liposomal magnetofection may be a promising method that allows the targeting of gene therapy to lung cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Design, development and characterization of multi-functionalized gold nanoparticles for biodetection and targeted boron delivery in BNCT applications

    Energy Technology Data Exchange (ETDEWEB)

    Mandal, Subhra [Department of Tumor Immunology, Radboud University Nijmegen Medical Centre (Netherlands); Bakeine, Gerald J., E-mail: Jamesbakeine1@yahoo.com [Department of Internal Medicine and Therapeutics-Section of Clinical Toxicology, University of Pavia, Piazza Botta 10, 27100 Pavia (Italy); Krol, Silke [Institute of Neurology, Fondazione IRCCS Carlo Besta, Milan (Italy); Ferrari, Cinzia; Clerici, Anna M.; Zonta, Cecilia; Cansolino, Laura [Department of Surgery, Laboratory of Experimental Surgery, University of Pavia (Italy); Ballarini, Francesca [Department of Nuclear and Theoretical Physics, University of Pavia (Italy); Bortolussi, Silva [Department of Nuclear and Theoretical Physics, University of Pavia (Italy)] [National Institute of Nuclear Physics (INFN), Section of Pavia (Italy); Stella, Subrina; Protti, Nicoletta [Department of Nuclear and Theoretical Physics, University of Pavia (Italy); Bruschi, Piero [National Institute of Nuclear Physics (INFN), Section of Pavia (Italy); Altieri, Saverio [Department of Nuclear and Theoretical Physics, University of Pavia (Italy)] [National Institute of Nuclear Physics (INFN), Section of Pavia (Italy)

    2011-12-15

    The aim of this study is to optimize targeted boron delivery to cancer cells and its tracking down to the cellular level. To this end, we describe the design and synthesis of novel nanovectors that double as targeted boron delivery agents and fluorescent imaging probes. Gold nanoparticles were coated with multilayers of polyelectrolytes functionalized with the fluorescent dye (FITC), boronophenylalanine and folic acid. In vitro confocal fluorescence microscopy demonstrated significant uptake of the nanoparticles in cancer cells that are known to overexpress folate receptors. - Highlights: Black-Right-Pointing-Pointer Synthesis of multi-labeled gold nanoparticles for selective boron delivery to tumor cells. Black-Right-Pointing-Pointer Tumor selectivity is achieved through folic acid receptor targeting. Black-Right-Pointing-Pointer Optical fluorescent microscopy allows tracking of cellular uptake of the gold nanoparticle. Black-Right-Pointing-Pointer In vitro tests demonstrate selective nanoparticle up in folate receptor positive tumor cells.

  19. Longitudinal comparison of quality of life after real-time tumor-tracking intensity-modulated radiation therapy and radical prostatectomy in patients with localized prostate cancer

    International Nuclear Information System (INIS)

    Shinohara, Nobuo; Maruyama, Satoru; Abe, Takashige; Nonomura, Katsuya; Shimizu, Shinichi; Nishioka, Kentaro; Shirato, Hiroki; C-Hatanaka, Kanako; Oba, Koji

    2013-01-01

    The purpose of this study was to compare the quality of life (QOL) in patients with localized prostate cancer (PC) after intensity-modulated radiation therapy assisted with a fluoroscopic real-time intensity-modulated radiation therapy (RT-IMRT) tumor-tracking system versus the QOL after radical prostatectomy (RP). Between 2003 and 2006, 71 patients were enrolled in this longitudinal prospective study. Each patient was allowed to decide which treatment modality they would receive. Of the 71 patients, 23 patients underwent RT-IMRT, while 48 opted for RP. No patient received neo-adjuvant or adjuvant hormone therapy. The global QOL and disease-specific-QOL were evaluated before treatment and again at 1, 3 and 5 years after treatment. There was no significant difference in the background characteristics between the two groups. The 5-year biochemical progression-free survival was 90% in the RT-IMRT and 79% in the RP group. In the RT-IMRT group, there was no significant deterioration of the global QOL or disease-specific QOL through 5 years post-treatment. In the RP group, the urinary function, sexual function, and sexual bother indicators significantly deteriorated after treatment. Urinary and sexual function was significantly better in the RT-IMRT group at 1, 3 and 5 years post-treatment compared to the RP group. RT-IMRT may be a preferable treatment for localized PC because of similar efficacy to RP but better post-treatment QOL. (author)

  20. Neo-angiogenesis metabolic biomarker of tumor-genesis tracking by infrared joystick contact imaging in personalized homecare system

    Science.gov (United States)

    Szu, Harold; Hoekstra, Philip; Landa, Joseph; Vydelingum, Nadarajen A.

    2014-05-01

    We describe an strong>affordable, harmless, and administrative (AHA) metabolic biomarker (MBM)strong> for homecare cancer screening. It may save hundreds of thousands of women's and thousands of men's lives every year from breast cancer and melanoma. The goal is to increase the specificity ofstrong> infrared (IR)strong> imagery to reduce the strong>false alarm rate (FAR). strong>The patient's hands are immersed in icy cold water, about 11oC, for 30 seconds. We then compare two IR images, taken before and after the cold stimulus, and the difference reveals an enhanced signal and noise ratio (SNR) at tumorigenesis sites since the contraction of capillaries under cold challenge is natural to healthy capillaries, except those newly built capillaries during angiogenesis (Folkman, Nature 1995). Concomitant with the genome and the phenome (molecular signaling by phosphor-mediate protein causing inflammation by strong>platelet activating factor (PAF)strong> that transform cells from benign to malignant is the amplification of strong>nitric oxide (NO)strong> syntheses, a short-lived reactive oxygen species (ROS) that dilates regional blood vessels; superseding normal autonomic nervous system regulation. A rapidly growing tumor site might implicate accumulation of strong>ROSstrong>, for which strong>NOstrong> can rapidly stretch the capillary bed system usually having thinning muscular lining known as strong>Neo-Angiogenesis (NA)strong> that could behave like strong>Leaky In-situ Faucet Effect (LIFE)strong> in response to cold challenge. To emphasize the state of art knowledge of strong>NAstrong>, we mentioned in passing the first generation of an anticapillary growth drug, strong>Avastinstrong> by Genetech; it is an antibody protein that is injected for metastasis, while the second generation drug; strong>Sorafenibstrong> by Bayers (2001) and strong>Sutentstrong> by Pfizer (2000) both target molecular signaling loci to block receptor associated tyrosine kinase induced

  1. WE-AB-303-11: Verification of a Deformable 4DCT Motion Model for Lung Tumor Tracking Using Different Driving Surrogates

    Energy Technology Data Exchange (ETDEWEB)

    Woelfelschneider, J [University Hospital Erlangen, Erlangen, DE (Germany); Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, DE (Germany); Seregni, M; Fassi, A; Baroni, G; Riboldi, M [Politecnico di Milano, Milano (Italy); Bert, C [University Hospital Erlangen, Erlangen, DE (Germany); Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, DE (Germany); GSI - Helmholtz Centre for Heavy Ion Research, Darmstadt, DE (Germany)

    2015-06-15

    Purpose: Tumor tracking is an advanced technique to treat intra-fractionally moving tumors. The aim of this study is to validate a surrogate-driven model based on four-dimensional computed tomography (4DCT) that is able to predict CT volumes corresponding to arbitrary respiratory states. Further, the comparison of three different driving surrogates is evaluated. Methods: This study is based on multiple 4DCTs of two patients treated for bronchial carcinoma and metastasis. Analyses for 18 additional patients are currently ongoing. The motion model was estimated from the planning 4DCT through deformable image registration. To predict a certain phase of a follow-up 4DCT, the model considers for inter-fractional variations (baseline correction) and intra-fractional respiratory parameters (amplitude and phase) derived from surrogates. In this evaluation, three different approaches were used to extract the motion surrogate: for each 4DCT phase, the 3D thoraco-abdominal surface motion, the body volume and the anterior-posterior motion of a virtual single external marker defined on the sternum were investigated. The estimated volumes resulting from the model were compared to the ground-truth clinical 4DCTs using absolute HU differences in the lung volume and landmarks localized using the Scale Invariant Feature Transform (SIFT). Results: The results show absolute HU differences between estimated and ground-truth images with median values limited to 55 HU and inter-quartile ranges (IQR) lower than 100 HU. Median 3D distances between about 1500 matching landmarks are below 2 mm for 3D surface motion and body volume methods. The single marker surrogates Result in increased median distances up to 0.6 mm. Analyses for the extended database incl. 20 patients are currently in progress. Conclusion: The results depend mainly on the image quality of the initial 4DCTs and the deformable image registration. All investigated surrogates can be used to estimate follow-up 4DCT phases

  2. Anti-HER2 immunoliposomes for selective delivery of electron paramagnetic resonance imaging probes to HER2-overexpressing breast tumor cells

    Science.gov (United States)

    Burks, Scott R.; Macedo, Luciana F.; Barth, Eugene D.; Tkaczuk, Katherine H.; Martin, Stuart S.; Rosen, Gerald M.; Halpern, Howard J.; Brodie, Angela M.

