WorldWideScience

Sample records for convection enhanced delivery

  1. Imaging of Convection Enhanced Delivery of Toxins in Humans

    Directory of Open Access Journals (Sweden)

    Allan H. Friedman

    2011-03-01

    Full Text Available Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of infiltrated brain and tumors. The efficacy of CED is determined through the distribution of the therapeutic agent to the targeted region. The vast majority of patients fail to receive a significant amount of coverage of the area at risk for tumor recurrence. Understanding this challenge, it is surprising that so little work has been done to monitor the delivery of therapeutic agents using this novel approach. Here we present a review of imaging in convection enhanced delivery monitoring of toxins in humans, and discuss future challenges in the field.

  2. Convection-enhanced delivery of liposomes to primate brain.

    Science.gov (United States)

    Krauze, Michal T; Forsayeth, John; Yin, Dali; Bankiewicz, Krystof S

    2009-01-01

    Direct delivery of therapeutic agents to the human central nervous system remains an inadequately studied field. Our group has extensively studied and refined a powerful method for distributing various macromolecules and nanoparticles into the parenchyma by means of a procedure called convection-enhanced delivery (CED). First, we developed an improved design of infusion cannula that greatly decreased the likelihood of reflux of infusate up the outside of the cannula. Second, we began to use liposomes loaded with the MRI contrast reagent, Gadoteridol (Gd), to track infusions into brain parenchyma in real time. This innovation generated a wealth of quantitative and qualitative data that in turn drove further improvements in CED. In this chapter, we review many of the recently devised methods needed to ensure controlled distribution of therapeutic agents in the brain.

  3. Convection-enhanced Delivery of Therapeutics for Malignant Gliomas

    Science.gov (United States)

    SAITO, Ryuta; TOMINAGA, Teiji

    2017-01-01

    Convection-enhanced delivery (CED) circumvents the blood–brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future. PMID:27980285

  4. Anatomical differences determine distribution of adenovirus after convection-enhanced delivery to the rat brain

    NARCIS (Netherlands)

    S. Idema (Sander); V. Caretti (Viola); M.L.M. Lamfers (Martine); V.W. Beusechem (Victor); D.P. Noske (David); W.P. Vandertop (Peter); C.M.F. Dirven (Clemens)

    2011-01-01

    textabstractBackground: Convection-enhanced delivery (CED) of adenoviruses offers the potential of widespread virus distribution in the brain. In CED, the volume of distribution (Vd) should be related to the volume of infusion (Vi) and not to dose, but when using adenoviruses contrasting results hav

  5. Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen.

    Science.gov (United States)

    Krauze, Michal T; Saito, Ryuta; Noble, Charles; Bringas, John; Forsayeth, John; McKnight, Tracy R; Park, John; Bankiewicz, Krystof S

    2005-11-01

    Convection-enhanced delivery has recently entered the clinic and represents a promising new therapeutic option in the field of neurodegenerative diseases and treatment of brain tumors. Understanding of the principles governing delivery and flow of macromolecules within the CNS is still poorly understood and requires more investigation of the microanatomy and fluid dynamics of the brain. Our previously established, reflux-free convection-enhanced delivery (CED) technique and real-time imaging MR method for monitoring CED delivery of liposomes in primate CNS allowed us to closely monitor infusions of putamen. Our findings indicate that CED in putamen is associated with perivascular transport of liposomes, throughout CNS arteries. The results may explain side effects seen in current clinical trials using CED. In addition, they clearly show the necessity for a monitoring technique for future direct delivery of therapeutic agents to the human central nervous system. Based on these findings, we believe that the physiological concept that the perivascular space serves as a conduit for distribution of endogenous molecules within the CNS also applies to interstitially infused agents.

  6. SIMULATING CONVECTION-ENHANCED DELIVERY IN THE PUTAMEN USING PROBABILISTIC TRACTOGRAPHY

    Science.gov (United States)

    Tromp, Do P.M.; Adluru, Nagesh; Alexander, Andrew L.; Emborg, Marina E.

    2016-01-01

    The treatment of brain diseases is complicated by the presence of the blood-brain barrier. This barrier limits the crossing of therapeutic molecules from the blood vessels into the brain. Today, direct intracerebral infusion applying convection-enhanced delivery (CED) is proposed to circumvent this problem and enhance the area of distribution of infusate beyond the parameters of diffusion. Several factors affect the efficacy, predictability and replicability of CED, such as the catheter model, infusion rate and site of infusion. We set out to investigate if probabilistic tractography can be used to model the infusion flow and predict the intracerebral movement of molecules. In this study we describe a modeling and analysis framework based upon probabilistic tractography. This framework was used to compare probabilistic tractography modeling and actual CED infusion measurements in the putamen of non-human primates, as this gray matter structure is proposed as a target for CED treatment of Parkinson’s disease.

  7. Convection enhanced delivery of different molecular weight tracers of gadolinium-tagged polylysine.

    Science.gov (United States)

    Hardy, Peter A; Keeley, Dan; Schorn, Greg; Forman, Eric; Ai, Yi; Venugopalan, Ramakrishna; Zhang, Zhiming; Bradley, Luke H

    2013-09-30

    Convection enhanced delivery (CED) is a powerful method of circumventing the blood-brain barrier (BBB) to deliver therapeutic compounds directly to the CNS. While inferring the CED distribution of a therapeutic compound by imaging a magnetic resonance (MR)-sensitive tracer has many advantages, however how the compound distribution is affected by the features of the delivery system, its target tissue, and its molecular properties, such as its binding characteristics, charge, and molecular weight (MW) are not fully understood. We used MR imaging of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-tagged polylysine compounds of various MW, in vitro and in vivo, to measure the dependence of compounds MW on CED distribution. For the in vitro studies, the correlation between volume of distribution (Vd) as a function of MW was determined by measuring the T1 of the infused tracers, into 0.6% agarose gels through a multiport catheter. The compounds distributed in the gels inversely proportional to their MW, consistent with convection and unobstructed diffusion through a porous media. For the in vivo studies, Gd-DTPA tagged compounds were infused into the non-human primate putamen, via an implanted multiport catheter connected to a MedStream™ pump, programmed to deliver a predetermined volume with alternating on-off periods to take advantage of the convective and diffusive contributions to Vd. Unlike the gel studies, the higher MW polylysine-tracer infusions did not freely distribute from the multiport catheter in the putamen, suggesting that distribution was impeded by other properties that should also be considered in future tracer design and CED infusion protocols.

  8. Convection enhanced delivery and in vivo imaging of polymeric nanoparticles for the treatment of malignant glioma

    Science.gov (United States)

    Mansour, Nassir; Pytel, Peter; Cahill, Kirk E; Voce, David J; Kang, Shijun; Spretz, Ruben; Welp, Ulrich; Noriega, Sandra E; Nunez, Luis; Larsen, Gustavo F; Weichselbaum, Ralph R.; Yamini, Bakhtiar

    2013-01-01

    A major obstacle to the management of malignant glioma is the inability to effectively deliver therapeutic agent to the tumor. In this study, we describe a polymeric nanoparticle vector that not only delivers viable therapeutic, but can also be tracked in vivo using MRI. Nanoparticles, produced by a non-emulsion technique, were fabricated to carry iron oxide within the shell and the chemotherapeutic agent, temozolomide (TMZ), as the payload. Nanoparticle properties were characterized and subsequently their endocytosis-mediated uptake by glioma cells demonstrated. Convection enhanced delivery (CED) can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. Infusion of nanoparticles does not result in observable animal toxicity relative to control. CED of TMZ bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control. In conclusion, the described nanoparticle vector represents a unique multifunctional platform that can be used for image-guided treatment of malignant glioma. PMID:23891990

  9. Convection-Enhanced Delivery (CED) in an Animal Model of Malignant Peripheral Nerve Sheath (MPNST) Tumors and Plexiform Neurofibromas (PN)

    Science.gov (United States)

    2012-09-01

    convection enhanced delivery in malignant peripheral nerve sheath tumors or plexiform neurofibromas at this time. References Perrin GQ, Fishbein L...2007. 85(6): p. 1347-1357. Perrin GQ, Li H, Fishbein L, et al., An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential

  10. Backflow-free catheters for efficient and safe convection-enhanced delivery of therapeutics.

    Science.gov (United States)

    Lueshen, Eric; Tangen, Kevin; Mehta, Ankit I; Linninger, Andreas

    2017-07-01

    Convection-enhanced delivery (CED) is an invasive drug delivery technique used to target specific regions of the brain for the treatment of cancer and neurodegenerative diseases while bypassing the blood-brain barrier. In order to prevent the possibility of backflow, low volumetric flow rates are applied which limit the achievable drug distribution volumes from CED. This can render CED treatment ineffective since a small convective flow produces narrow drug distribution inside the treatment region. Novel catheter designs and CED protocols are needed to improve the drug distribution inside the treatment region. This is especially important when administering toxic chemotherapeutics which could adversely affect other organs if backflow occurred and these drugs entered the circulating blood stream. In order to help elucidate the causes of backflow and to design backflow-free catheters, we have studied the impact that microfluid flow has on deformable brain phantom gels experimentally as well as numerically. We found that fluid injections into porous media have considerable effects on local transport properties such as porosity and hydraulic conductivity. These phenomena not only alter the bulk flow velocity distribution of the microfluid flow due to the changing porosity, but significantly modify flow direction and even volumetric flow distribution due to induced local hydraulic conductivity anisotropy. These studies led us to the development of novel backflow-free catheters with safe volumetric flow rates up to 10 µL/min. The catheter designs, numerical simulations and experimental results are described throughout this article. Copyright © 2017 IPEM. Published by Elsevier Ltd. All rights reserved.

  11. Convection enhanced delivery of carboranylporphyrins for neutron capture therapy of brain tumors.

    Science.gov (United States)

    Kawabata, Shinji; Yang, Weilian; Barth, Rolf F; Wu, Gong; Huo, Tianyao; Binns, Peter J; Riley, Kent J; Ongayi, Owendi; Gottumukkala, Vijay; Vicente, M Graça H

    2011-06-01

    Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive 10B is irradiated with low energy thermal neutrons to produce α-particles (10B[n,α] Li). Carboranylporphyrins are a class of substituted porphyrins containing multiple carborane clusters. Three of these compounds, designated H2TBP, H2TCP, and H2DCP, have been evaluated in the present study. The goals were two-fold. First, to determine their biodistribution following intracerebral (i.c.) administration by short term (30 min) convection enhanced delivery (CED) or sustained delivery over 24 h by Alzet™ osmotic pumps to F98 glioma bearing rats. Second, to determine the efficacy of H2TCP and H2TBP as boron delivery agents for BNCT in F98 glioma bearing rats. Tumor boron concentrations immediately after i.c. pump delivery were high and they remained so at 24 h. The corresponding normal brain concentrations were low and the blood and liver concentrations were undetectable. Based on these data, therapy studies were initiated at the Massachusetts Institute of Technology (MIT) Research Reactor (MITR) with H2TCP and H2TBP 24 h after CED or pump delivery. Mean survival times (MST) ± standard deviations of animals that had received H2TCP or H2TBP, followed by BNCT, were of 35 ± 4 and 44 ± 10 days, compared to 23 ± 3 and 27 ± 3 days, respectively, for untreated and irradiated controls. However, since the tumor boron concentrations of the carboranylporphyrins were 3-5× higher than intravenous (i.v.) boronophenylalanine (BPA), we had expected that the MSTs would have been greater. Histopathologic examination of brains of BNCT treated rats revealed that there were large numbers of porphyrin-laden macrophages, as well as extracellular accumulations of porphyrins, indicating that the seemingly high tumor boron concentrations did not represent the true tumor cellular uptake. Nevertheless, our data are the first to show that carboranyl porphyrins can be

  12. Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump.

    Science.gov (United States)

    Sonabend, Adam M; Stuart, R Morgan; Yun, Jonathan; Yanagihara, Ted; Mohajed, Hamed; Dashnaw, Steven; Bruce, Samuel S; Brown, Truman; Romanov, Alex; Sebastian, Manu; Arias-Mendoza, Fernando; Bagiella, Emilia; Canoll, Peter; Bruce, Jeffrey N

    2011-08-01

    Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 μM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.