    2014-01-01

    Electron paramagnetic resonance (EPR) imaging is an emerging modality that can detect and localize paramagnetic molecular probes (so-called spin probes) in vivo. We previously demonstrated that nitroxide spin probes can be encapsulated in liposomes at concentrations exceeding 100 mM, at which nitroxides exhibit a concentration-dependent quenching of their EPR signal that is analogous to the self-quenching of fluorescent molecules. Therefore, intact liposomes encapsulating high concentrations of nitroxides exhibit greatly attenuated EPR spectral signals, and endocytosis of such liposomes represents a cell-activated contrast-generating mechanism. After endocytosis, the encapsulated nitroxide is liberated and becomes greatly diluted in the intracellular milieu. This dequenches the nitroxides to generate a robust intracellular EPR signal. It is therefore possible to deliver a high concentration of nitroxides to cells while minimizing background signal from unendocytosed liposomes. We report here that intracellular EPR signal can be selectively generated in a specific cell type by exploiting its expression of Human Epidermal Growth Factor Receptor 2 (HER2). When targeted by anti-HER2 immunoliposomes encapsulating quenched nitroxides, Hc7 cells, which are novel HER2-overexpressing cells derived from the MCF7 breast tumor cell line, endocytose the liposomes copiously, in contrast to the parent MCF7 cells or control CV1 cells, which do not express HER2. HER2-dependent liposomal delivery enables Hc7 cells to accumulate 750 μM nitroxide intracellularly. Through the use of phantom models, we verify that this concentration of nitroxides is more than sufficient for EPR imaging, thus laying the foundation for using EPR imaging to visualize HER2-overexpressing Hc7 tumors in animals. PMID:20066490

  3. Systemic co-delivery of doxorubicin and siRNA using nanoparticles conjugated with EGFR-specific targeting peptide to enhance chemotherapy in ovarian tumor bearing mice

    Energy Technology Data Exchange (ETDEWEB)

    Liu, C. W.; Lin, W. J., E-mail: wjlin@ntu.edu.tw [National Taiwan University, Graduate Institute of Pharmaceutical Sciences, School of Pharmacy (China)

    2013-10-15

    This aim of this study was to develop peptide-conjugated nanoparticles (NPs) for systemic co-delivery of siRNA and doxorubicin to enhance chemotherapy in epidermal growth factor receptor (EGFR) high-expressed ovarian tumor bearing mice. The active targeting NPs were prepared using heptapeptide-conjugated poly(d,l-lactic-co-glycolic acid)-poly(ethylene glycol). The particle sizes of peptide-free and peptide-conjugated NPs were 159.3 {+-} 32.5 and 184.0 {+-} 52.9 nm, respectively, with zeta potential -21.3 {+-} 3.8 and -15.3 {+-} 2.8 mV. The peptide-conjugated NPs uptake were more efficient in EGFR high-expressed SKOV3 cells than in EGFR low-expressed HepG2 cells due to heptapeptide specificity. The NPs were used to deliver small molecule anticancer drug (e.g., doxorubicin) and large molecule genetic agent (e.g., siRNA). The IC{sub 50} of doxorubicin-loaded peptide-conjugated NPs (0.09 {+-} 0.06 {mu}M) was significantly lower than peptide-free NPs (5.72 {+-} 2.64 {mu}M). The similar result was observed in siRNA-loaded NPs. The peptide-conjugated NPs not only served as a nanocarrier to efficiently deliver doxorubicin and siRNA to EGFR high-expressed ovarian cancer cells but also increased the intracellular accumulation of the therapeutic agents to induce assured anti-tumor growth effect in vivo.

  4. Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery.

    Science.gov (United States)

    Naghibi Beidokhti, Hamid Reza; Ghaffarzadegan, Reza; Mirzakhanlouei, Sasan; Ghazizadeh, Leila; Dorkoosh, Farid Abedin

    2017-01-01

    The objective of this study was to investigate the combined influence of independent variables in the preparation of folic acid-chitosan-methotrexate nanoparticles (FA-Chi-MTX NPs). These NPs were designed and prepared for targeted drug delivery in tumor. The NPs of each batch were prepared by coaxial electrospray atomization method and evaluated for particle size (PS) and particle size distribution (PSD). The independent variables were selected to be concentration of FA-chitosan, ratio of shell solution flow rate to core solution flow rate, and applied voltage. The process design of experiments (DOE) was obtained with three factors in three levels by Design expert software. Box-Behnken design was used to select 15 batches of experiments randomly. The chemical structure of FA-chitosan was examined by FTIR. The NPs of each batch were collected separately, and morphologies of NPs were investigated by field emission scanning electron microscope (FE-SEM). The captured pictures of all batches were analyzed by ImageJ software. Mean PS and PSD were calculated for each batch. Polynomial equation was produced for each response. The FE-SEM results showed the mean diameter of the core-shell NPs was around 304 nm, and nearly 30% of the produced NPs are in the desirable range. Optimum formulations were selected. The validation of DOE optimization results showed errors around 2.5 and 2.3% for PS and PSD, respectively. Moreover, the feasibility of using prepared NPs to target tumor extracellular pH was shown, as drug release was greater in the pH of endosome (acidic medium). Finally, our results proved that FA-Chi-MTX NPs were active against the human epithelial cervical cancer (HeLa) cells.

  5. Multiseed liposomal drug delivery system using micelle gradient as driving force to improve amphiphilic drug retention and its anti-tumor efficacy.

    Science.gov (United States)

    Zhang, Wenli; Li, Caibin; Jin, Ya; Liu, Xinyue; Wang, Zhiyu; Shaw, John P; Baguley, Bruce C; Wu, Zimei; Liu, Jianping

    2018-11-01

    To improve drug retention in carriers for amphiphilic asulacrine (ASL), a novel active loading method using micelle gradient was developed to fabricate the ASL-loaded multiseed liposomes (ASL-ML). The empty ML were prepared by hydrating a thin film with empty micelles. Then the micelles in liposomal compartment acting as 'micelle pool' drove the drug to be loaded after the outer micelles were removed. Some reasoning studies including critical micelle concentration (CMC) determination, influencing factors tests on entrapment efficiency (EE), structure visualization, and drug release were carried out to explore the mechanism of active loading, ASL location, and the structure of ASL-ML. Comparisons were made between pre-loading and active loading method. Finally, the extended drug retention capacity of ML was evaluated through pharmacokinetic, drug tissue irritancy, and in vivo anti-tumor activity studies. Comprehensive results from fluorescent and transmission electron microscope (TEM) observation, encapsulation efficiency (EE) comparison, and release studies demonstrated the formation of ML-shell structure for ASL-ML without inter-carrier fusion. The location of drug mainly in inner micelles as well as the superiority of post-loading to the pre-loading method , in which drug in micelles shifted onto the bilayer membrane was an additional positive of this delivery system. It was observed that the drug amphiphilicity and interaction of micelles with drug were the two prerequisites for this active loading method. The extended retention capacity of ML has been verified through the prolonged half-life, reduced paw-lick responses in rats, and enhanced tumor inhibition in model mice. In conclusion, ASL-ML prepared by active loading method can effectively load drug into micelles with expected structure and improve drug retention.

  6. Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.

    Science.gov (United States)

    Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane; Zhang, Ben; Moncelet, Damien; Isaacs, Lyle; Briken, Volker

    2016-03-07

    Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.