  13. Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents

    Science.gov (United States)

    Krauze, Michal T.; Saito, Ryuta; Noble, Charles; Tamas, Matyas; Bringas, John; Park, John W.; Berger, Mitchel S.; Bankiewicz, Krystof

    2013-01-01

    Object Clinical application of the convection-enhanced delivery (CED) technique is currently limited by low infusion speed and reflux of the delivered agent. The authors developed and evaluated a new step-design cannula to overcome present limitations and to introduce a rapid, reflux-free CED method for future clinical trials. Methods The CED of 0.4% trypan blue dye was performed in agarose gel to test cannula needles for distribution and reflux. Infusion rates ranging from 0.5 to 50 μl/minute were used. Agarose gel findings were translated into a study in rats and then in cynomolgus monkeys (Macaca fascicularis) by using trypan blue and liposomes to confirm the efficacy of the reflux-free step-design cannula in vivo. Results of agarose gel studies showed reflux-free infusion with high flow rates using the step-design cannula. Data from the study in rats confirmed the agarose gel findings and also revealed increasing tissue damage at a flow rate above 5-μl/minute. Robust reflux-free delivery and distribution of liposomes was achieved using the step-design cannula in brains in both rats and nonhuman primates. Conclusions The authors developed a new step-design cannula for CED that effectively prevents reflux in vivo and maximizes the distribution of agents delivered in the brain. Data in the present study show reflux-free infusion with a constant volume of distribution in the rat brain over a broad range of flow rates. Reflux-free delivery of liposomes into nonhuman primate brain was also established using the cannula. This step-design cannula may allow reflux-free distribution and shorten the duration of infusion in future clinical applications of CED in humans. PMID:16304999

  14. Characterizing Thermal Augmentation of Convection-Enhanced Drug Delivery with the Fiberoptic Microneedle Device

    Directory of Open Access Journals (Sweden)

    R. Lyle Hood

    2015-09-01

    Full Text Available Convection-enhanced delivery (CED is a promising technique leveraging pressure-driven flow to increase penetration of infused drugs into interstitial spaces. We have developed a fiberoptic microneedle device for inducing local sub-lethal hyperthermia to further improve CED drug distribution volumes, and this study seeks to quantitatively characterize this approach in agarose tissue phantoms. Infusions of dye were conducted in 0.6% (w/w agarose tissue phantoms with isothermal conditions at 15 °C, 20 °C, 25 °C, and 30 °C. Infusion metrics were quantified using a custom shadowgraphy setup and image-processing algorithm. These data were used to build an empirical predictive temporal model of distribution volume as a function of phantom temperature. A second set of proof-of-concept experiments was conducted to evaluate a novel fiberoptic device capable of generating local photothermal heating during fluid infusion. The isothermal infusions showed a positive correlation between temperature and distribution volume, with the volume at 30 °C showing a 7-fold increase at 100 min over the 15 °C isothermal case. Infusions during photothermal heating (1064 nm at 500 mW showed a similar effect with a 3.5-fold increase at 4 h over the control (0 mW. These results and analyses serve to provide insight into and characterization of heat-mediated enhancement of volumetric dispersal.

  15. Image-guided convection-enhanced delivery of GDNF protein into monkey putamen.

    Science.gov (United States)

    Gimenez, Francisco; Krauze, Michal T; Valles, Francisco; Hadaczek, Piotr; Bringas, John; Sharma, Nitasha; Forsayeth, John; Bankiewicz, Krystof S

    2011-01-01

    Recently, we developed an MRI-based method that enables tracking of parenchymal infusions of therapeutic agents by inclusion of a contrast reagent in the infusate. We show that both liposomal Gadoteridol (GDL) and free Gadoteridol (Gd) can be used for MRI-monitored infusions into the non-human primate (NHP) putamen to predict the distribution of GDNF protein after convection-enhanced delivery (CED). GDNF and both MRI tracers showed good co-distribution within the putamen and other brain regions. Although the CED infusion technique can distribute GDNF protein over large brain regions, continuous administration of GDNF could cause undesired effects that could counteract the benefits of CED as demonstrated in this study when large volumes of GDNF were delivered that lead to GDNF leakage into CSF. These limitations can be addressed by employing an intermittent CED schedule that permits consistent target coverage without GDNF leakage into CSF or white matter. We present an approach intracranial GDNF infusions that can be optimized by means of real-time monitoring via MRI. Adoption of this new standard, along with advanced, reflux-resistant cannulae, may permit reconsideration of direct GDNF infusion into parenchyma as a clinical strategy, since previous clinical studies involving chronic infusion of recombinant glial cell line-derived neurotrophic factor (GDNF) to the putamen for the treatment of Parkinson's disease have yielded mixed results, a state of affairs that may in part be attributed to suboptimal infusion parameters.

  16. Canine spontaneous glioma: a translational model system for convection-enhanced delivery.

    Science.gov (United States)

    Dickinson, Peter J; LeCouteur, Richard A; Higgins, Robert J; Bringas, John R; Larson, Richard F; Yamashita, Yoji; Krauze, Michal T; Forsayeth, John; Noble, Charles O; Drummond, Daryl C; Kirpotin, Dmitri B; Park, John W; Berger, Mitchel S; Bankiewicz, Krystof S

    2010-09-01

    Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.

  17. Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals.

    Science.gov (United States)

    Wang, Weijun; Sivakumar, Walavan; Torres, Shering; Jhaveri, Niyati; Vaikari, Vijaya Pooja; Gong, Alex; Howard, Adam; Golden, Encouse B; Louie, Stan G; Schönthal, Axel H; Hofman, Florence M; Chen, Thomas C

    2015-03-01

    OBJECT Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution. METHODS Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels. RESULTS The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD

  18. 78 FR 77471 - Prospective Grant of Exclusive License for: Convection Enhanced Delivery of a Therapeutic Agent...

    Science.gov (United States)

    2013-12-23

    ... macromolecular MRI contrast agents such as chelated Gd(III). These macromolecular imaging agents have clearance... Enhanced Delivery of a Therapeutic Agent With a Surrogate Tracer for Treating Cancer and Urological... Agents'', U.S. Provisional Patent Application 60/413,673 (filed September 24, 2002;...

  19. Influence of neuropathology on convection-enhanced delivery in the rat hippocampus.

    Directory of Open Access Journals (Sweden)

    Svetlana Kantorovich

    Full Text Available Local drug delivery techniques, such as convention-enhanced delivery (CED, are promising novel strategies for delivering therapeutic agents otherwise limited by systemic toxicity and blood-brain-barrier restrictions. CED uses positive pressure to deliver infusate homogeneously into interstitial space, but its distribution is dependent upon appropriate tissue targeting and underlying neuroarchitecture. To investigate effects of local tissue pathology and associated edema on infusate distribution, CED was applied to the hippocampi of rats that underwent electrically-induced, self-sustaining status epilepticus (SE, a prolonged seizure. Infusion occurred 24 hours post-SE, using a macromolecular tracer, the magnetic resonance (MR contrast agent gadolinium chelated with diethylene triamine penta-acetic acid and covalently attached to albumin (Gd-albumin. High-resolution T1- and T2-relaxation-weighted MR images were acquired at 11.1 Tesla in vivo prior to infusion to generate baseline contrast enhancement images and visualize morphological changes, respectively. T1-weighted imaging was repeated post-infusion to visualize final contrast-agent distribution profiles. Histological analysis was performed following imaging to characterize injury. Infusions of Gd-albumin into injured hippocampi resulted in larger distribution volumes that correlated with increased injury severity, as measured by hyperintense regions seen in T2-weighted images and corresponding histological assessments of neuronal degeneration, myelin degradation, astrocytosis, and microglial activation. Edematous regions included the CA3 hippocampal subfield, ventral subiculum, piriform and entorhinal cortex, amygdalar nuclei, middle and laterodorsal/lateroposterior thalamic nuclei. This study demonstrates MR-visualized injury processes are reflective of cellular alterations that influence local distribution volume, and provides a quantitative basis for the planning of local therapeutic

  20. Influence of neuropathology on convection-enhanced delivery in the rat hippocampus.

    Science.gov (United States)

    Kantorovich, Svetlana; Astary, Garrett W; King, Michael A; Mareci, Thomas H; Sarntinoranont, Malisa; Carney, Paul R

    2013-01-01

    Local drug delivery techniques, such as convention-enhanced delivery (CED), are promising novel strategies for delivering therapeutic agents otherwise limited by systemic toxicity and blood-brain-barrier restrictions. CED uses positive pressure to deliver infusate homogeneously into interstitial space, but its distribution is dependent upon appropriate tissue targeting and underlying neuroarchitecture. To investigate effects of local tissue pathology and associated edema on infusate distribution, CED was applied to the hippocampi of rats that underwent electrically-induced, self-sustaining status epilepticus (SE), a prolonged seizure. Infusion occurred 24 hours post-SE, using a macromolecular tracer, the magnetic resonance (MR) contrast agent gadolinium chelated with diethylene triamine penta-acetic acid and covalently attached to albumin (Gd-albumin). High-resolution T1- and T2-relaxation-weighted MR images were acquired at 11.1 Tesla in vivo prior to infusion to generate baseline contrast enhancement images and visualize morphological changes, respectively. T1-weighted imaging was repeated post-infusion to visualize final contrast-agent distribution profiles. Histological analysis was performed following imaging to characterize injury. Infusions of Gd-albumin into injured hippocampi resulted in larger distribution volumes that correlated with increased injury severity, as measured by hyperintense regions seen in T2-weighted images and corresponding histological assessments of neuronal degeneration, myelin degradation, astrocytosis, and microglial activation. Edematous regions included the CA3 hippocampal subfield, ventral subiculum, piriform and entorhinal cortex, amygdalar nuclei, middle and laterodorsal/lateroposterior thalamic nuclei. This study demonstrates MR-visualized injury processes are reflective of cellular alterations that influence local distribution volume, and provides a quantitative basis for the planning of local therapeutic delivery strategies

  1. Safety of real-time convection-enhanced delivery of liposomes to primate brain: a long-term retrospective.

    Science.gov (United States)

    Krauze, Michal T; Vandenberg, Scott R; Yamashita, Yoji; Saito, Ryuta; Forsayeth, John; Noble, Charles; Park, John; Bankiewicz, Krystof S

    2008-04-01

    Convection-enhanced delivery (CED) is gaining popularity in direct brain infusions. Our group has pioneered the use of liposomes loaded with the MRI contrast reagent as a means to track and quantitate CED in the primate brain through real-time MRI. When co-infused with therapeutic nanoparticles, these tracking liposomes provide us with unprecedented precision in the management of infusions into discrete brain regions. In order to translate real-time CED into clinical application, several important parameters must be defined. In this study, we have analyzed all our cumulative animal data to answer a number of questions as to whether real-time CED in primates depends on concentration of infusate, is reproducible, allows prediction of distribution in a given anatomic structure, and whether it has long term pathological consequences. Our retrospective analysis indicates that real-time CED is highly predictable; repeated procedures yielded identical results, and no long-term brain pathologies were found. We conclude that introduction of our technique to clinical application would enhance accuracy and patient safety when compared to current non-monitored delivery trials.

  2. Convection-enhanced delivery of MANF--volume of distribution analysis in porcine putamen and substantia nigra.

    Science.gov (United States)

    Barua, N U; Bienemann, A S; Woolley, M; Wyatt, M J; Johnson, D; Lewis, O; Irving, C; Pritchard, G; Gill, S

    2015-10-15

    Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20kDa human protein which has both neuroprotective and neurorestorative activity on dopaminergic neurons and therefore may have application for the treatment of Parkinson's Disease. The aims of this study were to determine the translational potential of convection-enhanced delivery (CED) of MANF for the treatment of PD by studying its distribution in porcine putamen and substantia nigra and to correlate histological distribution with co-infused gadolinium-DTPA using real-time magnetic resonance imaging. We describe the distribution of MANF in porcine putamen and substantia nigra using an implantable CED catheter system using co-infused gadolinium-DTPA to allow real-time MRI tracking of infusate distribution. The distribution of gadolinium-DTPA on MRI correlated well with immunohistochemical analysis of MANF distribution. Volumetric analysis of MANF IHC staining indicated a volume of infusion (Vi) to volume of distribution (Vd) ratio of 3 in putamen and 2 in substantia nigra. This study confirms the translational potential of CED of MANF as a novel treatment strategy in PD and also supports the co-infusion of gadolinium as a proxy measure of MANF distribution in future clinical studies. Further study is required to determine the optimum infusion regime, flow rate and frequency of infusions in human trials.

  3. Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts.

    Science.gov (United States)

    Krauze, Michal T; Noble, Charles O; Kawaguchi, Tomohiro; Drummond, Daryl; Kirpotin, Dmitri B; Yamashita, Yoji; Kullberg, Erika; Forsayeth, John; Park, John W; Bankiewicz, Krystof S

    2007-10-01

    We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts. In this study, we have evaluated the combination of a newly developed nanoparticle/liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin. Both drugs were detectable in the CNS for more than 36 days after a single CED application. Tissue half-life was 16.7 days for nLs-CPT-11 and 10.9 days for Doxil. The combination of the two agents produced synergistic cytotoxicity in vitro. In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly. Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed. These findings have implications for further clinical applications of CED-based treatment of brain tumors.

  4. Convection-enhancement delivery of platinum-based drugs and Lipoplatin™ to optimize the concomitant effect with radiotherapy in F98 glioma rat model

    OpenAIRE

    SHI, MINGHAN; Fortin, David; Sanche, Léon; Paquette, Benoit

    2015-01-01

    The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin™-liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by facto...

  5. Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats.