  7. SU-F-R-54: CT-Texture Based Early Tumor Treatment Response Assessment During Radiation Therapy Delivery: Small Cell Versus Non-Small Cell Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Paul, J; Gore, E; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States)

    2016-06-15

    Purpose: Tumor treatment response may potentially be assessed during radiation therapy (RT) by analyzing changes in CT-textures. We investigated the different early RT-responses between small cell (SCLC) and non-small cell lung cancer (NSCLC) as assessed by CT-texture. Methods: Daily diagnostic-quality CT acquired during routine CT-guided RT using a CT-on-Rails for 13-NSCLC and 5-SCLC patients were analyzed. These patient had ages ranging from 45–78 and 38–63 years, respectively, for NSCLC and SCLC groups, and tumor-stages ranging from T2-T4, and were treated with either RT or chemotherapy and RT with 45–66Gy/ 20–34 fractions. Gross-tumor volume (GTV) contour was generated on each daily CT by populating GTV contour from simulation to daily CTs with manual editing if necessary. CT-texture parameters, such as Hounsfield Unit (HU) histogram, mean HU, skewness, kurtosis, entropy, and short-run high-gray level emphasis (SRHGLE), were calculated in GTV from each daily CT-set using an in house software tool. Difference in changes of these texture parameters during RT between NSCLC and SCLC was analyzed and compared with GTV volume changes. Results: Radiation-induced changes in CT-texture were different between SCLC and NSCLC. Average changes from first to the last fractions for NSCLC and SCLC in GTV were 28±10(12–44) and 30±15(11–47) HU (mean HU reduction), 12.7% and 18.3% (entropy), 50% and 55% (SRHGLE), 19% and 22% (kurtosis), and 5.2% and 22% (skewness), respectively. Good correlation in kurtosis changes and GTV was seen (R{sup 2}=0.8923) for SCLC, but not for NSCLC (R{sup 2}=0.4748). SCLC had better correlations between GTV volume reduction and entropy (SCLC R{sup 2}=0.847; NSCLC R{sup 2}=0.6485), skewness (SCLC R{sup 2}=0.935; NSCLC R{sup 2}=0.7666), or SRHGLE (SCLC R{sup 2}=0.9619; NSCLC R{sup 2}=0.787). Conclusion: NSCLC and SCLC exhibited different early RT-responses as assessed by CT-texture changes during RT-delivery. The observed larger changes in

  8. Experimental investigation of a moving averaging algorithm for motion perpendicular to the leaf travel direction in dynamic MLC target tracking

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Jai-Woong; Sawant, Amit; Suh, Yelin; Cho, Byung-Chul; Suh, Tae-Suk; Keall, Paul [Department of Biomedical Engineering, College of Medicine, Catholic University of Korea, Seoul, Korea 131-700 and Research Institute of Biomedical Engineering, Catholic University of Korea, Seoul, 131-700 (Korea, Republic of); Department of Radiation Oncology, Stanford University, Stanford, California 94305 (United States); Department of Radiation Oncology, Stanford University, Stanford, California 94305 (United States) and Department of Radiation Oncology, Asan Medical Center, Seoul, 138-736 (Korea, Republic of); Department of Biomedical Engineering, College of Medicine, Catholic University of Korea, Seoul, 131-700 and Research Institute of Biomedical Engineering, Catholic University of Korea, Seoul, 131-700 (Korea, Republic of); Department of Radiation Oncology, Stanford University, Stanford, California 94305 (United States) and Radiation Physics Laboratory, Sydney Medical School, University of Sydney, 2006 (Australia)

    2011-07-15

    Purpose: In dynamic multileaf collimator (MLC) motion tracking with complex intensity-modulated radiation therapy (IMRT) fields, target motion perpendicular to the MLC leaf travel direction can cause beam holds, which increase beam delivery time by up to a factor of 4. As a means to balance delivery efficiency and accuracy, a moving average algorithm was incorporated into a dynamic MLC motion tracking system (i.e., moving average tracking) to account for target motion perpendicular to the MLC leaf travel direction. The experimental investigation of the moving average algorithm compared with real-time tracking and no compensation beam delivery is described. Methods: The properties of the moving average algorithm were measured and compared with those of real-time tracking (dynamic MLC motion tracking accounting for both target motion parallel and perpendicular to the leaf travel direction) and no compensation beam delivery. The algorithm was investigated using a synthetic motion trace with a baseline drift and four patient-measured 3D tumor motion traces representing regular and irregular motions with varying baseline drifts. Each motion trace was reproduced by a moving platform. The delivery efficiency, geometric accuracy, and dosimetric accuracy were evaluated for conformal, step-and-shoot IMRT, and dynamic sliding window IMRT treatment plans using the synthetic and patient motion traces. The dosimetric accuracy was quantified via a {gamma}-test with a 3%/3 mm criterion. Results: The delivery efficiency ranged from 89 to 100% for moving average tracking, 26%-100% for real-time tracking, and 100% (by definition) for no compensation. The root-mean-square geometric error ranged from 3.2 to 4.0 mm for moving average tracking, 0.7-1.1 mm for real-time tracking, and 3.7-7.2 mm for no compensation. The percentage of dosimetric points failing the {gamma}-test ranged from 4 to 30% for moving average tracking, 0%-23% for real-time tracking, and 10%-47% for no compensation

  9. Experimental investigation of a moving averaging algorithm for motion perpendicular to the leaf travel direction in dynamic MLC target tracking.

    Science.gov (United States)

    Yoon, Jai-Woong; Sawant, Amit; Suh, Yelin; Cho, Byung-Chul; Suh, Tae-Suk; Keall, Paul

    2011-07-01

    In dynamic multileaf collimator (MLC) motion tracking with complex intensity-modulated radiation therapy (IMRT) fields, target motion perpendicular to the MLC leaf travel direction can cause beam holds, which increase beam delivery time by up to a factor of 4. As a means to balance delivery efficiency and accuracy, a moving average algorithm was incorporated into a dynamic MLC motion tracking system (i.e., moving average tracking) to account for target motion perpendicular to the MLC leaf travel direction. The experimental investigation of the moving average algorithm compared with real-time tracking and no compensation beam delivery is described. The properties of the moving average algorithm were measured and compared with those of real-time tracking (dynamic MLC motion tracking accounting for both target motion parallel and perpendicular to the leaf travel direction) and no compensation beam delivery. The algorithm was investigated using a synthetic motion trace with a baseline drift and four patient-measured 3D tumor motion traces representing regular and irregular motions with varying baseline drifts. Each motion trace was reproduced by a moving platform. The delivery efficiency, geometric accuracy, and dosimetric accuracy were evaluated for conformal, step-and-shoot IMRT, and dynamic sliding window IMRT treatment plans using the synthetic and patient motion traces. The dosimetric accuracy was quantified via a tgamma-test with a 3%/3 mm criterion. The delivery efficiency ranged from 89 to 100% for moving average tracking, 26%-100% for real-time tracking, and 100% (by definition) for no compensation. The root-mean-square geometric error ranged from 3.2 to 4.0 mm for moving average tracking, 0.7-1.1 mm for real-time tracking, and 3.7-7.2 mm for no compensation. The percentage of dosimetric points failing the gamma-test ranged from 4 to 30% for moving average tracking, 0%-23% for real-time tracking, and 10%-47% for no compensation. The delivery efficiency of

  10. TH-C-12A-02: Comparison of Two RapidArc Delivery Strategies in Stereotactic Body Radiotherapy of Stage I and II Peripheral Lung Tumors with Unflattened Beams

    International Nuclear Information System (INIS)

    Huang, B; Lu, J; Chen, J; Chen, C; Lin, P; Kuang, Y

    2014-01-01

    Purpose: The full arcs strategy used in SBRT with RapidArc and unflattened (FFF) beams in large and heterogeneous peripheral non-smallcell lung cancer (NSCLC) appears to be suboptimal as it increases the disadvantageous dose to the contralateral lung, which potentially increases the toxicity to surrounding tissues. In this study, we investigated, for the first time, the dose delivery strategies using partial arcs (PA) and the fully rotational arcs with avoidance sectors (FAAS) for SBRT with FFF beams in peripheral NSCLC patients. Methods: Eighteen patients with NSCLC (stage I and II) were selected for this study. Nine patients with a GTV <= 10cc were designated as the small tumor group. The remaining nine patients with a GTV between 10 cc and 44 cc were assigned to the large tumor group. The treatment plans were generated in eighteen patients using PA and FAAS, respectively, and delivered with a Varian TrueBeam Linac. Dosimetry of the target and organs at risk (OAR), total MU, out-of-field dose, and delivery time were analyzed. Delta4 and Portal dosimetry were employed to evaluate the delivery accuracy. Results: or the small tumor group, the FAAS plans significantly achieved a better conformity index, the lower total MU and out-of-field dose, a shorter treatment time, and the reduced doses to cord, heart, and lung (p < 0.05). But the target doses were slightly higher than that delivered by PA plans. For the large tumor group, the PA plans significantly attained a better conformity index and a shorter treatment time (p < 0.05). Furthermore, all plans achieved a high pass rate, with all the gamma indices greater than 97% at the Γ 3mm, 3% threshold. Conclusion: This study suggests that FAAS strategy is more beneficial for small tumor patients undergoing lung SBRT with FFF beams. However, for large tumor patients, PA strategy is recommended. NIH/NIGMS grant U54 GM104944, Lincy Endowed Assistant Professorship

  11. Tracking of cell nuclei for assessment of in vitro uptake kinetics in ultrasound-mediated drug delivery using fibered confocal fluorescence microscopy.