    Directory of Open Access Journals (Sweden)

    Tianyao Huo

    Full Text Available The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (NSCLC. The second, produced in our laboratory, was based on the ability of cisplatin to form coordination complexes with lipid cholesteryl hemisuccinate (CHEMS. The in vitro tumoricidal activity of the former previously has been described in detail by other investigators. The CHEMS liposomal formulation had a Pt loading efficiency of 25% and showed more potent in vitro cytotoxicity against F98 glioma cells than free cisplatin at 24 h. In vivo CHEMS liposomes showed high retention at 24 h after intracerebral (i.c. convection enhanced delivery (CED to F98 glioma bearing rats. Neurotoxicologic studies were carried out in non-tumor bearing Fischer rats following i.c. CED of Lipoplatin™ or CHEMS liposomes or their "hollow" counterparts. Unexpectedly, Lipoplatin™ was highly neurotoxic when given i.c. by CED and resulted in death immediately following or within a few days after administration. Similarly "hollow" Lipoplatin™ liposomes showed similar neurotoxicity indicating that this was due to the liposomes themselves rather than the cisplatin. This was particularly surprising since Lipoplatin™ has been well tolerated when administered intravenously. In contrast, CHEMS liposomes and their "hollow" counterparts were clinically well tolerated. However, a variety of dose dependent neuropathologic changes from none to severe were seen at either 10 or 14 d following their administration. These findings suggest that further refinements in the design and formulation of cisplatin containing liposomes will be required before they can be administered i.c. by CED for the treatment of brain tumors and that a formulation that may be safe when given

  6. An evaluation of the relationships between catheter design and tissue mechanics in achieving high-flow convection-enhanced delivery.

    Science.gov (United States)

    White, Edward; Bienemann, Alison; Malone, John; Megraw, Lisa; Bunnun, Chotirote; Wyatt, Marcella; Gill, Steven

    2011-07-15

    Convection-enhanced delivery (CED) is a rational technique for the direct intracranial administration of a range of therapeutic agents. CED critically depends on the use of a catheter with a narrow outer diameter and low infusion rate. Failure to adhere to these requirements can lead to reflux of infusate along the catheter-brain interface and damage at the catheter-tip. In this study we have tested the hypothesis that the relationship between infusion parameters and infusate distribution, including reflux, is critically dependent on the occurrence of tissue damage. The relationship between catheter outer diameter and the extent of blood-brain barrier disruption and subsequent tissue oedema was evaluated following catheter insertion into the striatum of rats. Three patterns of infusate distribution were observed: (1) Reflux restricted to the traumatised tissue around the catheter site. (2) Distribution in the white matter beyond the area of tissue trauma. (3) Widespread distribution in the striatum, which occurred only with catheters of an outer diameter of 0.35 mm or less. Extensive tissue damage occurred with a 0.2mm outer diameter catheter. This damage was completely prevented by rounding the catheter-tip. Infusions into pig brain demonstrated that high-flow CED could be performed in a large brain in both grey and white matter using a 0.2mm outer diameter catheter, with minimal reflux or MRI-evidence of tissue damage. This study demonstrates that by minimising tissue damage from catheter design and insertion, high flow-rate CED can be utilised to distribute therapeutic agents over large volumes of brain within clinically practical timescales.

  7. Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats.

    Science.gov (United States)

    Huo, Tianyao; Barth, Rolf F; Yang, Weilian; Nakkula, Robin J; Koynova, Rumiana; Tenchov, Boris; Chaudhury, Abhik Ray; Agius, Lawrence; Boulikas, Teni; Elleaume, Helene; Lee, Robert J

    2012-01-01

    The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (NSCLC). The second, produced in our laboratory, was based on the ability of cisplatin to form coordination complexes with lipid cholesteryl hemisuccinate (CHEMS). The in vitro tumoricidal activity of the former previously has been described in detail by other investigators. The CHEMS liposomal formulation had a Pt loading efficiency of 25% and showed more potent in vitro cytotoxicity against F98 glioma cells than free cisplatin at 24 h. In vivo CHEMS liposomes showed high retention at 24 h after intracerebral (i.c.) convection enhanced delivery (CED) to F98 glioma bearing rats. Neurotoxicologic studies were carried out in non-tumor bearing Fischer rats following i.c. CED of Lipoplatin™ or CHEMS liposomes or their "hollow" counterparts. Unexpectedly, Lipoplatin™ was highly neurotoxic when given i.c. by CED and resulted in death immediately following or within a few days after administration. Similarly "hollow" Lipoplatin™ liposomes showed similar neurotoxicity indicating that this was due to the liposomes themselves rather than the cisplatin. This was particularly surprising since Lipoplatin™ has been well tolerated when administered intravenously. In contrast, CHEMS liposomes and their "hollow" counterparts were clinically well tolerated. However, a variety of dose dependent neuropathologic changes from none to severe were seen at either 10 or 14 d following their administration. These findings suggest that further refinements in the design and formulation of cisplatin containing liposomes will be required before they can be administered i.c. by CED for the treatment of brain tumors and that a formulation that may be safe when given systemically may be

  8. Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain.

    Science.gov (United States)

    Mano, Yui; Saito, Ryuta; Haga, Yoichi; Matsunaga, Tadao; Zhang, Rong; Chonan, Masashi; Haryu, Shinya; Shoji, Takuhiro; Sato, Aya; Sonoda, Yukihiko; Tsuruoka, Noriko; Nishiyachi, Keisuke; Sumiyoshi, Akira; Nonaka, Hiroi; Kawashima, Ryuta; Tominaga, Teiji

    2016-05-01

    OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 μl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 μl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way

  9. Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma.

    Science.gov (United States)

    Sewing, A Charlotte P; Lagerweij, Tonny; van Vuurden, Dannis G; Meel, Michaël H; Veringa, Susanna J E; Carcaboso, Angel M; Gaillard, Pieter J; Peter Vandertop, W; Wesseling, Pieter; Noske, David; Kaspers, Gertjan J L; Hulleman, Esther

    2017-05-01

    OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models. METHODS The sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model. RESULTS Both pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors. CONCLUSIONS Local delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic

  10. Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and a topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts1

    Science.gov (United States)

    Yamashita, Yoji; Krauze, Michal T.; Kawaguchi, Tomohiro; Noble, Charles O.; Drummond, Daryl C.; Park, John W.; Bankiewicz, Krystof S.

    2007-01-01

    Despite multimodal treatment options, the response and survival rates for patients with malignant gliomas remain dismal. Clinical trials with convection-enhanced delivery (CED) have recently opened a new window in neuro-oncology to the direct delivery of chemotherapeutics to the CNS, circumventing the blood-brain barrier and reducing systemic side effects. Our previous CED studies with liposomal chemotherapeutics have shown promising antitumor activity in rodent brain tumor models. In this study, we evaluated a combination of nanoliposomal topotecan (nLs-TPT) and pegylated liposomal doxorubicin (PLD) to enhance efficacy in our brain tumor models, and to establish a CED treatment capable of improving survival from malignant brain tumors. Both liposomal drugs decreased key enzymes involved in tumor cell replication in vitro. Synergistic effects of nLs-TPT and PLD on U87MG cell death were found. The combination displayed excellent efficacy in a CED-based survival study 10 days after tumor cell implantation. Animals in the control group and those in single-agent groups had a median survival of less than 30 days, whereas the combination group experienced a median survival of more than 90 days. We conclude that CED of two liposomal chemotherapeutics (nLs-TPT and PLD) may be an effective treatment option for malignant gliomas. PMID:17018695

  11. Low-intensity training increases peak arm VO2 by enhancing both convective and diffusive O2 delivery

    DEFF Research Database (Denmark)

    Boushel, R; Ara, I; Gnaiger, E;

    2014-01-01

    It is an ongoing discussion the extent to which oxygen delivery and oxygen extraction contribute to an increased muscle oxygen uptake during dynamic exercise. It has been proposed that local muscle factors including the capillary bed and mitochondrial oxidative capacity play a large role in prolo...

  12. Intracranial elimination of human glioblastoma brain tumors in nude rats using the bispecific ligand-directed toxin, DTEGF13 and convection enhanced delivery.

    Science.gov (United States)

    Oh, Seunguk; Ohlfest, John R; Todhunter, Deborah A; Vallera, Vincent D; Hall, Walter A; Chen, Hua; Vallera, Daniel A

    2009-12-01

    A bispecific ligand-directed toxin (BLT) consisting of human interleukin-13, epithelial growth factor, and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma. In vitro, DTEGF13 selectively killed the human glioblastoma cell line U87-luc as well as other human glioblastomas. DTEGF13 fulfilled the requirement of a successful BLT by having greater activity than either of its monospecific counterparts or their mixture proving it necessary to have both ligands on the same single chain molecule. Aggressive brain tumors established intracranially (IC) in nude rats with U87 glioma genetically marked with a firefly luciferase reporter gene were treated with two injections of DTEGF13 using convection enhanced delivery resulting in tumor eradication in 50% of the rats which survived with tumor free status at least 110 days post tumor inoculation. An irrelevant BLT control did not protect establishing specificity. The bispecific DTEGF13 MTD dose was measured at 2 microg/injection or 0.5 microg/kg and toxicity studies indicated safety in this dose. Combination of monospecific DTEGF and DTIL13 did not inhibit tumor growth. ELISA assay indicated that anti-DT antibodies were not generated in normal immunocompetent rats given identical intracranial DTEGF13 therapy. Thus, DTEGF13 is safe and efficacious as an alternative drug for glioblastoma therapy and warrants further study.

  13. Long-lasting attenuation of amygdala-kindled seizures after convection-enhanced delivery of botulinum neurotoxins a and B into the amygdala in rats.

    Science.gov (United States)

    Gasior, Maciej; Tang, Rebecca; Rogawski, Michael A

    2013-09-01

    Botulinum neurotoxins (BoNTs) are well recognized to cause potent, selective, and long-lasting neuroparalytic actions by blocking cholinergic neurotransmission to muscles and glands. There is evidence that BoNT isoforms can also inhibit neurotransmission in the brain. In this study, we examined whether locally delivered BoNT/A and BoNT/B can attenuate kindling measures in amygdala-kindled rats. Male rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received a single infusion of vehicle or BoNT/A or BoNT/B at doses of 1, 3.2, or 10 ng over a 20-minute period by convection-enhanced delivery. Electrographic (EEG) and behavioral kindling measures were determined at selected times during the 3- to 64-day period after the infusion. BoNT/B produced a dose-dependent elevation in after-discharge threshold and duration and a reduction in the seizure stage and duration of behavioral seizures that lasted for up to 50 days after infusion. BoNT/A had similar effects on EEG measures; behavioral seizure measures were also reduced, but the effect did not reach statistical significance. The effects of both toxins on EEG and behavioral measures progressively resolved during the latter half of the observation period. Animals gained weight normally, maintained normal body temperature, and did not show altered behavior. This study demonstrates for the first time that locally delivered BoNTs can produce prolonged inhibition of brain excitability, indicating that they could be useful for the treatment of brain disorders, including epilepsy, that would benefit from long-lasting suppression of neurotransmission within a circumscribed brain region.

  14. Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model1

    Science.gov (United States)

    Saito, Ryuta; Krauze, Michal T.; Noble, Charles O.; Drummond, Daryl C.; Kirpotin, Dmitri B.; Berger, Mitchel S.; Park, John W.; Bankiewicz, Krystof S.

    2006-01-01

    Treatment of malignant gliomas represents one of the most formidable challenges in oncology. The combination of surgery, radiation, and chemotherapy yields median survivals of less than one year. Here we demonstrate the use of a minimally invasive surgical technique, convection-enhanced delivery (CED), for local administration of a novel nanoparticle liposome containing topotecan. CED of this liposomal topotecan (Ls-TPT) resulted in extended brain tissue retention (t½ = 1.5 days), whereas free topotecan was rapidly cleared (t½ = 0.1 days) after CED. The favorable pharmacokinetic profile of extended topotecan release for about seven days, along with biodistribution featuring perivascular accumulation of the nanoparticles, provided, in addition to the known topoisomerase I inhibition, an effective antiangiogenic therapy. In the rat intracranial U87MG tumor model, vascular targeting of Ls-TPT with CED was associated with reductions in laminin expression and vascular density compared to free topotecan or control treatments. A single CED treatment on day 7 showed that free topotecan conferred no survival benefit versus control. However, Ls-TPT produced a significant (P = 0.0002) survival benefit, with six of seven complete cures. Larger U87MG tumors, where CED of Ls-TPT on day 12 resulted in one of six cures, indicated the necessity to cover the entire tumor with the infused therapeutic agent. CED of Ls-TPT was also efficacious in the intracranial U251MG tumor model (P = 0.0005 versus control). We conclude that the combination of a novel nanoparticle Ls-TPT and CED administration was very effective in treating experimental brain tumors. PMID:16723630

  15. Convection-enhancement delivery of platinum-based drugs and Lipoplatin™ to optimize the concomitant effect with radiotherapy in F98 glioma rat model

    Science.gov (United States)

    Shi, Minghan; Fortin, David; Sanche, Léon; Paquette, Benoit

    2015-01-01

    The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin™-liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by factors varying between 17 and 111, the concentration of these platinum-based drugs in the brain tumor compared to intra-venous (i.v.) administration, and by 9- to 34-fold, when compared to intra-arterial (i.a.) administration. Furthermore, CED resulted in a better systemic tolerance to platinum drugs compared to their i.a. injection. Among the drugs tested, carboplatin showed the highest maximum tolerated dose (MTD). Treatment with carboplatin resulted in the best median survival time (MeST) (38.5 days), which was further increased by the addition of radiotherapy (54.0 days). Although the DNA-bound platinum adduct were higher at 4 h after CED than 24 h for carboplatin group, combination with radiotherapy led to similar improvement of median survival time. However, less toxicity was observed in animals irradiated 24 h after CED-based chemotherapy. In conclusion, CED increased the accumulation of platinum drugs in tumor, reduced the toxicity, and resulted in a higher median survival time. The best treatment was obtained in animals treated with carboplatin and irradiated 24 h later. PMID:25784204

  16. Convection-enhancement delivery of platinum-based drugs and Lipoplatin(TM) to optimize the concomitant effect with radiotherapy in F98 glioma rat model.