    Science.gov (United States)

    Derieppe, Marc; de Senneville, Baudouin Denis; Kuijf, Hugo; Moonen, Chrit; Bos, Clemens

    2014-10-01

    Previously, we demonstrated the feasibility to monitor ultrasound-mediated uptake of a cell-impermeable model drug in real time with fibered confocal fluorescence microscopy. Here, we present a complete post-processing methodology, which corrects for cell displacements, to improve the accuracy of pharmacokinetic parameter estimation. Nucleus detection was performed based on the radial symmetry transform algorithm. Cell tracking used an iterative closest point approach. Pharmacokinetic parameters were calculated by fitting a two-compartment model to the time-intensity curves of individual cells. Cells were tracked successfully, improving time-intensity curve accuracy and pharmacokinetic parameter estimation. With tracking, 93 % of the 370 nuclei showed a fluorescence signal variation that was well-described by a two-compartment model. In addition, parameter distributions were narrower, thus increasing precision. Dedicated image analysis was implemented and enabled studying ultrasound-mediated model drug uptake kinetics in hundreds of cells per experiment, using fiber-based confocal fluorescence microscopy.

  12. Multifunctional Nanoparticles for Brain Tumor Diagnosis and Therapy

    Science.gov (United States)

    Cheng, Yu; Morshed, Ramin; Auffinger, Brenda; Tobias, Alex L.; Lesniak, Maciej S.

    2013-01-01

    Brain tumors are a diverse group of neoplasms that often carry a poor prognosis for patients. Despite tremendous efforts to develop diagnostic tools and therapeutic avenues, the treatment of brain tumors remains a formidable challenge in the field of neuro-oncology. Physiological barriers including the blood-brain barrier result in insufficient accumulation of therapeutic agents at the site of a tumor, preventing adequate destruction of malignant cells. Furthermore, there is a need for improvements in brain tumor imaging to allow for better characterization and delineation of tumors, visualization of malignant tissue during surgery, and tracking of response to chemotherapy and radiotherapy. Multifunctional nanoparticles offer the potential to improve upon many of these issues and may lead to breakthroughs in brain tumor management. In this review, we discuss the diagnostic and therapeutic applications of nanoparticles for brain tumors with an emphasis on innovative approaches in tumor targeting, tumor imaging, and therapeutic agent delivery. Clinically feasible nanoparticle administration strategies for brain tumor patients are also examined. Furthermore, we address the barriers towards clinical implementation of multifunctional nanoparticles in the context of brain tumor management. PMID:24060923

  13. “Marker of Self” CD47 on lentiviral vectors decreases macrophage-mediated clearance and increases delivery to SIRPA-expressing lung carcinoma tumors

    Directory of Open Access Journals (Sweden)

    Nisha G Sosale

    2016-01-01

    Full Text Available Lentiviruses infect many cell types and are now widely used for gene delivery in vitro, but in vivo uptake of these foreign vectors by macrophages is a limitation. Lentivectors are produced here from packaging cells that overexpress “Marker of Self” CD47, which inhibits macrophage uptake of cells when prophagocytic factors are also displayed. Single particle analyses show “hCD47-Lenti” display properly oriented human-CD47 for interactions with the macrophage's inhibitory receptor SIRPA. Macrophages derived from human and NOD/SCID/Il2rg−/− (NSG mice show a SIRPA-dependent decrease in transduction, i.e., transgene expression, by hCD47-Lenti compared to control Lenti. Consistent with known “Self” signaling pathways, macrophage transduction by control Lenti is decreased by drug inhibition of Myosin-II to the same levels as hCD47-Lenti. In contrast, human lung carcinoma cells express SIRPA and use it to enhance transduction by hCD47-Lenti- as illustrated by more efficient gene deletion using CRISPR/Cas9. Intravenous injection of hCD47-Lenti into NSG mice shows hCD47 prolongs circulation, unless a blocking anti-SIRPA is preinjected. In vivo transduction of spleen and liver macrophages also decreases for hCD47-Lenti while transduction of lung carcinoma xenografts increases. hCD47 could be useful when macrophage uptake is limiting on other viral vectors that are emerging in cancer treatments (e.g., Measles glycoprotein-pseudotyped lentivectors and also in targeting various SIRPA-expressing tumors such as glioblastomas.

  14. UAV Delivery Monitoring System

    Directory of Open Access Journals (Sweden)

    San Khin Thida

    2018-01-01

    Full Text Available UAV-based delivery systems are increasingly being used in the logistics field, particularly to achieve faster last-mile delivery. This study develops a UAV delivery system that manages delivery order assignments, autonomous flight operation, real time control for UAV flights, and delivery status tracking. To manage the delivery item assignments, we apply the concurrent scheduler approach with a genetic algorithm. The present paper describes real time flight data based on a micro air vehicle communication protocol (MAVLink. It also presents the detailed hardware components used for the field tests. Finally, we provide UAV component analysis to choose the suitable components for delivery in terms of battery capacity, flight time, payload weight and motor thrust ratio.

  15. Assessment of two novel ventilatory surrogates for use in the delivery of gated/tracked radiotherapy for non-small cell lung cancer

    International Nuclear Information System (INIS)

    Hughes, Simon; McClelland, James; Tarte, Segolene; Lawrence, David; Ahmad, Shahreen; Hawkes, David; Landau, David

    2009-01-01

    Background: In selected patients with NSCLC the therapeutic index of radical radiotherapy can be improved with gating/tracking technology. Both techniques require real-time information on target location. This is often derived from a surrogate ventilatory signal. We assessed the correlation of two novel surrogate ventilatory signals with a spirometer-derived signal. The novel signals were obtained using the VisionRT stereoscopic camera system. The VisionRT-Tracked-Point (VRT-TP) signal was derived from tracking a point located midway between the umbilicus and xiphisternum. The VisionRT-Surface-Derived-Volume (VRT-SDV) signal was derived from 3D body surface imaging of the torso. Both have potential advantages over the current surrogate signals. Methods: Eleven subjects with NSCLC were recruited. Each was positioned as for radiotherapy treatment, and then instructed to breathe in five different modes: normal, abdominal, thoracic, deep and shallow breathing. Synchronous ventilatory signals were recorded for later analysis. The signals were analysed for correlation across all modes of breathing, and phase shifts. The VRT-SDV was also assessed for its ability to determine the mode of breathing. Results: Both novel respiratory signals showed good correlation (r > 0.80) with spirometry in 9 of 11 subjects. For all subjects the correlation with spirometry was better for the VRT-SDV signal than for the VRT-TP signal. Only one subject displayed a phase shift between the VisionRT-derived signals and spirometry. The VRT-SDV signal could also differentiate between different modes of breathing. Unlike the spirometer-derived signal, neither VisionRT-derived signal was subject to drift. Conclusion: Both the VRT-TP and VRT-SDV signals have potential applications in ventilatory-gated and tracked radiotherapy. They can also be used as a signal for sorting 4DCT images, and to drive 4DCT single- and multiple-parameter motion models.

  16. A ternary-complex of a suicide gene, a RAGE-binding peptide, and polyethylenimine as a gene delivery system with anti-tumor and anti-angiogenic dual effects in glioblastoma.

    Science.gov (United States)

    Choi, Eunji; Oh, Jungju; Lee, Dahee; Lee, Jaewon; Tan, Xiaonan; Kim, Minkyung; Kim, Gyeungyun; Piao, Chunxian; Lee, Minhyung

    2018-04-13

    The receptor for advanced glycation end-products (RAGE) is involved in tumor angiogenesis. Inhibition of RAGE might be an effective anti-angiogenic therapy for cancer. In this study, a cationic RAGE-binding peptide (RBP) was produced as an antagonist of RAGE, and a ternary-complex consisting of RBP, polyethylenimine (2 kDa, PEI2k), and a suicide gene (pHSVtk) was developed as a gene delivery system with dual functions: the anti-tumor effect of pHSVtk and anti-angiogenic effect of RBP. As an antagonist of RAGE, RBP decreased the secretion of vascular-endothelial growth factor (VEGF) in activated macrophages and reduced the tube-formation of endothelial cells in vitro. In in vitro transfection assays, the RBP/PEI2k/plasmid DNA (pDNA) ternary-complex had higher transfection efficiency than the PEI2k/pDNA binary-complex. In an intracranial glioblastoma animal model, the RBP/PEI2k/pHSVtk ternary-complex reduced α-smooth muscle actin expression, suggesting that the complex has an anti-angiogenic effect. In addition, the ternary-complex had higher pHSVtk delivery efficiency than the PEI2k/pHSVtk and PEI25k/pHSVtk binary-complexes in an animal model. As a result, the ternary-complex induced apoptosis and reduced tumor volume more effectively than the PEI2k/pHSVtk and PEI25k/pHSVtk binary-complexes. In conclusion, due to its dual anti-tumor and anti-angiogenesis effects, the RBP/PEI2k/pHSVtk ternary-complex might be an efficient gene delivery system for the treatment of glioblastoma. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Robotic radiosurgery. Treating tumors that move with respiration

    International Nuclear Information System (INIS)

    Urschel, Harold C. Jr.; Kresl, John J.; Luketich, James D.; Papiez, Lech; Timmerman, Robert D.; Schulz, Raymond A.

    2007-01-01

    Addresses in detail all aspects of the use of robotic radiosurgery to treat tumors of the lung, liver, and pancreas Includes full consideration of tumor tracking techniques, dosimetry, radiobiology, and fiducial placement strategies Written by leading experts Includes many high quality illustrations Stereotactic radiosurgery continues to evolve in ways that allow this powerful technology to reach and treat more tumors in more patients. This volume in the Robotic Radiosurgery series is devoted to theory and practice in the emerging field of stereotactic radiosurgery (also called stereotactic body radiation therapy) for extracranial tumors, particularly those that move as patients breathe. The book is divided into six sections. The first three sections address tumor motion due to respiration and tumor tracking techniques; dosimetry, radiobiology, and imaging; and fiducial placement systems. The fourth and fifth sections then discuss in depth the use of robotic radiosurgery to treat lung and abdominal tumors, respectively, and a final section explains emerging concepts and techniques. Within this framework, detailed information is provided on the technology and methodology for delivery of high doses of radiation to moving targets, radiobiological and radiological principles, and the challenges faced by clinicians performing extracranial stereotactic radiosurgery. Furthermore, there are thorough reviews of the general clinical literature on stereotactic radiation treatment of tumors of the lungs, liver, and pancreas, and the latest clinical data from clinicians conducting clinical studies using the CyberKnife registered Robotic Radiosurgery System. Special attention is given to the frameless robotic radiosurgery device known as the CyberKnife, the only image-guided radiosurgery system that utilizes intelligent robotics to track, detect, and correct for changes in tumor position during treatments. Tumors that move with respiration are treated with the CyberKnife using a

  18. Robotic radiosurgery. Treating tumors that move with respiration

    Energy Technology Data Exchange (ETDEWEB)

    Urschel, Harold C. Jr. [Baylor University Medical Center, Dallas, TX (United States). Chair of Cardiovascular and Thoracic Surgical Research, Education and Clinical Excellence; Kresl, John J. [Arizona Oncology Services at St. Joseph' s Hospital and Medical Center, Phoenix, AZ (United States). Dept. of Radiation Oncology; Luketich, James D. [University of Pittsburgh Medical Center PUH, Pittsburgh, PA (United States). The Heart, Lung and Esophageal Surgery Inst.; Papiez, Lech; Timmerman, Robert D. [University of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Radiation Oncology; Schulz, Raymond A. (eds.)

    2007-07-01

    Addresses in detail all aspects of the use of robotic radiosurgery to treat tumors of the lung, liver, and pancreas Includes full consideration of tumor tracking techniques, dosimetry, radiobiology, and fiducial placement strategies Written by leading experts Includes many high quality illustrations Stereotactic radiosurgery continues to evolve in ways that allow this powerful technology to reach and treat more tumors in more patients. This volume in the Robotic Radiosurgery series is devoted to theory and practice in the emerging field of stereotactic radiosurgery (also called stereotactic body radiation therapy) for extracranial tumors, particularly those that move as patients breathe. The book is divided into six sections. The first three sections address tumor motion due to respiration and tumor tracking techniques; dosimetry, radiobiology, and imaging; and fiducial placement systems. The fourth and fifth sections then discuss in depth the use of robotic radiosurgery to treat lung and abdominal tumors, respectively, and a final section explains emerging concepts and techniques. Within this framework, detailed information is provided on the technology and methodology for delivery of high doses of radiation to moving targets, radiobiological and radiological principles, and the challenges faced by clinicians performing extracranial stereotactic radiosurgery. Furthermore, there are thorough reviews of the general clinical literature on stereotactic radiation treatment of tumors of the lungs, liver, and pancreas, and the latest clinical data from clinicians conducting clinical studies using the CyberKnife {sup registered} Robotic Radiosurgery System. Special attention is given to the frameless robotic radiosurgery device known as the CyberKnife, the only image-guided radiosurgery system that utilizes intelligent robotics to track, detect, and correct for changes in tumor position during treatments. Tumors that move with respiration are treated with the Cyber

  19. Engineering of magnetic DNA nanoparticles for tumor-targeted therapy

    International Nuclear Information System (INIS)

    Hosseinkhani, Hossein; Chen Yiru; He Wenjie; Hong Poda; Yu, Dah-Shyong; Domb, Abraham J.

    2013-01-01

    This study aims to engineer novel targeted delivery system composed of magnetic DNA nanoparticles to be effective as an efficient targeted gene therapy vehicle for tumor therapy. A polysaccharide, dextran, was chosen as the vector of plasmid DNA-encoded NK4 that acts as an HGF-antagonist and anti-angiogenic regulator for inhibitions of tumor growth, invasion, and metastasis. Spermine (Sm) was chemically introduced to the hydroxyl groups of dextran to obtain dextran-Sm. When Fe 2+ solution was added to the mixture of dextran-Sm and a plasmid DNA, homogenous DNA nanoparticles were formed via chemical metal coordination bonding with average size of 230 nm. Characterization of DNA nanoparticles was performed via dynamic light scattering measurement, electrophoretic light scattering measurement, as well as transmission electron microscope. DNA nanoparticles effectively condensed plasmid DNA into nanoparticles and enhanced the stability of DNA, while significantly improved transfection efficiency in vitro and tumor accumulation in vivo. In addition, magnetic DNA nanoparticles exhibited high efficiency in antitumor therapy with regards to tumor growth as well as survival of animals evaluated in the presence of external magnetic field. We conclude that the magnetic properties of these DNA nanoparticles would enhance the tracking of non-viral gene delivery systems when administrated in vivo in a test model. These findings suggest that DNA nanoparticles effectively deliver DNA to tumor and thereby inhibiting tumor growth.

  20. Engineering of magnetic DNA nanoparticles for tumor-targeted therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hosseinkhani, Hossein, E-mail: hosseinkhani@yahoo.com [Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology (Taiwan Tech) (China); Chen Yiru [National Yang-Ming University, Department of Biomedical Engineering (China); He Wenjie; Hong Poda [Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology (Taiwan Tech) (China); Yu, Dah-Shyong [Nanomedicine Research Center, National Defense Medical Center (China); Domb, Abraham J. [Institute of Drug Research, The Center for Nanoscience and Nanotechnology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem (Israel)

    2013-01-15

    This study aims to engineer novel targeted delivery system composed of magnetic DNA nanoparticles to be effective as an efficient targeted gene therapy vehicle for tumor therapy. A polysaccharide, dextran, was chosen as the vector of plasmid DNA-encoded NK4 that acts as an HGF-antagonist and anti-angiogenic regulator for inhibitions of tumor growth, invasion, and metastasis. Spermine (Sm) was chemically introduced to the hydroxyl groups of dextran to obtain dextran-Sm. When Fe{sup 2+} solution was added to the mixture of dextran-Sm and a plasmid DNA, homogenous DNA nanoparticles were formed via chemical metal coordination bonding with average size of 230 nm. Characterization of DNA nanoparticles was performed via dynamic light scattering measurement, electrophoretic light scattering measurement, as well as transmission electron microscope. DNA nanoparticles effectively condensed plasmid DNA into nanoparticles and enhanced the stability of DNA, while significantly improved transfection efficiency in vitro and tumor accumulation in vivo. In addition, magnetic DNA nanoparticles exhibited high efficiency in antitumor therapy with regards to tumor growth as well as survival of animals evaluated in the presence of external magnetic field. We conclude that the magnetic properties of these DNA nanoparticles would enhance the tracking of non-viral gene delivery systems when administrated in vivo in a test model. These findings suggest that DNA nanoparticles effectively deliver DNA to tumor and thereby inhibiting tumor growth.