    Science.gov (United States)

    Shi, Minghan; Fortin, David; Sanche, Léon; Paquette, Benoit

    2015-06-01

    The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum-based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin(TM) - liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by factors varying between 17 and 111, the concentration of these platinum-based drugs in the brain tumor compared to intra-venous (i.v.) administration, and by 9- to 34-fold, when compared to intra-arterial (i.a.) administration. Furthermore, CED resulted in a better systemic tolerance to platinum drugs compared to their i.a. injection. Among the drugs tested, carboplatin showed the highest maximum tolerated dose (MTD). Treatment with carboplatin resulted in the best median survival time (MeST) (38.5 days), which was further increased by the addition of radiotherapy (54.0 days). Although the DNA-bound platinum adduct were higher at 4 h after CED than 24 h for carboplatin group, combination with radiotherapy led to similar improvement of median survival time. However, less toxicity was observed in animals irradiated 24 h after CED-based chemotherapy. In conclusion, CED increased the accumulation of platinum drugs in tumor, reduced the toxicity, and resulted in a higher median survival time. The best treatment was obtained in animals treated with carboplatin and irradiated 24 h later.

  17. Benchmarking the ERG valve tip and MRI Interventions Smart Flow neurocatheter convection-enhanced delivery system's performance in a gel model of the brain: employing infusion protocols proposed for gene therapy for Parkinson's disease

    Science.gov (United States)

    Sillay, Karl; Schomberg, Dominic; Hinchman, Angelica; Kumbier, Lauren; Ross, Chris; Kubota, Ken; Brodsky, Ethan; Miranpuri, Gurwattan

    2012-04-01

    Convection-enhanced delivery (CED) is an advanced infusion technique used to deliver therapeutic agents into the brain. CED has shown promise in recent clinical trials. Independent verification of published parameters is warranted with benchmark testing of published parameters in applicable models such as gel phantoms, ex vivo tissue and in vivo non-human animal models to effectively inform planned and future clinical therapies. In the current study, specific performance characteristics of two CED infusion catheter systems, such as backflow, infusion cloud morphology, volume of distribution (mm3) versus the infused volume (mm3) (Vd/Vi) ratios, rate of infusion (µl min-1) and pressure (mmHg), were examined to ensure published performance standards for the ERG valve-tip (VT) catheter. We tested the hypothesis that the ERG VT catheter with an infusion protocol of a steady 1 µl min-1 functionality is comparable to the newly FDA approved MRI Interventions Smart Flow (SF) catheter with the UCSF infusion protocol in an agarose gel model. In the gel phantom models, no significant difference was found in performance parameters between the VT and SF catheter. We report, for the first time, such benchmark characteristics in CED between these two otherwise similar single-end port VT with stylet and end-port non-stylet infusion systems. Results of the current study in agarose gel models suggest that the performance of the VT catheter is comparable to the SF catheter and warrants further investigation as a tool in the armamentarium of CED techniques for eventual clinical use and application.

  18. Enhancement of laminar convective heat transfer using microparticle suspensions

    Science.gov (United States)

    Zhu, Jiu Yang; Tang, Shiyang; Yi, Pyshar; Baum, Thomas; Khoshmanesh, Khashayar; Ghorbani, Kamran

    2016-04-01

    This paper investigates the enhancement of convective heat transfer within a sub-millimetre diameter copper tube using Al2O3, Co3O4 and CuO microparticle suspensions. Experiments are conducted at different particle concentrations of 1.0, 2.0 and 5.0 wt% and at various flow rates ranging from 250 to 1000 µl/min. Both experimental measurements and numerical analyses are employed to obtain the convective heat transfer coefficient. The results indicate a significant enhancement in convective heat transfer coefficient due to the implementation of microparticle suspensions. For the case of Al2O3 microparticle suspension with 5.0 wt% concentration, a 20.3 % enhancement in convective heat transfer coefficient is obtained over deionised water. This is comparable to the case of Al2O3 nanofluid at the same concentration. Hence, there is a potential for the microparticle suspensions to be used for cooling of compact integrated systems.

  19. Enhancement of laminar convective heat transfer using microparticle suspensions

    Science.gov (United States)

    Zhu, Jiu Yang; Tang, Shiyang; Yi, Pyshar; Baum, Thomas; Khoshmanesh, Khashayar; Ghorbani, Kamran

    2017-01-01

    This paper investigates the enhancement of convective heat transfer within a sub-millimetre diameter copper tube using Al2O3, Co3O4 and CuO microparticle suspensions. Experiments are conducted at different particle concentrations of 1.0, 2.0 and 5.0 wt% and at various flow rates ranging from 250 to 1000 µl/min. Both experimental measurements and numerical analyses are employed to obtain the convective heat transfer coefficient. The results indicate a significant enhancement in convective heat transfer coefficient due to the implementation of microparticle suspensions. For the case of Al2O3 microparticle suspension with 5.0 wt% concentration, a 20.3 % enhancement in convective heat transfer coefficient is obtained over deionised water. This is comparable to the case of Al2O3 nanofluid at the same concentration. Hence, there is a potential for the microparticle suspensions to be used for cooling of compact integrated systems.

  20. Evidence of convective heat transfer enhancement induced by spinodal decomposition.

    Science.gov (United States)

    Poesio, P; Lezzi, A M; Beretta, G P

    2007-06-01

    Spinodal decomposition can be driven by either diffusion or self-induced convection; the importance of convection relative to diffusion depends on the Péclet number, defined as the ratio between convective and diffusive mass fluxes. Diffusion is the dominating mechanism of phase segregation when the Péclet number is small - i.e., when viscosity and diffusivity are large - or when the domain characteristic size is small. For low-viscosity mixtures, convection is the dominating process and the segregation is very rapid as it takes a few seconds compared to the hours needed in the case of pure diffusion. In such cases, strong convective motion of the phase segregating domains is generated even in small-size systems and is almost independent of the temperature difference as long as it is below the transition value. We study experimentally the enhancement of heat transfer in a 1-mm -thick cell. A water-acetonitrile-toulene mixture is quenched into a two-phase region so as to induce convection-driven spinodal decomposition. The heat transfer rate is measured and compared to that obtained in the absence of convective motion. A substantial reduction in the cooling time obtains in the case of spinodal decomposition. The heat transfer enhancement induced by this self-induced, disordered but effectively convective effect may be exploited in the cooling or heating of small-scale systems whereby forced convection cannot be achieved because of the small sizes involved. A scaling analysis of the data based on the diffuse interface H model for a symmetric mixture near the equilibrium point yields very encouraging agreement and insights.

  1. Nanoparticle Delivery Enhancement With Acoustically Activated Microbubbles

    Science.gov (United States)

    Mullin, Lee B; Phillips, Linsey C; Dayton, Paul A

    2013-01-01

    The application of microbubbles and ultrasound to deliver nanoparticle carriers for drug and gene delivery is an area that has expanded greatly in recent years. Under ultrasound exposure, microbubbles can enhance nanoparticle delivery by increasing cellular and vascular permeability. In this review, the underlying mechanisms of enhanced nanoparticle delivery with ultrasound and microbubbles and various proposed delivery techniques are discussed. Additionally, types of nanoparticles currently being investigated in preclinical studies, as well as the general limitations and benefits of a microbubble-based approach to nanoparticle delivery are reviewed. PMID:23287914

  2. Numerical study on passive convective mass transfer enhancement

    Science.gov (United States)

    Aravind, G. P.; Muhammed Rafi, K. M.; Deepu, M.

    2017-04-01

    Passive mixing mechanisms are widely used for heat and mass transfer enhancement. Vortices generated in flowfield lead to gradients that favour convective mass transfer. Computations on enhancement of convective mass transfer of sublimating solid fuel by baroclinic torque generated vortices in the wake of a swept ramp placed in high speed flow is presented here. Advection Upstream Splitting Method (AUSM) based computational scheme employed in the present study, to solve compressible turbulent flow field involving species transport, could capture the complex flow features resulted by vortex boundary layer and shock boundary layer interactions. Convective mass transfer is found to get improved in regions near boundary layer by horseshoe vortex and further transported to other regions by counter rotating vortex pair. Vortices resulted by flow expansion near aft wall of wedge and recompression wave-boundary layer interactions also promotes convective mass transport. Extensive computations have been carried out to reveal the role of vortices dominance at various lateral sweep angles in promotion of convective mass transfer in turbulent boundary layer.

  3. Observations of an enhanced convection channel in the cusp ionosphere

    Energy Technology Data Exchange (ETDEWEB)

    Pinnock, M.; Rodger, A.S.; Dudeney, J.R. (Natural Environment Research Council, Cambridge (United Kingdom)); Baker, K.B.; Neweli, P.T.; Greenwald, R.A. (Johns Hopkins Univ., Laurel, MD (United States)); Greenspan, M.E. (Boston Univ., MA (United States))

    1993-03-01

    Transient or patchy magnetic field line merging on the dayside magnetopause, giving rise to flux transfer events (FTEs), is thought to play a significant role in energizing high-latitude ionospheric convection during periods of southward interplanetary magnetic field. Several transient velocity patterns in the cusp ionosphere have been presented as candidate FTE signatures. Instrument limitations, combined with uncertainties about ionospheric signature of FTEs have yet to be presented. This paper describes combined observations by the PACE HF backscatter radar and the DMSP F9 polar-orbiting satellite of a transient velocity signature in the southern hemispheric cusp. The prevailing solar wind conditions suggest that it is the result of enhanced magnetic merging at the magnetopause. The satellite particle precipitation data associated with the transient are typically cusplike in nature. The presence of spatially discrete patches of accelerated ions at the equatorward edge of the cusp is consistent with the ion acceleration that could occur with merging. The combined radar line-of-sight velocity data and the satellite transverse plasma drift data are consistent with a channel of enhanced convection superposed on the ambient cusp plasma flow. This channel is at least 900 km in longitudinal extent but only 100 km wide. It is zonally aligned for most of its extent, except at the western limit where it rotates sharply poleward. Weak return flow is observed outside the channel. These observations are compared with and contrasted to similar events seen by the EISCAT radar and by optical instruments. 30 refs., 2 figs.

  4. Enhancing transdermal drug delivery with electroporation.

    Science.gov (United States)

    Wong, Tak-Wah; Ko, Shu-Fen; Hui, Sek-Wen

    2008-01-01

    The application of electroporation to enhance transdermal delivery has opened up a new possibility to introduce larger molecules such as peptide hormones and vaccines as well as minigenes and RNAi etc. through the transdermal route. Many devices have been developed to deliver the pulse electric field needed to permeate the skin. These devices include both non-puncturing surface electrodes as well as puncturing electrodes of different geometrical arrangements. The latter type uses electroporation only to increase uptake of molecules injected through the puncturing electrode or syringe. Different electroporation protocols have been developed to maximize transport, uptake and minimizing pain. Synergistic effect of chemical enhancers and physical (sonic, vibrational and thermal) treatments are used to enhance the transport. This article reviews the patents pertaining to the instrumentation as well as application protocols of transdermal delivery, uptake enhancement and interstitial fluid sampling by electroporation.

  5. Convective heat transfer enhancement inside tubes using inserted helical coils

    Science.gov (United States)

    Ali, R. K.; Sharafeldeen, M. A.; Berbish, N. S.; Moawed, M. A.

    2016-01-01

    Convective heat transfer was experimentally investigated in tubes with helical coils inserts in turbulent flow regime within Reynolds number range of 14400 ≤ Re ≤ 42900. The present work aims to extend the experimental data available on wire coil inserts to cover wire diameter ratio from 0.044 to 0.133 and coil pitch ratio from 1 to 5. Uniform heat flux was applied to the external surface of the tube and air was selected as fluid. The effects of Reynolds number and wire diameter and coil pitch ratios on the Nusselt number and friction factor were studied. The enhancement efficiency and performance criteria ranges are of (46.9-82.6%) and (100.1-128%) within the investigated range of the different parameters, respectively. Correlations are obtained for the average Nusselt number and friction factor utilizing the present measurements within the investigated range of geometrical parameters and Re.

  6. PENETRATION ENHANCERS: A NOVEL STRATEGY FOR ENHANCING TRANSDERMAL DRUG DELIVERY

    Directory of Open Access Journals (Sweden)

    Singla Vikas

    2011-12-01

    Full Text Available Skin penetration enhancers have been used to improve bioavailability and increase the range of drugs to be administered by topical and transdermal route. Enhancement in skin penetration via modification of the stratum corneum by hydration, or via use of chemical enhancers acting on the structure of the stratum corneum lipids and keratin, partitioning and solubility effects. The mechanism of action of penetration enhancers are used as an aid in potential clinical applications. Synthetic chemicals generally used for this purposes are rapidly losing their value in transdermal patches due to reports of their absorption into the systemic circulation and subsequent possible toxic effect upon long term application. Terpenes are included in the list of Generally Recognized as Safe (GRAS substances and have low irritancy potential. In this review, we have discussed the chemical penetration as well as natural penetration enhancement technology for transdermal drug delivery as well as the probable mechanisms of action.

  7. Testosterone ethosomes for enhanced transdermal delivery.

    Science.gov (United States)

    Ainbinder, Denize; Touitou, Elka

    2005-01-01

    Physiological decrease in testosterone levels in men with age causes various changes with clinical significance. Recent testosterone replacement therapy is based mainly on transdermal nonpatch delivery systems. These products have the drawback of application on extremely large areas to achieve required hormone blood levels. The objective of the present study was to design and test a testosterone nonpatch formulation using ethosomes for enhanced transdermal absorption. The ethosomal formulation was characterized by transmission electron microscopy and dynamic light scattering for structure and size distribution and by ultracentrifugation for entrapment capacity. To evaluate the feasibility of this delivery system to enhance testosterone permeation through the skin, first the systemic absorption in rats was compared with a currently used gel (AndroGel). Further, theoretical estimation of testosterone blood concentration following ethosomal application in men was made. For this purpose, in vitro permeation experiments through human skin were performed to establish testosterone skin permeation values. In the design of these experiments, testosterone solubility in various solutions was measured and the effect of the receiver medium on the skin barrier function was assessed by confocal laser scanning microscopy. Theoretical estimation shows that testosterone human plasma concentration value in the upper part of the physiological range could be achieved by application of the ethosomal formulation on an area of 40 cm(2). This area is about 10 times smaller than required with current nonpatch formulations. Our work shows that the ethosomal formulation could enhance testosterone systemic absorption and also be used for designing new products that could solve the weaknesses of the current testosterone replacement therapies.

  8. Microneedle-iontophoresis combinations for enhanced transdermal drug delivery.

    Science.gov (United States)

    Donnelly, Ryan F; Garland, Martin J; Alkilani, Ahlam Zaid

    2014-01-01

    It has recently been proposed that the combination of skin barrier impairment using microneedles (MNs) coupled with iontophoresis (ITP) may broaden the range of drugs suitable for transdermal delivery as well as enabling the rate of delivery to be achieved with precise electronic control. However, few reports exist on the combination of ITP with in situ drug-loaded polymeric MN delivery systems. Our in vitro permeation studies revealed that MN enhances transdermal drug delivery. The combination of dissolving MN and ITP did not further enhance the extent of delivery of the low molecular weight drug ibuprofen sodium after short application periods. However, the extent of peptide/protein delivery was significantly enhanced when ITP was used in combination with hydrogel-forming MN arrays. As such, hydrogel-forming MN arrays show promise for the electrically controlled transdermal delivery of biomacromolecules in a simple, one-step approach, though further technical developments will be necessary before patient benefit is realized.

  9. TRANSDERMAL DRUG DELIVERY AND METHODS TO ENHANCE IT

    Directory of Open Access Journals (Sweden)

    E. G. Kuznetsova

    2016-01-01

    Full Text Available The paper presents the common methods employed in recent years for enhancing transdermal delivery of drug substances when applying transdermal therapeutic delivery systems. The chemical, physical and mechanical methods to enhance the transport of macromolecular compounds through the skin are considered in details. 

  10. Oral delivery strategies for nutraceuticals: Delivery vehicles and absorption enhancers

    OpenAIRE

    Gleeson, John P.; Ryan, Sinéad M.; Braden, David James

    2016-01-01

    Lifestyle issues contribute to the development of obesity, type 2 diabetes, and cardiovascular disease. Together with appropriate diet and exercise, nutraceuticals may contribute to managing prevention at an early stage prior to therapeutic intervention. However, many useful food-derived bioactive compounds will not sufficiently permeate the small intestine to yield efficacy without appropriate oral delivery technology. The pharmaceutical industry uses commercialised approaches for oral deliv...

  11. Electroporation-enhanced delivery of nucleic acid vaccines.

    Science.gov (United States)

    Broderick, Kate E; Humeau, Laurent M

    2015-02-01

    The naked delivery of nucleic acid vaccines is notoriously inefficient, and an enabling delivery technology is required to direct efficiently these constructs intracellularly. A delivery technology capable of enhancing nucleic acid uptake in both cells in tissues and in culture is electroporation (EP). EP is a physical delivery mechanism that increases the permeability of mammalian cell membranes and allows the trafficking of large macromolecules into the cell. EP has now been used extensively in the clinic and been shown to be an effective method to increase both the uptake of the construct and the breadth and magnitude of the resulting immune responses. Excitingly, 2014 saw the announcement of the first EP-enhanced DNA vaccine Phase II trial demonstrating clinical efficacy. This review seeks to introduce the reader to EP as a technology to enhance the delivery of DNA and RNA vaccines and highlight several published clinical trials using this delivery modality.

  12. Aerosolized liposomes with dipalmitoyl phosphatidylcholine enhance pulmonary insulin delivery.

    Science.gov (United States)

    Chono, Sumio; Fukuchi, Rie; Seki, Toshinobu; Morimoto, Kazuhiro

    2009-07-20

    The pulmonary insulin delivery characteristics of liposomes were examined. Aerosolized liposomes containing insulin were administered into rat lungs and the enhancing effect on insulin delivery was evaluated by changes of plasma glucose levels. Liposomes with dipalmitoyl phosphatidylcholine (DPPC) enhanced pulmonary insulin delivery in rats, however, liposomes with dilauroyl, dimyristoyl, distearoyl or dioleoyl phosphatidylcholine did not. Liposomes with DPPC also enhanced the in vitro permeation of FITC dextran (Mw 4400, FD-4) through the calu-3 cell monolayer by reducing the transepithelial electrical resistance and did not harm lung tissues in rats. These findings suggest that liposomes with DPPC enhance pulmonary insulin delivery by opening the epithelial cell space in the pulmonary mucosa not mucosal cell damage. Liposomes with DPPC could be useful as a pulmonary delivery system for peptide and protein drugs.

  13. Enhancement of convective heat transfer coefficient of ethylene glycol base cuprous oxide (Cu2O) nanofluids

    Science.gov (United States)

    Hassan, Ali; Ramzan, Naveed; Umer, Asim; Ahmad, Ayyaz; Muryam, Hina

    2017-08-01

    The enhancement in the convective heat transfer coefficient of the ethylene glycol (EG) base cuprous oxide (Cu2O) nanofluids were investigated. The nanofluids of different volume concentrations i-e 1%, 2.5% and 4.5% were prepared by the two step method. Cuprous oxide (Cu2O) nanoparticles were ultrasonically stirred for four hours in the ethylene glycol (EG). The experimental study has been performed through circular tube geometry in laminar flow regime at average Reynolds numbers 36, 71 and 116. The constant heat flux Q = 4000 (W/m2) was maintained during this work. Substantial enhancement was observed in the convective heat transfer coefficient of ethylene glycol (EG) base cuprous oxide (Cu2O) nanofluids than the base fluid. The maximum 74% enhancement was observed in convective heat transfer coefficient at 4.5 vol% concentration and Re = 116.

  14. Novel biodegradable nanocarriers for enhanced drug delivery.

    Science.gov (United States)

    Gagliardi, Mariacristina

    2016-12-01

    With the refinement of functional properties, the interest around biodegradable materials, in biorelated applications and, in particular, in their use as controlled drug-delivery systems, increased in the last decades. Biodegradable materials are an ideal platform to obtain nanoparticles for spatiotemporal controlled drug delivery for the in vivo administration, thanks to their biocompatibility, functionalizability, the control exerted on delivery rates and the complete degradation. Their application in systems for cancer treatment, brain and cardiovascular diseases is already a consolidated practice in research, while the bench-to-bedside translation is still late. This review aims at summarizing reported applications of biodegradable materials to obtain drug-delivery nanoparticles in the last few years, giving a complete overview of pros and cons related to degradable nanomedicaments.

  15. Iontophoretically Enhanced Ciclopirox Delivery into and Across Human Nail Plate

    OpenAIRE

    HAO, JINSONG; Smith, Kelly A.; Li, S. Kevin

    2009-01-01

    Transungual delivery of antifungal drugs is hindered by the low permeability of human nail plates, and as such, repeated dosing over a long period of time is necessary for effective treatment. The objectives of this study were to explore the possibilities of (a) enhancing the delivery of ciclopirox (CIC) across human nail plates and (b) sustaining CIC delivery from the larger resultant drug depot in the nail plates with constant voltage iontophoresis. In vitro passive and 9 V cathodal iontoph...

  16. Iontophoretically Enhanced Ciclopirox Delivery into and Across Human Nail Plate

    OpenAIRE

    Hao, Jinsong; Smith, Kelly A; Li, S. Kevin

    2009-01-01

    Transungual delivery of antifungal drugs is hindered by the low permeability of human nail plates, and as such, repeated dosing over a long period of time is necessary for effective treatment. The objectives of this study were to explore the possibilities of (a) enhancing the delivery of ciclopirox (CIC) across human nail plates and (b) sustaining CIC delivery from the larger resultant drug depot in the nail plates with constant voltage iontophoresis. In vitro passive and 9 V cathodal iontoph...

  17. Bioavailability of phytochemicals and its enhancement by drug delivery systems.

    Science.gov (United States)

    Aqil, Farrukh; Munagala, Radha; Jeyabalan, Jeyaprakash; Vadhanam, Manicka V

    2013-06-28

    Issues of poor oral bioavailability of cancer chemopreventives have hindered progress in cancer prevention. Novel delivery systems that modulate the pharmacokinetics of existing drugs, such as nanoparticles, cyclodextrins, niosomes, liposomes and implants, could be used to enhance the delivery of chemopreventive agents to target sites. The development of new approaches in prevention and treatment of cancer could encompass new delivery systems for approved and newly investigated compounds. In this review, we discuss some of the delivery approaches that have already made an impact by either delivering a drug to target tissue or increasing its bioavailability by many fold.

  18. Mathematical analysis for internal filtration of convection-enhanced high-flux hemodialyzer.

    Science.gov (United States)

    Lee, Jung Chan; Lee, Kyungsoo; Kim, Hee Chan

    2012-10-01

    Structural modifications using a conventional hemodialyzer improved the internal filtration and clearance of middle molecular weight wastes by enhanced convection effect. In this study, we employed a mathematical model describing the internal filtration rate as well as the hemodynamic and hematologic parameters in highflux dialyzer to interpret the previous reported experimental results. Conventional high-flux hemodialysis and convection-enhanced high-flux hemodialysis were configured in the mathematical forms and integrated into the iterative numerical method to predict the internal filtration phenomena inside the dialyzers during dialysis. The distributions of blood pressure, dialysate pressure, oncotic pressure, blood flow rates, dialysate flow rates, local ultrafiltration, hematocrit, protein concentration and blood viscosity along the axial length of dialyzer were calculated in order to estimate the internal filtration volume. The results show that the filtration volumes by internal filtration is two times higher in a convection-enhanced high-flux hemodialyzer than in a conventional high-flux hemodialzer and explains the experimental result of improved clearance of middle molecular size waste in convection-enhanced high-flux hemodialyzer.

  19. Novel chemical permeation enhancers for transdermal drug delivery

    Directory of Open Access Journals (Sweden)

    Yang Chen

    2014-04-01

    Full Text Available Transdermal drug delivery has been accepted as a potential non-invasive route of drug administration, with advantages of prolonged therapeutic action, decreased side effect, easy use and better patient compliance. However, development of transdermal products is primarily hindered by the low permeability of the skin. To overcome this barrier effect, numerous new chemicals have been synthesized as potential permeation enhancers for transdermal drug delivery. In this review, we presented an overview of the investigations in this field, and further implications on selection or design of suitable permeation enhancers for transdermal drug delivery were also discussed.

  20. Synergistic effect of enhancers for transdermal drug delivery.

    Science.gov (United States)

    Mitragotri, S

    2000-11-01

    Transdermal drug delivery offers a non-invasive route of drug administration, although its applications are limited by low skin permeability. Various enhancers including iontophoresis, chemicals, ultrasound, and electroporation have been shown to enhance transdermal drug transport. Although all these methods have been individually shown to enhance transdermal drug transport, their combinations have often been found to enhance transdermal transport more effectively than each of them alone. This paper summarizes literature studies on these combinations with respect to their efficacy and mechanisms.