  1. A comparison of two clinical correlation models used for real-time tumor tracking of semi-periodic motion: A focus on geometrical accuracy in lung and liver cancer patients

    International Nuclear Information System (INIS)

    Poels, Kenneth; Dhont, Jennifer; Verellen, Dirk; Blanck, Oliver; Ernst, Floris; Vandemeulebroucke, Jef; Depuydt, Tom; Storme, Guy; De Ridder, Mark

    2015-01-01

    Purpose: A head-to-head comparison of two clinical correlation models with a focus on geometrical accuracy for internal tumor motion estimation during real-time tumor tracking (RTTT). Methods and materials: Both the CyberKnife (CK) and the Vero systems perform RTTT with a correlation model that is able to describe hysteresis in the breathing motion. The CK dual-quadratic (DQ) model consists of two polynomial functions describing the trajectory of the tumor for inhale and exhale breathing motion, respectively. The Vero model is based on a two-dimensional (2D) function depending on position and speed of the external breathing signal to describe a closed-loop tumor trajectory. In this study, 20 s of internal motion data, using an 11 Hz (on average) full fluoroscopy (FF) sequence, was used for training of the CK and Vero models. Further, a subsampled set of 15 internal tumor positions (15p) equally spread over the different phases of the breathing motion was used for separate training of the CK DQ model. Also a linear model was trained using 15p and FF tumor motion data. Fifteen liver and lung cancer patients, treated on the Vero system with RTTT, were retrospectively evaluated comparing the CK FF, CK 15p and Vero FF models using an in-house developed simulator. The distance between estimated target position and the tumor position localized by X-ray imaging was measured in the beams-eye view (BEV) to calculate the 95th percentile BEV modeling errors (ME 95,BEV ). Additionally, the percentage of ME 95,BEV smaller than 5 mm (P 5mm ) was determined for all correlation models. Results: In general, no significant difference (p > 0.05, paired t-test) was found between the CK FF and Vero models. Based on patient-specific evaluation of the geometrical accuracy of the linear, CK DQ and Vero correlation models, no statistical necessity (p > 0.05, two-way ANOVA) of including hysteresis in correlation models was proven, although during inhale breathing motion, the linear model

  2. Stem cell tracking using iron oxide nanoparticles

    Directory of Open Access Journals (Sweden)

    Bull E

    2014-03-01

    Full Text Available Elizabeth Bull,1 Seyed Yazdan Madani,1 Roosey Sheth,1 Amelia Seifalian,1 Mark Green,2 Alexander M Seifalian1,31UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, London, 2Department of Physics, King’s College London, Strand Campus, London, UK; 3Royal Free London National Health Service Foundation Trust Hospital, London, UKAbstract: Superparamagnetic iron oxide nanoparticles (SPIONs are an exciting advancement in the field of nanotechnology. They expand the possibilities of noninvasive analysis and have many useful properties, making them potential candidates for numerous novel applications. Notably, they have been shown that they can be tracked by magnetic resonance imaging (MRI and are capable of conjugation with various cell types, including stem cells. In-depth research has been undertaken to establish these benefits, so that a deeper level of understanding of stem cell migratory pathways and differentiation, tumor migration, and improved drug delivery can be achieved. Stem cells have the ability to treat and cure many debilitating diseases with limited side effects, but a main problem that arises is in the noninvasive tracking and analysis of these stem cells. Recently, researchers have acknowledged the use of SPIONs for this purpose and have set out to establish suitable protocols for coating and attachment, so as to bring MRI tracking of SPION-labeled stem cells into common practice. This review paper explains the manner in which SPIONs are produced, conjugated, and tracked using MRI, as well as a discussion on their limitations. A concise summary of recently researched magnetic particle coatings is provided, and the effects of SPIONs on stem cells are evaluated, while animal and human studies investigating the role of SPIONs in stem cell tracking will be explored.Keywords: stem cells, nanoparticle, magnetic

  3. Registration of clinical volumes to beams-eye-view images for real-time tracking

    Energy Technology Data Exchange (ETDEWEB)

    Bryant, Jonathan H.; Rottmann, Joerg; Lewis, John H.; Mishra, Pankaj; Berbeco, Ross I., E-mail: rberbeco@lroc.harvard.edu [Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115 (United States); Keall, Paul J. [Radiation Physics Laboratory, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006 (Australia)

    2014-12-15

    Purpose: The authors combine the registration of 2D beam’s eye view (BEV) images and 3D planning computed tomography (CT) images, with relative, markerless tumor tracking to provide automatic absolute tracking of physician defined volumes such as the gross tumor volume (GTV). Methods: During treatment of lung SBRT cases, BEV images were continuously acquired with an electronic portal imaging device (EPID) operating in cine mode. For absolute registration of physician-defined volumes, an intensity based 2D/3D registration to the planning CT was performed using the end-of-exhale (EoE) phase of the four dimensional computed tomography (4DCT). The volume was converted from Hounsfield units into electron density by a calibration curve and digitally reconstructed radiographs (DRRs) were generated for each beam geometry. Using normalized cross correlation between the DRR and an EoE BEV image, the best in-plane rigid transformation was found. The transformation was applied to physician-defined contours in the planning CT, mapping them into the EPID image domain. A robust multiregion method of relative markerless lung tumor tracking quantified deviations from the EoE position. Results: The success of 2D/3D registration was demonstrated at the EoE breathing phase. By registering at this phase and then employing a separate technique for relative tracking, the authors are able to successfully track target volumes in the BEV images throughout the entire treatment delivery. Conclusions: Through the combination of EPID/4DCT registration and relative tracking, a necessary step toward the clinical implementation of BEV tracking has been completed. The knowledge of tumor volumes relative to the treatment field is important for future applications like real-time motion management, adaptive radiotherapy, and delivered dose calculations.

  4. Towards antibody-drug conjugates and prodrug strategies with extracellular stimuli-responsive drug delivery in the tumor microenvironment for cancer therapy.

    Science.gov (United States)

    Joubert, Nicolas; Denevault-Sabourin, Caroline; Bryden, Francesca; Viaud-Massuard, Marie-Claude

    2017-12-15

    The design of innovative anticancer chemotherapies with superior antitumor efficacy and reduced toxicity continues to be a challenging endeavor. Recently, the success of Adcetris ® and Kadcyla ® made antibody-drug conjugates (ADCs) serious contenders to reach the envied status of Paul Ehrlich's "magic bullet". However, ADCs classically target overexpressed and internalizing antigens at the surface of cancer cells, and in solid tumors are associated with poor tumor penetration, insufficient targeting in heterogeneous tumors, and appearance of several resistance mechanisms. In this context, alternative non-internalizing ADCs and prodrugs have been developed to circumvent these limitations, in which the drug can be selectively released by an extracellular stimulus in the tumor microenvironment. Each strategy and method of activation will be discussed as potential alternatives to internalizing ADCs for cancer therapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Long-term MRI cell tracking after intraventricular delivery in a patient with global cerebral ischemia and prospects for magnetic navigation of stem cells within the CSF.

    Directory of Open Access Journals (Sweden)

    Miroslaw Janowski

    Full Text Available The purpose of the study was to evaluate the long-term clinical tracking of magnetically labeled stem cells after intracerebroventricular transplantation as well as to investigate in vitro feasibility for magnetic guidance of cell therapy within large fluid compartments.After approval by our Institutional Review Board, an 18-month-old patient, diagnosed as being in a vegetative state due to global cerebral ischemia, underwent cell transplantation to the frontal horn of the lateral ventricle, with umbilical cord blood-derived stem cells labeled with superparamagnetic iron oxide (SPIO contrast agent. The patient was followed over 33 months with clinical examinations and MRI. To evaluate the forces governing the distribution of cells within the fluid compartment of the ventricular system in vivo, a gravity-driven sedimentation assay and a magnetic field-driven cell attraction assay were developed in vitro.Twenty-four hours post-transplantation, MR imaging (MRI was able to detect hypointense cells in the occipital horn of the lateral ventricle. The signal gradually decreased over 4 months and became undetectable at 33 months. In vitro, no significant difference in cell sedimentation between SPIO-labeled and unlabeled cells was observed (p = NS. An external magnet was effective in attracting cells over distances comparable to the size of human lateral ventricles.MR imaging of SPIO-labeled cells allows monitoring of cells within lateral ventricles. While the initial biodistribution is governed by gravity-driven sedimentation, an external magnetic field may possibly be applied to further direct the distribution of labeled cells within large fluid compartments such as the ventricular system.

  6. Vanishing tumor in pregnancy

    Directory of Open Access Journals (Sweden)

    M V Vimal

    2012-01-01

    Full Text Available A patient with microprolactinoma, who had two successful pregnancies, is described for management issues. First pregnancy was uneventful. During the second pregnancy, the tumor enlarged to macroprolactinoma with headache and blurring of vision which was managed successfully with bromocriptine. Post delivery, complete disappearance of the tumor was documented.

  7. Vanishing tumor in pregnancy

    Science.gov (United States)

    Vimal, M. V.; Budyal, Sweta; Kasliwal, Rajeev; Jagtap, Varsha S.; Lila, Anurag R.; Bandgar, Tushar; Menon, Padmavathy; Shah, Nalini S.