  1. Comparative enhancing effects of electret with chemical enhancers on transdermal delivery of meloxicam in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Cui, L L; Hou, X M; Li, G D [Department of Inorganic Chemistry, College of Pharmacy, Second Military Medical University, Shanghai, 200433 (China); Jiang, J; Liang, Y Y; Xin, X [Department of Physics and Mathematics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, 200433 (China)], E-mail: cuilili39@hotmail.com, E-mail: JJiang0827@hotmail.com

    2008-12-01

    Electret offers enhancing effect in transdermal drug delivery for altering of the arrangement of lipid molecules in the stratum corneum, forming many transient permeable apertures and enhancing the transdermal drug delivery. In this paper, meloxicam patch formulations were developed to make the comparative study of transdermal drug delivery between electret and chemical enhancers. Patches were made into control, electret, chemical enhancer and electret with chemical enhancer ones, according to the preparation procedure. The electret combined with chemical enhancer patch was designed to probe the incorporation between electret and chemical enhancer in transdermal drug delivery. The meloxicam release from the patch was found to increase in order of blank, chemical enhancer, electret and electret with chemical enhancer patch, in general.

  2. Enhanced Controlled Transdermal Delivery of Torasemide Using ...

    African Journals Online (AJOL)

    Erah

    Purpose: To develop an ethylene-vinyl acetate (EVA) matrix system containing ... Methods: The solubility of torasemide was studied at various volume fraction of polyethylene glycol ... matrix across the skin, enhancers (propylene glycol derivatives, fatty acids, glycerides, pyrrolidones and ..... penetration enhancer is feasible.

  3. Enhanced summer convective rainfall at Alpine high elevations in response to climate warming

    Science.gov (United States)

    Giorgi, Filippo; Torma, Csaba; Coppola, Erika; Ban, Nikolina; Schär, Christoph; Somot, Samuel

    2016-08-01

    Global climate projections consistently indicate a future decrease in summer precipitation over the European Alps. However, topography can substantially modulate precipitation change signals. For example, the shadowing effect by topographic barriers can modify winter precipitation change patterns, and orographic convection might also play an important role. Here we analyse summer precipitation over the Alpine region in an ensemble of twenty-first-century projections with high-resolution (~12 km) regional climate models driven by recent global climate model simulations. A broad-scale summer precipitation reduction is projected by both model ensembles. However, the regional models simulate an increase in precipitation over the high Alpine elevations that is not present in the global simulations. This is associated with increased convective rainfall due to enhanced potential instability by high-elevation surface heating and moistening. The robustness of this signal, which is found also for precipitation extremes, is supported by the consistency across models and future time slices, the identification of an underlying mechanism (enhanced convection), results from a convection-resolving simulation, the statistical significance of the signal and the consistency with some observed trends. Our results challenge the picture of a ubiquitous decrease of summer precipitation over the Alps found in coarse-scale projections.

  4. Enhancing endosomal escape for nanoparticle mediated siRNA delivery

    Science.gov (United States)

    Ma, Da

    2014-05-01

    Gene therapy with siRNA is a promising biotechnology to treat cancer and other diseases. To realize siRNA-based gene therapy, a safe and efficient delivery method is essential. Nanoparticle mediated siRNA delivery is of great importance to overcome biological barriers for systemic delivery in vivo. Based on recent discoveries, endosomal escape is a critical biological barrier to be overcome for siRNA delivery. This feature article focuses on endosomal escape strategies used for nanoparticle mediated siRNA delivery, including cationic polymers, pH sensitive polymers, calcium phosphate, and cell penetrating peptides. Work has been done to develop different endosomal escape strategies based on nanoparticle types, administration routes, and target organ/cell types. Also, enhancement of endosomal escape has been considered along with other aspects of siRNA delivery to ensure target specific accumulation, high cell uptake, and low toxicity. By enhancing endosomal escape and overcoming other biological barriers, great progress has been achieved in nanoparticle mediated siRNA delivery.

  5. Enhanced convective heat transfer using graphene dispersed nanofluids.

    Science.gov (United States)

    Baby, Tessy Theres; Ramaprabhu, Sundara

    2011-04-04

    Nanofluids are having wide area of application in electronic and cooling industry. In the present work, hydrogen exfoliated graphene (HEG) dispersed deionized (DI) water, and ethylene glycol (EG) based nanofluids were developed. Further, thermal conductivity and heat transfer properties of these nanofluids were systematically investigated. HEG was synthesized by exfoliating graphite oxide in H2 atmosphere at 200°C. The nanofluids were prepared by dispersing functionalized HEG (f-HEG) in DI water and EG without the use of any surfactant. HEG and f-HEG were characterized by powder X-ray diffractometry, electron microscopy, Raman and FTIR spectroscopy. Thermal and electrical conductivities of f-HEG dispersed DI water and EG based nanofluids were measured for different volume fractions and at different temperatures. A 0.05% volume fraction of f-HEG dispersed DI water based nanofluid shows an enhancement in thermal conductivity of about 16% at 25°C and 75% at 50°C. The enhancement in Nusselts number for these nanofluids is more than that of thermal conductivity.

  6. Enhanced convective heat transfer using graphene dispersed nanofluids

    Directory of Open Access Journals (Sweden)

    Baby Tessy

    2011-01-01

    Full Text Available Abstract Nanofluids are having wide area of application in electronic and cooling industry. In the present work, hydrogen exfoliated graphene (HEG dispersed deionized (DI water, and ethylene glycol (EG based nanofluids were developed. Further, thermal conductivity and heat transfer properties of these nanofluids were systematically investigated. HEG was synthesized by exfoliating graphite oxide in H2 atmosphere at 200°C. The nanofluids were prepared by dispersing functionalized HEG (f-HEG in DI water and EG without the use of any surfactant. HEG and f-HEG were characterized by powder X-ray diffractometry, electron microscopy, Raman and FTIR spectroscopy. Thermal and electrical conductivities of f-HEG dispersed DI water and EG based nanofluids were measured for different volume fractions and at different temperatures. A 0.05% volume fraction of f-HEG dispersed DI water based nanofluid shows an enhancement in thermal conductivity of about 16% at 25°C and 75% at 50°C. The enhancement in Nusselts number for these nanofluids is more than that of thermal conductivity.

  7. A general theoretical principle for single-phase convection heat transfer enhancement

    Institute of Scientific and Technical Information of China (English)

    WANG SongPing; CHEN QingLin; ZHANG BingJian; HUA Ben

    2009-01-01

    The main methods of single-phase convection heat transfer enhancement are analyzed in this paper,and the unity of contradiction between heat transfer enhancement and energy consumption(or exergy destruction)is expounded.The thermodynamic relationship between heat(or exergy)transfer efficiency and energy consumption(or exergy destruction)as well as driving forces is established,and a general theoretical principle for single-phase convection heat transfer enhancement is further obtained.The principle shows that temperature gradient field distribution and velocity field distribution constrain each other,and that the optimum heat transfer efficiency can be obtained when they are synergetic.If the level of the synergy of temperature gradient field distribution with velocity field distribution is determined,the relative uniform temperature gradient is required,and vice versa.The principle also shows the relationship of relative temperature gradient with specific heat and coefficient of heat conductivity.The deduced results can be used as a theoretical guidance for single-phase convection heat transfer enhancement and optimum design of heat exchangers.

  8. A general theoretical principle for single-phase convection heat transfer enhancement

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The main methods of single-phase convection heat transfer enhancement are analyzed in this paper, and the unity of contradiction between heat transfer enhancement and energy consumption(or exergy destruction)is expounded.The thermodynamic relationship between heat(or exergy)transfer efficiency and energy consumption(or exergy destruction)as well as driving forces is established,and a general theoretical principle for single-phase convection heat transfer enhancement is further obtained. The principle shows that temperature gradient field distribution and velocity field distribution constrain each other,and that the optimum heat transfer efficiency can be obtained when they are synergetic.If the level of the synergy of temperature gradient field distribution with velocity field distribution is determined,the relative uniform temperature gradient is required,and vice versa.The principle also shows the relationship of relative temperature gradient with specific heat and coefficient of heat conductivity.The deduced results can be used as a theoretical guidance for single-phase convection heat transfer enhancement and optimum design of heat exchangers.

  9. Enhanced transdermal delivery of ketobemidone with prodrugs

    DEFF Research Database (Denmark)

    Hansen, L.B.; Fullerton, A.; Christrup, Lona Louring;

    1992-01-01

    The feasibility of achieving transdermal delivery of the opioid analgesic ketobemidone was assessed in human skin penetration studies in vitro using both ketobemidone itself and three carbonate ester prodrugs formed at the phenolic hydroxyl group. Whereas ketobemidone itself only showed a limited...... ability to permeate the skin from either polar or apolar vehicles the ester prodrugs very readily penetrated through the skin from solutions in isopropyl myristate and, in particular, from ethanol and ethanol-water solutions. Thus, steady-state fluxes in the range of 40-140 μg ketobemidone base/cm per h...... were observed for the ketobemidone esters from 20% w/v solutions in ethanol and ethanol-water (3:1 and 1:1 v/v) vehicles. The esters were rapidly hydrolyzed to the parent drug in the presence of skin enzymes and only from ketobemidone was detected in the receptor phase. The study demonstrates...

  10. Initiatives to Enhance Primary Care Delivery

    Directory of Open Access Journals (Sweden)

    Jan L. Losby

    2015-01-01

    Full Text Available Objectives: Increasing demands on primary care providers have created a need for systems-level initiatives to improve primary care delivery. The purpose of this article is to describe and present outcomes for 2 such initiatives: the Pennsylvania Academy of Family Physicians’ Residency Program Collaborative (RPC and the St Johnsbury Vermont Community Health Team (CHT. Methods: Researchers conducted case studies of the initiatives using mixed methods, including secondary analysis of program and electronic health record data, systematic document review, and interviews. Results: The RPC is a learning collaborative that teaches quality improvement and patient centeredness to primary care providers, residents, clinical support staff, and administrative staff in residency programs. Results show that participation in a higher number of live learning sessions resulted in a significant increase in patient-centered medical home recognition attainment and significant improvements in performance in diabetic process measures including eye examinations (14.3%, P = .004, eye referrals (13.82%, P = .013, foot examinations (15.73%, P = .003, smoking cessation (15.83%, P = .012, and self-management goals (25.45%, P = .001. As a community-clinical linkages model, CHT involves primary care practices, community health workers (CHWs, and community partners. Results suggest that CHT members successfully work together to coordinate comprehensive care for the individuals they serve. Further, individuals exposed to CHWs experienced increased stability in access to health insurance (P = .001 and prescription drugs (P = .000 and the need for health education counseling (P = .000. Conclusion: Findings from this study indicate that these 2 system-level strategies have the promise to improve primary care delivery. Additional research can determine the extent to which these strategies can improve other health outcomes.

  11. Evaluation of chemical enhancers in the transdermal delivery of lidocaine.

    Science.gov (United States)

    Lee, Philip J; Ahmad, Naina; Langer, Robert; Mitragotri, Samir; Prasad Shastri, V

    2006-02-03

    The effect of various classes of chemical enhancers was investigated for the transdermal delivery of the anesthetic lidocaine across pig and human skin in vitro. The lipid disrupting agents (LDA) oleic acid, oleyl alcohol, butenediol, and decanoic acid by themselves or in combination with isopropyl myristate (IPM) showed no significant flux enhancement. However, the binary system of IPM/n-methyl pyrrolidone (IPM/NMP) improved drug transport. At 2% lidocaine dose, this synergistic enhancement peaked at 25:75 (v/v) IPM:NMP with a steady state flux of 57.6 +/- 8.4 microg cm(-2) h(-1) through human skin. This observed flux corresponds to a four-fold enhancement over a 100% NMP solution and over 25-fold increase over 100% IPM at the same drug concentration (p enhancement due to LDA. These findings allow a more rational approach for designing oil-based formulations for the transdermal delivery of lidocaine free base and similar drugs.

  12. Hollow Pollen Shells to Enhance Drug Delivery

    Directory of Open Access Journals (Sweden)

    Alberto Diego-Taboada

    2014-03-01

    Full Text Available Pollen grain and spore shells are natural microcapsules designed to protect the genetic material of the plant from external damage. The shell is made up of two layers, the inner layer (intine, made largely of cellulose, and the outer layer (exine, composed mainly of sporopollenin. The relative proportion of each varies according to the plant species. The structure of sporopollenin has not been fully characterised but different studies suggest the presence of conjugated phenols, which provide antioxidant properties to the microcapsule and UV (ultraviolet protection to the material inside it. These microcapsule shells have many advantageous properties, such as homogeneity in size, resilience to both alkalis and acids, and the ability to withstand temperatures up to 250 °C. These hollow microcapsules have the ability to encapsulate and release actives in a controlled manner. Their mucoadhesion to intestinal tissues may contribute to the extended contact of the sporopollenin with the intestinal mucosa leading to an increased efficiency of delivery of nutraceuticals and drugs. The hollow microcapsules can be filled with a solution of the active or active in a liquid form by simply mixing both together, and in some cases operating a vacuum. The active payload can be released in the human body depending on pressure on the microcapsule, solubility and/or pH factors. Active release can be controlled by adding a coating on the shell, or co-encapsulation with the active inside the shell.

  13. Natural Terpenes as Penetration Enhancers for Transdermal Drug Delivery

    OpenAIRE

    Jun Chen; Qiu-Dong Jiang; Ya-Ping Chai; Hui Zhang; Pei Peng; Xi-Xiong Yang

    2016-01-01

    The greatest hindrance for transdermal drug delivery (TDD) is the barrier property of skin, especially the stratum corneum (SC). Various methodologies have been investigated and developed to enhance the penetration of drugs through the skin. Among them, the most popular approach is the application of penetration enhancers (PEs), including natural terpenes, a very safe and effective class of PEs. In the present paper, we focused on terpenes as skin PEs for TDD. The mechanism of their action, t...

  14. Convection's enhancement in thermal micro pipes using extra fluid and shape memory material

    Science.gov (United States)

    Mihai, Ioan; Sprinceana, Siviu

    2016-12-01

    Up to now, there have been developed various applications of thermal micro pipes[1-3], such as refrigerating systems, high heat flux electronics cooling, and biological devices etc., based on vacuum vaporization followed by a convective phenomenon that allows vapor transfer from the vaporization area to the condensation one. This article presents studies carried out on the enhancement of the convective phenomenon taking place in flat thermal micro pipes. The proposed method[4] is aimed at the cooling of power electronics components, such as microprocessors. The conducted research focused on the use of shape memory materials that allow, by a semi-active method, to bring extra fluid in the vaporization area of the thermal micro pipe. The conducted investigations analyzed the variation of the liquid layer thickness in the trapezoidal micro channels and the thermal flow change over time. The modification of liquid flow was studied in correlation with the capacity of the polysynthetic material to retain the most extra fluid in its pores. The enhancement of the convective heat transfer phenomenon in flat thermal micro pipes was investigated in correspondence to the increase of liquid quantity in the vaporization zone. The charts obtained by aid of Mathcad[5] allowed to represent the evolution during a period of time (or with the pipe's length) of the liquid film thickness, the flow and the thermal flow, as a function of the liquid supply variation due to the shape memory materials and the modification of the working temperature.

  15. Multi-stage polar cap convection response to enhanced interplanetary driving

    Science.gov (United States)

    Sandholt, Per Even; Farrugia, Charlie; Andalsvik, Yngvild

    2013-04-01

    In two case studies we investigate the response of ionospheric convection to enhanced magnetopause reconnection rate leading to repetitive substorm activity. Our interplanetary (IP) driver is coronal mass ejections (CMEs). The aim is to estimate the cross-polar cap potential (CPCP) at high temporal resolution (1 min). To achieve this, we use a method where we combine direct measurements of the CPCP from satellite ion drift data, which have limited temporal coverage, with high-resolution (1 min) ground observations of equivalent convection in the central polar cap, obtained from the polar cap index in the northern hemisphere (PCN). In our CPCP estimates we distinguish between contributions from different sectors of the polar cap (center and periphery) as well as from the dayside and nightside sources. The polar cap (PC) periphery is characterized by channels of enhanced antisunward flows, which are particularly pronounced in the winter hemisphere. These flow channels are continuously monitored by ground data from the IMAGE chain of magnetometers in Svalbard - Scandinavia - Finland. They are discussed as stages in the evolution of the Dungey flux circulation cycle driven by both dayside and nightside sources. Following Siscoe et al. (2011) we distinguish between two stages of the evolution of the convection response, i.e., an initial transient phase, and a subsequent persistent phase.

  16. Luminaries-level structure improvement of LEDs for heat dissipation enhancement under natural convection

    Indian Academy of Sciences (India)

    Ke Wu; Le Wang; Yi-Bo Yu; Zhi-Yi Huang; Pei Liang

    2013-12-01

    Heat dissipation enhancement of LED luminaries is of great significance to the large-scale application of LED. Luminaries-level structure improvement by the method of boring through-hole is adopted to intensify heat dissipation. Furthermore, the natural convection heat transfer process of LED luminaries is simulated by computational fluid dynamics (CFD) model before and after the structural modification. As shown by computational results, boring through-hole is beneficial to develop bottomto-top natural convection, eliminate local circumfluence, and finally form better flow pattern. Analysis based on field synergy principle shows that boring through-hole across LED luminaries improves the synergy between flow field and temperature field, and effectively decreases the thermal resistance of luminaries-level heat dissipation structure. Under the same computational conditions, by luminaries-level structure improvement the highest temperature of heat sink is decreased by about 8° C and the average heat transfer coefficient is increased by 45.8%.

  17. Potential of enhancing a natural convection loop with a thermomagnetically pumped ferrofluid

    CERN Document Server

    Aursand, Eskil; Lervåg, Karl Yngve; Lund, Halvor

    2016-01-01

    The feasibility of using a thermomagnetically pumped ferrofluid to enhance the performance of a natural convection cooling loop is investigated. First, a simplified analytical estimate for the thermomagnetic pumping action is derived, and then design rules for optimal solenoid and ferrofluid are presented. The design rules are used to set up a medium-scale (1 m, 10-1000 W) case study, which is modeled using a previously published and validated model (Aursand et al. [1]). The results show that the thermomagnetic driving force is significant compared to the natural convection driving force, and may in some cases greatly surpass it. The results also indicate that cooling performance can be increased by factors up to 4 and 2 in the single-phase and two- phase regimes, respectively, even when taking into the account the added heat from the solenoid. The performance increases can alternatively be used to obtain a reduction in heat-sink size by up to 75 %.

  18. Development of the ambroxol gels for enhanced transdermal delivery.

    Science.gov (United States)

    Cho, Cheong-Weon; Choi, Jun-Shik; Shin, Sang-Chul

    2008-03-01

    Ambroxol is an expectoration improver and mucolytic agent that has been used to treat acute and chronic disorders. However, ambroxol needs to be administered percutaneously in order to avoid systemic adverse effects, such as headache, drowsiness, dizziness, and insomnia, which can occur after oral administration. The aim of this study was to develop a gel preparation containing a permeation enhancer to enhance the delivery of ambroxol. The ambroxol gels were prepared using hydroxypropyl methylcellulose (HPMC) and poloxamer 407. The release characteristics of the drug from the gels were examined according to the receptor medium, drug concentration, and temperature. The rate of drug permeation into the skin was enhanced by incorporating various enhancers such as the ethylene glycols, the propylene glycols, the glycerides, the non-ionic surfactants, and the fatty acids into the gels. The permeation study through mouse skin was examined at 37 C. The rate of drug release increased with increasing drug concentration and temperature. Among the enhancers used, propylene glycol mono caprylate showed the best enhancing effects. The estimated activation energy of release (Ea), which was calculated from the slope of a log P versus 1000/T plot, was 14.80, 14.22, 13.91, and 12.46 kcal/mol for ambroxol loading doses of 2, 3, 4, and 5%, respectively. The results of this study show that the gel preparation of ambroxol containing a permeation enhancer could be developed for the enhanced transdermal delivery of ambroxol.

  19. A new brain drug delivery strategy: focused ultrasound-enhanced intranasal drug delivery.

    Directory of Open Access Journals (Sweden)

    Hong Chen

    Full Text Available Central nervous system (CNS diseases are difficult to treat because of the blood-brain barrier (BBB, which prevents most drugs from entering into the brain. Intranasal (i.n. administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+i.n. for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After i.n. administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (i.v. drug injection is employed, FUS was also applied after i.v. injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+i.n. enhanced drug delivery within the targeted region compared with that achieved by i.n. only. Despite the fact that the i.n. route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+i.n. was not significantly different from that of FUS+i.v.. As a new drug delivery platform, the FUS+i.n. technique is potentially useful for treating CNS diseases.

  20. A new brain drug delivery strategy: focused ultrasound-enhanced intranasal drug delivery.

    Science.gov (United States)

    Chen, Hong; Chen, Cherry C; Acosta, Camilo; Wu, Shih-Ying; Sun, Tao; Konofagou, Elisa E

    2014-01-01

    Central nervous system (CNS) diseases are difficult to treat because of the blood-brain barrier (BBB), which prevents most drugs from entering into the brain. Intranasal (i.n.) administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS) in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+i.n.) for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After i.n. administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (i.v.) drug injection is employed, FUS was also applied after i.v. injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+i.n. enhanced drug delivery within the targeted region compared with that achieved by i.n. only. Despite the fact that the i.n. route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+i.n. was not significantly different from that of FUS+i.v.. As a new drug delivery platform, the FUS+i.n. technique is potentially useful for treating CNS diseases.

  1. Cutaneous delivery of natural antioxidants: the enhancement approaches.

    Science.gov (United States)

    Aljuffali, Ibrahim A; Hsu, Ching-Yun; Lin, Yin-Ku; Fang, Jia-You

    2015-01-01

    Topically applied natural antioxidants can be an effective treatment for inhibiting oxidative damage and photoaging of the skin. Due to the barrier function of the stratum corneum (SC), it is necessary to use an enhancement approach to promote the cutaneous absorption of natural antioxidants. Some factors that should be considered when developing delivery systems for natural antioxidants include increased solubility, enhanced storage stability, improved permeability and bioavailability, skin targeting, and minimal side effects. This review describes the skin delivery systems for natural antioxidant permeation that have been developed during the last decade. The antioxidants introduced include vitamins, polyphenols, and carotenoids. Various types of formulations are employed to improve the skin penetration of the antioxidants, such as hydrogels, cyclodextrin, microemulsions, nanoparticles, liposomes and niosomes. This review focuses on the introduction of natural antioxidants used in skin protection, the mechanisms of antioxidant activity on the skin, and formulation designs for enhancing absorption and efficacy.

  2. Smart surface-enhanced Raman scattering traceable drug delivery systems.

    Science.gov (United States)

    Liu, Lei; Tang, Yonghong; Dai, Sheng; Kleitz, Freddy; Qiao, Shi Zhang

    2016-07-07

    A novel smart nanoparticle-based system has been developed for tracking intracellular drug delivery through surface-enhanced Raman scattering (SERS). This new drug delivery system (DDS) shows targeted cytotoxicity towards cancer cells via pH-cleavable covalent carboxylic hydrazone links and the SERS tracing capability based on gold@silica nanocarriers. Doxorubicin, as a model anticancer drug, was employed to compare SERS with conventional fluorescence tracing approaches. It is evident that SERS demonstrates higher sensitivity and resolution, revealing intracellular details, as the strengths of the original Raman signals can be amplified by SERS. Importantly, non-destructive SERS will provide the designed DDS with great autonomy and potential to study the dynamic procedures of non-fluorescent drug delivery into living cells.

  3. Smart surface-enhanced Raman scattering traceable drug delivery systems

    Science.gov (United States)

    Liu, Lei; Tang, Yonghong; Dai, Sheng; Kleitz, Freddy; Qiao, Shi Zhang

    2016-06-01

    A novel smart nanoparticle-based system has been developed for tracking intracellular drug delivery through surface-enhanced Raman scattering (SERS). This new drug delivery system (DDS) shows targeted cytotoxicity towards cancer cells via pH-cleavable covalent carboxylic hydrazone links and the SERS tracing capability based on gold@silica nanocarriers. Doxorubicin, as a model anticancer drug, was employed to compare SERS with conventional fluorescence tracing approaches. It is evident that SERS demonstrates higher sensitivity and resolution, revealing intracellular details, as the strengths of the original Raman signals can be amplified by SERS. Importantly, non-destructive SERS will provide the designed DDS with great autonomy and potential to study the dynamic procedures of non-fluorescent drug delivery into living cells.A novel smart nanoparticle-based system has been developed for tracking intracellular drug delivery through surface-enhanced Raman scattering (SERS). This new drug delivery system (DDS) shows targeted cytotoxicity towards cancer cells via pH-cleavable covalent carboxylic hydrazone links and the SERS tracing capability based on gold@silica nanocarriers. Doxorubicin, as a model anticancer drug, was employed to compare SERS with conventional fluorescence tracing approaches. It is evident that SERS demonstrates higher sensitivity and resolution, revealing intracellular details, as the strengths of the original Raman signals can be amplified by SERS. Importantly, non-destructive SERS will provide the designed DDS with great autonomy and potential to study the dynamic procedures of non-fluorescent drug delivery into living cells. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr03869g

  4. Iontophoretically enhanced ciclopirox delivery into and across human nail plate.

    Science.gov (United States)

    Hao, Jinsong; Smith, Kelly A; Li, S Kevin

    2009-10-01

    Transungual delivery of antifungal drugs is hindered by the low permeability of human nail plates, and as such, repeated dosing over a long period of time is necessary for effective treatment. The objectives of this study were to explore the possibilities of (a) enhancing the delivery of ciclopirox (CIC) across human nail plates and (b) sustaining CIC delivery from the larger resultant drug depot in the nail plates with constant voltage iontophoresis. In vitro passive and 9 V cathodal iontophoretic transport experiments of CIC across human nails were performed. Transungual CIC delivery with Penlac was the control. The amounts of CIC released from and deposited in the nails were determined in drug release and extraction experiments, respectively. Iontophoresis increased the flux of CIC permeated across the nail approximately 10 times compared to passive delivery from the same formulation or from Penlac. A significant amount of CIC was loaded into and released from the nails; the CIC concentrations were estimated to be above the minimum inhibitory concentrations of CIC for dermatophytic molds. The apparent transport lag time decreased in iontophoretic transport. The results demonstrate that iontophoresis was able to deliver an effective amount of CIC into and across the nails, and this suggests the feasibility of a constant voltage battery-powered transungual iontophoretic device.