    2012-01-01

    A patient with microprolactinoma, who had two successful pregnancies, is described for management issues. First pregnancy was uneventful. During the second pregnancy, the tumor enlarged to macroprolactinoma with headache and blurring of vision which was managed successfully with bromocriptine. Post delivery, complete disappearance of the tumor was documented. PMID:23226664

  8. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and anti-tumor effects

    Science.gov (United States)

    Osada, Takuya; Berglund, Peter; Morse, Michael A.; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R.; Clay, Timothy M.; Smith, Jonathan; Lyerly, H. Kim

    2013-01-01

    We recently demonstrated that Venezuelan equine encephalitis (VEE) virus-based replicon particles (VRP) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP expressing Interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and anti-tumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)) and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12 and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing anti-tumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. PMID:22488274

  9. Needle track seeding after percutaneous microwave ablation of malignant liver tumors under ultrasound guidance: Analysis of 14-year experience with 1462 patients at a single center

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Jie, E-mail: yu-jie301@hotmail.com [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853 (China); Liang, Ping, E-mail: liangping301@hotmail.com [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853 (China); Yu, Xiao-ling, E-mail: dyuxl301@yahoo.com.cn [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853 (China); Cheng, Zhi-gang, E-mail: qlczg@hotmail.com [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853 (China); Han, Zhi-yu, E-mail: hanzhiyu301@hotmail.com [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853 (China); Dong, Bao-wei, E-mail: dongbw301@yahoo.com [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853 (China)

    2012-10-15

    Objective: To determine the incidence and risk factors associated with needle tract seeding after percutaneous microwave ablation (MWA) of liver cancer under ultrasound guidance. Materials and methods: Over a 14-year period, a total of 1462 patients with 2530 malignant nodules were treated by MWA. The influence of age, sex, Child-pugh classification, tumor size, tumor position, previous biopsy, insertion number and antenna type on the risk of neoplastic seeding was assessed. The survival of seeding patients after the MWA was analyzed. Results: Eleven patients with 12 nodules (0.47% per tumor, 0.75% per patient) were identified with needle tract seeding with an interval time of 6–37 (median 10) months after MWA. The mean size of the seeding nodule was 2.3 ± 0.7 cm (from 1.3 to 3.9 cm). Only previous biopsy was significantly associated with neoplastic seeding (P = 0.02). All the seeding lesions were successfully treated by resection, MWA, radiation or high intensity focus ultrasound. The median survival period of the 11 patients after the MWA was 36.0 months. The cumulative survival rates of the 11 patients after the MWA at 1-, 2-, 3-, 4- and 5-year were 90.9%, 72.7%, 62.3%, 31.2% and 15.6%, respectively. Conclusion: The results showed that the neoplastic seeding was a low risk complication of percutaneous MWA of liver cancer and was considered acceptable in general.

  10. pH-sensitive polymeric cisplatin-ion complex with styrene-maleic acid copolymer exhibits tumor-selective drug delivery and antitumor activity as a result of the enhanced permeability and retention effect.

    Science.gov (United States)

    Saisyo, Atsuyuki; Nakamura, Hideaki; Fang, Jun; Tsukigawa, Kenji; Greish, Khaled; Furukawa, Hiroyuki; Maeda, Hiroshi

    2016-02-01

    Cisplatin (CDDP) is widely used to treat various cancers. However, its distribution to normal tissues causes serious adverse effects. For this study, we synthesized a complex of styrene-maleic acid copolymer (SMA) and CDDP (SMA-CDDP), which formed polymeric micelles, to achieve tumor-selective drug delivery based on the enhanced permeability and retention (EPR) effect. SMA-CDDP is obtained by regulating the pH of the reaction solution of SMA and CDDP. The mean SMA-CDDP particle size was 102.5 nm in PBS according to electrophoretic light scattering, and the CDDP content was 20.1% (w/w). The release rate of free CDDP derivatives from the SMA-CDDP complex at physiological pH was quite slow (0.75%/day), whereas it was much faster at pH 5.5 (4.4%/day). SMA-CDDP thus had weaker in vitro toxicity at pH 7.4 but higher cytotoxicity at pH 5.5. In vivo pharmacokinetic studies showed a 5-fold higher tumor concentration of SMA-CDDP than of free CDDP. SMA-CDDP had more effective antitumor potential but lower toxicity than did free CDDP in mice after i.v. administration. Administration of parental free CDDP at 4 mg/kg×3 caused a weight loss of more than 5%; SMA-CDDP at 60 mg/kg (CDDP equivalent)×3 caused no significant weight change but markedly suppressed S-180 tumor growth. These findings together suggested using micelles of the SMA-CDDP complex as a cancer chemotherapeutic agent because of beneficial properties-tumor-selective accumulation and relatively rapid drug release at the acidic pH of the tumor-which resulted in superior antitumor effects and fewer side effects compared with free CDDP. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. SU-G-BRA-16: Target Dose Comparison for Dynamic MLC Tracking and Mid- Ventilation Planning in Lung Radiotherapy Subject to Intrafractional Baseline Drifts

    Energy Technology Data Exchange (ETDEWEB)

    Menten, MJ; Fast, MF; Nill, S; Oelfke, U [Joint Department of Physics at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London (United Kingdom)

    2016-06-15

    Purpose: Lung tumor motion during radiotherapy can be accounted for by expanded treatment margins, for example using a mid-ventilation planning approach, or by localizing the tumor in real-time and adapting the treatment beam with multileaf collimator (MLC) tracking. This study evaluates the effect of intrafractional changes in the average tumor position (baseline drifts) on these two treatment techniques. Methods: Lung stereotactic treatment plans (9-beam IMRT, 54Gy/3 fractions, mean treatment time: 9.63min) were generated for three patients: either for delivery with MLC tracking (isotropic GTV-to-PTV margin: 2.6mm) or planned with a mid-ventilation approach and delivered without online motion compensation (GTV-to-PTV margin: 4.4-6.3mm). Delivery to a breathing patient was simulated using DynaTrack, our in-house tracking and delivery software. Baseline drifts in cranial and posterior direction were simulated at a rate of 0.5, 1.0 or 1.5mm/min. For dose reconstruction, the corresponding 4DCT phase was selected for each time point of the delivery. Baseline drifts were accounted for by rigidly shifting the CT to ensure correct relative beam-to-target positioning. Afterwards, the doses delivered to each 4DCT phase were accumulated deformably on the mid-ventilation phase using research RayStation v4.6 and dose coverage of the GTV was evaluated. Results: When using the mid-ventilation planning approach, dose coverage of the tumor deteriorated substantially in the presence of baseline drifts. The reduction in D98% coverage of the GTV in a single fraction ranged from 0.4-1.2, 0.6-3.3 and 4.5-6.2Gy, respectively, for the different drift rates. With MLC tracking the GTV D98% coverage remained unchanged (+/− 0.1Gy) regardless of drift. Conclusion: Intrafractional baseline drifts reduce the tumor dose in treatments based on mid-ventilation planning. In rare, large target baseline drifts tumor dose coverage may drop below the prescription, potentially affecting clinical

  12. Ternary complexes of folate-PEG-appended dendrimer (G4)/α-cyclodextrin conjugate, siRNA and low-molecular-weight polysaccharide sacran as a novel tumor-selective siRNA delivery system.

    Science.gov (United States)

    Ohyama, Ayumu; Higashi, Taishi; Motoyama, Keiichi; Arima, Hidetoshi

    2017-06-01

    We previously developed a tumor-selective siRNA carrier by preparing polyamidoamine dendrimer (generation 4, G4) conjugates with α-cyclodextrin and folate-polyethylene glycol (Fol-PαC (G4)). In the present study, we developed ternary complexes of Fol-PαC (G4)/siRNA with low-molecular-weight-sacrans to achieve more effective siRNA transfer activity. Among the different molecular-weight sacrans, i.e. sacran 100, 1000 and 10,000 (MW 44,889Da, 943,692Da and 1,488,281Da, respectively), sacran 100 significantly increased the cellular uptake and the RNAi effects of Fol-PαC (G4)/siRNA binary complex with negligible cytotoxicity in KB cells (folate receptor-α positive cells). In addition, the ζ-potential and particle size of Fol-PαC (G4)/siRNA complex were decreased by the ternary complexation with sacran 100. Importantly, the in vivo RNAi effect of the ternary complex after the intravenous administration to tumor-bearing BALB/c mice was significantly higher than that of the binary complex. In conclusion, Fol-PαC (G4)/siRNA/sacran 100 ternary complex has a potential as a novel tumor-selective siRNA delivery system. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Simultaneous quantification of tumor uptake for targeted and non-targeted liposomes and their encapsulated contents by ICP-MS

    Science.gov (United States)

    Cheng, Zhiliang; Zaki, Ajlan Al; Hui, James Z; Tsourkas, Andrew

    2012-01-01

    Liposomes are intensively being developed for biomedical applications including drug and gene delivery. However, targeted liposomal delivery in cancer treatment is a very complicated multi-step process. Unfavorable liposome biodistribution upon intravenous administration and membrane destabilization in blood circulation could result in only a very small fraction of cargo reaching the tumors. It would therefore be desirable to develop new quantitative strategies to track liposomal delivery systems to improve the therapeutic index and decrease systemic toxicity. Here, we developed a simple and non-radiative method to quantify the tumor uptake of targeted and non-targeted control liposomes as well as their encapsulated contents simultaneously. Specifically, four different chelated lanthanide metals were encapsulated or surface-conjugated onto tumor-targeted and non-targeted liposomes, respectively. The two liposome formulations were then injected into tumor-bearing mice simultaneously and their tumor delivery was determined quantitatively via inductively coupled plasma-mass spectroscopy (ICP-MS), allowing for direct comparisons. Tumor uptake of the liposomes themselves and their encapsulated contents were consistent with targeted and non-targeted liposome formulations that were injected individually. PMID:22882145

  14. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

    Science.gov (United States)

    Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

    2016-01-01

    Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

  15. Two step mechanisms of tumor selective delivery of N-(2-hydroxypropyl)methacrylamide copolymer conjugated with pirarubicin via an acid-cleavable linkage

    Czech Academy of Sciences Publication Activity Database

    Nakamura, H.; Etrych, Tomáš; Chytil, Petr; Ohkubo, M.; Fang, J.; Ulbrich, Karel; Maeda, H.

    2014-01-01

    Roč. 174, 28 January (2014), s. 81-87 ISSN 0168-3659 Grant - others:AV ČR(CZ) AP0802 Program:Akademická prémie - Praemium Academiae Institutional support: RVO:61389013 Keywords : HPMA polymer conjugate * pirarubicin (THP) * tumor selectivity Subject RIV: CD - Macromolecular Chemistry Impact factor: 7.705, year: 2014

  16. Delivery presentations

    Science.gov (United States)

    Pregnancy - delivery presentation; Labor - delivery presentation; Occiput posterior; Occiput anterior; Brow presentation ... The mother can walk, rock, and try different delivery positions during labor to help encourage the baby ...

  17. Tracked vehicles in hazardous environments

    International Nuclear Information System (INIS)

    Jones, S.; Walton, P.J.

    1993-01-01

    A programme of remote inspections has been conducted on the Magnox steel reactor pressure vessel at Trawsfynydd Power Station using climbing vehicles. Tracked remotely operated vehicles supported the inspection programme by assisting with the delivery and recovery of the climbing vehicles and facilitating the use of various accessory packages. This paper presents details of the support project, the tracked vehicles and of the uses made of them during the inspection programme. (author)

  18. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model

    Directory of Open Access Journals (Sweden)

    Choi G

    2016-01-01

    Full Text Available Goeun Choi,1 Huiyan Piao,1 Zeid A Alothman,2 Ajayan Vinu,3 Chae-Ok Yun,4 Jin-Ho Choy1 1Center for Intelligent Nano-Bio Materials, Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Korea; 2Advanced Materials Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia; 3Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia; 4Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea Abstract: Methotrexate (MTX, an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco’s Modified Eagle’s Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection. Keywords: anionic clay, biodistribution, cervical cancer, colloidal stability, layered double hydroxide, methotrexate 

  19. pH-Responsive Tumor-Targetable Theranostic Nanovectors Based on Core Crosslinked (CCL Micelles with Fluorescence and Magnetic Resonance (MR Dual Imaging Modalities and Drug Delivery Performance

    Directory of Open Access Journals (Sweden)

    Sidan Tian

    2016-06-01

    Full Text Available The development of novel theranostic nanovectors is of particular interest in treating formidable diseases (e.g., cancers. Herein, we report a new tumor-targetable theranostic agent based on core crosslinked (CCL micelles, possessing tumor targetable moieties and fluorescence and magnetic resonance (MR dual imaging modalities. An azide-terminated diblock copolymer, N3-POEGMA-b-P(DPA-co-GMA, was synthesized via consecutive atom transfer radical polymerization (ATRP, where OEGMA, DPA, and GMA are oligo(ethylene glycolmethyl ether methacrylate, 2-(diisopropylaminoethyl methacrylate, and glycidyl methacrylate, respectively. The resulting diblock copolymer was further functionalized with DOTA(Gd (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid or benzaldehyde moieties via copper(I-catalyzed alkyne-azide cycloaddition (CuAAC chemistry, resulting in the formation of DOTA(Gd-POEGMA-b-P(DPA-co-GMA and benzaldehyde-POEGMA-b-P(DPA-co-GMA copolymers. The resultant block copolymers co-assembled into mixed micelles at neutral pH in the presence of tetrakis[4-(2-mercaptoethoxyphenyl]ethylene (TPE-4SH, which underwent spontaneous crosslinking reactions with GMA residues embedded within the micellar cores, simultaneously switching on TPE fluorescence due to the restriction of intramolecular rotation. Moreover, camptothecin (CPT was encapsulated into the crosslinked cores at neutral pH, and tumor-targeting pH low insertion peptide (pHLIP, sequence: AEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTCG moieties were attached to the coronas through the Schiff base chemistry, yielding a theranostic nanovector with fluorescence and MR dual imaging modalities and tumor-targeting capability. The nanovectors can be efficiently taken up by A549 cells, as monitored by TPE fluorescence. After internalization, intracellular acidic pH triggered the release of loaded CPT, killing cancer cells in a selective manner. On the other hand, the nanovectors labeled with DOTA

  20. Real-time dynamic MR image reconstruction using compressed sensing and principal component analysis (CS-PCA): Demonstration in lung tumor tracking.

    Science.gov (United States)

    Dietz, Bryson; Yip, Eugene; Yun, Jihyun; Fallone, B Gino; Wachowicz, Keith

    2017-08-01

    This work presents a real-time dynamic image reconstruction technique, which combines compressed sensing and principal component analysis (CS-PCA), to achieve real-time adaptive radiotherapy with the use of a linac-magnetic resonance imaging system. Six retrospective fully sampled dynamic data sets of patients diagnosed with non-small-cell lung cancer were used to investigate the CS-PCA algorithm. Using a database of fully sampled k-space, principal components (PC's) were calculated to aid in the reconstruction of undersampled images. Missing k-space data were calculated by projecting the current undersampled k-space data onto the PC's to generate the corresponding PC weights. The weighted PC's were summed together, and the missing k-space was iteratively updated. To gain insight into how the reconstruction might proceed at lower fields, 6× noise was added to the 3T data to investigate how the algorithm handles noisy data. Acceleration factors ranging from 2 to 10× were investigated using CS-PCA and Split Bregman CS for comparison. Metrics to determine the reconstruction quality included the normalized mean square error (NMSE), as well as the dice coefficients (DC) and centroid displacement of the tumor segmentations. Our results demonstrate that CS-PCA performed superior than CS alone. The CS-PCA patient averaged DC for 3T and 6× noise added data remained above 0.9 for acceleration factors up to 10×. The patient averaged NMSE gradually increased with increasing acceleration; however, it remained below 0.06 up to an acceleration factor of 10× for both 3T and 6× noise added data. The CS-PCA reconstruction speed ranged from 5 to 20 ms (Intel i7-4710HQ CPU @ 2.5 GHz), depending on the chosen parameters. A real-time reconstruction technique was developed for adaptive radiotherapy using a Linac-MRI system. Our CS-PCA algorithm can achieve tumor contours with DC greater than 0.9 and NMSE less than 0.06 at acceleration factors of up to, and including, 10×. The

  1. Probabilistic fiber tracking of the language and motor white matter pathways of the supplementary motor area (SMA) in patients with brain tumors.

    Science.gov (United States)

    Jenabi, Mehrnaz; Peck, Kyung K; Young, Robert J; Brennan, Nicole; Holodny, Andrei I

    2014-12-01

    Accurate localization of anatomically and functionally separate SMA tracts is important to improve planning prior to neurosurgery. Using fMRI and probabilistic DTI techniques, we assessed the connectivity between the frontal language area (Broca's area) and the rostral pre-SMA (language SMA) and caudal SMA proper (motor SMA). Twenty brain tumor patients completed motor and language fMRI paradigms and DTI. Peaks of functional activity in the language SMA, motor SMA and Broca's area were used to define seed regions for probabilistic tractography. fMRI and probabilistic tractography identified separate and unique pathways connecting the SMA to Broca's area - the language SMA pathway and the motor SMA pathway. For all subjects, the language SMA pathway had a larger number of voxels (PProbabilistic tractography can identify unique white matter tracts that connect language SMA and motor SMA to Broca's area. The language SMA is more significantly connected to Broca's area than is the motor subdivision of the SMA proper. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  2. Elimination of ghost markers during dual sensor-based infrared tracking of multiple individual reflective markers

    International Nuclear Information System (INIS)

    Stroian, G.; Falco, T.; Seuntjens, J.P.

    2004-01-01

    The accuracy of dose