  5. Nanoparticles and nanostructured carriers for drug delivery and contrast enhancement

    Science.gov (United States)

    Godage, Olga S.; Bucharskaya, Alla B.; Navolokin, Nikita A.; German, Sergey V.; Zuev, Viktor V.; Terentyuk, Georgy S.; Maslyakova, Galina N.; Gorin, Dmitry A.

    2016-04-01

    Currently, nanotechnologies are widely used in science and industry. It is known that the application of drug delivery nanostructured carriers for biomedicine is one of the promising areas of nanotechnology. Nanostructured carriers can be used in the diagnosis process for detecting a neoplastic tumor cells in peripheral blood, for contrast enhancement on magnetic resonance imaging (MRI), as well as for targeted drug delivery to tumor tissues. Agents for the targeted delivery (nanoparticles, liposomes, microcapsules, and etc) can affect the healthy tissues and organs, cause side effects and have a toxic effect. Therefore, it necessary to study the morphological changes that occur not only in the "target", such as a tumor, but also the internal organs, taking place under the influence of both the agents for targeted drug delivery and physical impact induced remote controlled drug release. Thus , the aim of our work is selection of the most promising agents for targeted drug delivery to tumor and contrast agents for in vivo visualization of tumor tissue boundaries , as well as their impact on the organs and tissues as results of nanostructured object biodistribution.

  6. Enhanced skin deposition and delivery of voriconazole using ethosomal preparations.

    Science.gov (United States)

    Faisal, Waleed; Soliman, Ghareb M; Hamdan, Ahmed M

    2016-10-19

    Despite its broad-spectrum antifungal properties, voriconazole has many side effects when administered systemically. The aim of this work was to develop an ethosomal topical delivery system for voriconazole and test its potential to enhance the antifungal properties and skin delivery of the drug. Voriconazole was encapsulated into various ethosomal preparations and the effect of phospholipid and ethanol concentrations on the ethosomes properties were evaluated. The ethosomes were evaluated for drug encapsulation efficiency, particle size and morphology and antifungal efficacy. Drug permeability and deposition were tested in rat abdominal skin. Drug encapsulation efficiency of up to 46% was obtained and it increased with increasing the phospholipid concentration, whereas the opposite effect was observed for the ethanol concentration. The ethosomes had a size of 420-600 nm and negative zeta potential. The particle size of the ethosomes increased by increasing their ethanol content. The ethosomes achieved similar inhibition zones against Aspergillus flavus at a 2-fold lower drug concentration compared with drug solution in dimethyl sulfoxide. The ex vivo drug permeability through rat abdominal skin was ∼6-fold higher for the ethosomes compared with the drug hydroalcoholic solution. Similarly, the amount of drug deposited in the skin was higher for the ethosomes and was dependent on the ethanol concentration of the ethosomes. These results confirm that voriconazole ethosomal preparations are promising topical delivery systems that can enhance the drug antifungal efficacy and improve its skin delivery.

  7. Deformable liposomes and ethosomes: mechanism of enhanced skin delivery.

    Science.gov (United States)

    Elsayed, Mustafa M A; Abdallah, Ossama Y; Naggar, Viviane F; Khalafallah, Nawal M

    2006-09-28

    Despite intensive research, the mechanisms by which vesicular systems deliver drugs into intact skin are not yet fully understood. In the current study, possible mechanisms by which deformable liposomes and ethosomes improve skin delivery of ketotifen under non-occlusive conditions were investigated. In vitro permeation and skin deposition behavior of deformable liposomes and ethosomes, having ketotifen both inside and outside the vesicles (no separation of free ketotifen), having ketotifen only inside the vesicles (free ketotifen separated) and having ketotifen only outside the vesicles (ketotifen solution added to empty vesicles), was studied using rabbit pinna skin. Results suggested that both the penetration enhancing effect and the intact vesicle permeation into the stratum corneum might play a role in improving skin delivery of drugs by deformable liposomes, under non-occlusive conditions, and that the penetration enhancing effect was of greater importance in case of ketotifen. Regarding ethosomes, results indicated that ketotifen should be incorporated in ethosomal vesicles for optimum skin delivery. Ethosomes were not able to improve skin delivery of non-entrapped ketotifen.

  8. Enhanced stratospheric water vapor over the summertime continental United States and the role of overshooting convection

    Science.gov (United States)

    Herman, Robert L.; Ray, Eric A.; Rosenlof, Karen H.; Bedka, Kristopher M.; Schwartz, Michael J.; Read, William G.; Troy, Robert F.; Chin, Keith; Christensen, Lance E.; Fu, Dejian; Stachnik, Robert A.; Bui, T. Paul; Dean-Day, Jonathan M.

    2017-05-01

    The NASA ER-2 aircraft sampled the lower stratosphere over North America during the field mission for the NASA Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC4RS). This study reports observations of convectively influenced air parcels with enhanced water vapor in the overworld stratosphere over the summertime continental United States and investigates three case studies in detail. Water vapor mixing ratios greater than 10 ppmv, which is much higher than the background 4 to 6 ppmv of the overworld stratosphere, were measured by the JPL Laser Hygrometer (JLH Mark2) at altitudes between 16.0 and 17.5 km (potential temperatures of approximately 380 to 410 K). Overshooting cloud tops (OTs) are identified from a SEAC4RS OT detection product based on satellite infrared window channel brightness temperature gradients. Through trajectory analysis, we make the connection between these in situ water measurements and OT. Back trajectory analysis ties enhanced water to OT 1 to 7 days prior to the intercept by the aircraft. The trajectory paths are dominated by the North American monsoon (NAM) anticyclonic circulation. This connection suggests that ice is convectively transported to the overworld stratosphere in OT events and subsequently sublimated; such events may irreversibly enhance stratospheric water vapor in the summer over Mexico and the United States. A regional context is provided by water observations from the Aura Microwave Limb Sounder (MLS).

  9. Evaluation of Diclofenac Prodrugs for Enhancing Transdermal Delivery

    OpenAIRE

    Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

    2013-01-01

    The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD), and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates, and bioconversion rates. ...

  10. Results of Experiments on Convective Precipitation Enhancement in the Camaguey Experimental Area, Cuba.

    Science.gov (United States)

    Koloskov, Boris; Zimin, Boris; Beliaev, Vitaly; Seregin, Yury; Chernikov, Albert; Petrov, Victor; Valdés, Mario; Martínez, Daniel; Pérez, Carlos A.; Puente, Guillermo

    1996-09-01

    Experiments on randomized seeding of individual convective clouds and cloud clusters were conducted in the Camaguey experimental area, Cuba, from 1985 through 1990 in order to elucidate whether cold-cloud dynamic seeding can be used to augment convective rainfall. An information measuring system was set up, and primary tools included three instrumented aircraft (AN-26, AN-12 CYCLONE, IL-14), MRL-5 and ARS-3 radars, a system for radiosounding, two special rain gauge networks, and surface weather stations.A total of 232 randomized experiments were carried out during this experimentation period, and 117 individual clouds and 115 cloud clusters were studied during 136 `go' days. Pyrotechnic flares containing silver iodide were ejected in a selected cloud when the seeder aircraft was flying through its top. The seeding effects were monitored by the MRL-5 radar, which was equipped with an automated system for digital processing of data.A total of 46 convective clouds, 29 seeded and 17 nonseeded, were studied during an exploratory experiment in 1985. Analyses of the radar properties of seeded and nonseeded clouds have indicated that the response of convective clouds to AgI seeding is dependent on their type, and the treatment within the range of cloud tops from 6 to 8 km—that is, at top temperatures between 10° and 20°C, is found to increase their maximum height by 13% and the lifetime by 30%, and to enhance rainfall.A confirmatory phase of the experiment in the Camaguey experimental area was conducted during 1986 90. A total of 46 individual convective clouds, 24 seeded and 22 nonseeded, were identified, and their properties were determined using three-dimensional radar data. The results have shown that the AgI seeding of growing clouds with top temperatures over the range from 10° to 20°C increases their lifetime by 24%, maximum height by 9%, area by 64%, and rain volume by 120%, as compared to unseeded clouds. The lifetime, area, and rainfall results are

  11. Mixed Convection Heat Transfer Enhancement in a Vented Cavity Filled with a Nanofluid

    Directory of Open Access Journals (Sweden)

    Ahmed BAHLAOUI

    2016-01-01

    Full Text Available In this paper, a numerical investigation is carried out on mixed convection in a vertical vented rectangular enclosure filled with Al2O3-water nanofluid. The mixed convection effect is attained by heating the right wall by a constant hot temperature and cooling the cavity by an injected or sucked imposed flow. The effects of some pertinent parameters such as the Reynolds number, 100  Re  5000, the solid volume fraction of the nanoparticles, 0    0.1, and the aspect ratio of the cavity, 1  A  4, on flow and temperature patterns as well as on the heat transfer rate within the enclosure are presented for the two ventilation modes. For a value of the aspect ratio A = 2, the obtained results demonstrate that the increase of volume fraction of nanoparticles contributes to an enhancement of the heat transfer and to an increase of the mean temperature within the cavity. Also, it was revealed that the fluid suction mode yields the best heat transfer performance. In the case when A is varied from 1 to 4, it was obtained that the heat transfer enhancement, using nanofluids, is more pronounced at shallow enclosures than at tall ones.

  12. Enhancing and targeting nucleic acid delivery by magnetic force.

    Science.gov (United States)

    Plank, Christian; Anton, Martina; Rudolph, Carsten; Rosenecker, Joseph; Krötz, Florian

    2003-08-01

    Insufficient contact of inherently highly active nucleic acid delivery systems with target cells is a primary reason for their often observed limited efficacy. Physical methods of targeting can overcome this limitation and reduce the risk of undesired side effects due to non-target site delivery. The authors and others have developed a novel means of physical targeting, exploiting magnetic force acting on nucleic acid vectors associated with magnetic particles in order to mediate the rapid contact of vectors with target cells. Here, the principles of magnetic drug and nucleic acid delivery are reviewed, and the facts and potentials of the technique for research and therapeutic applications are discussed. Magnetically enhanced nucleic acid delivery - magnetofection - is universally applicable to viral and non-viral vectors, is extraordinarily rapid, simple and yields saturation level transfection at low dose in vitro. The method is useful for site-specific vector targeting in vivo. Exploiting the full potential of the technique requires an interdisciplinary research effort in magnetic field physics, magnetic particle chemistry, pharmaceutical formulation and medical application.

  13. Enhanced skin delivery of vismodegib by microneedle treatment.

    Science.gov (United States)

    Nguyen, Hiep X; Banga, Ajay K

    2015-08-01

    The present study investigated the effects of microneedle treatment (maltose microneedles, Admin Pen™ 1200, and Admin Pen™ 1500) on in vitro transdermal delivery of vismodegib with different needle lengths, skin equilibration times, and microneedle insertion durations. The influence of microneedle treatment on the dimensions of microchannels (dye binding, calcein imaging, histology, and confocal microscopy studies), transepidermal water loss, and skin permeability of vismodegib was also evaluated. Skin viscoelasticity was assessed using a rheometer, and microneedle geometry was characterized by scanning electron microscopy. Permeation studies of vismodegib through dermatomed porcine ear skin were conducted using vertical Franz diffusion cells. Skin irritation potential of vismodegib formulation was assessed using an in vitro reconstructed human epidermis model. Results of the in vitro permeation studies revealed significant enhancement in permeation of vismodegib through microneedle-treated skin. As the needle length increased from 500 to 1100 and 1400 μm, drug delivery increased from 14.50 ± 2.35 to 32.38 ± 3.33 and 74.40 ± 15.86 μg/cm(2), respectively. Positive correlation between drug permeability and microneedle treatment duration was observed. The equilibration time was also found to affect the delivery of vismodegib. Thus, changes in microneedle length, equilibration time, and duration of treatment altered transdermal delivery of vismodegib.

  14. Enhanced transdermal delivery of granisetron by using iontophoresis.

    Science.gov (United States)

    Panzade, Prabhakar; Heda, Ashish; Puranik, Prashant; Patni, Mayur; Mogal, Vipul

    2012-01-01

    The purpose of the present study was to explore the passive and electrically assisted transdermal transport of Granisetron hydrochloride (GRA) in solution and gel formulation through iontophoresis and also the feasibility of delivering therapeutic amounts of drug for the treatment of chemotherapy-induced nausea and vomiting. In this study, iontophoretic permeation of GRA through guinea pig skin using silver-silver chloride electrode was performed and the effects of different variables on this phenomenon were evaluated. Preliminary in-vitro studies using aqueous GRA formulations investigating the effect of drug concentration (5, 10, 15 and 20 mg mL(-1)) on passive permeation, current density (0.2, 0.4 and 0.5 mA cm(-2)), mode of current application, penetration enhancers and effect of application duration were performed. As expected, GRA delivery was found to be increased with the elevation in drug concentration and current density. Anodal continuous current delivery was more effective in the permeation of GRA than the pulsed current method. Penetration enhancers were ineffective to show synergistic effect in conjunction with iontophoresis. It was evident that reservoir in the skin was not formed during the iontophoretic delivery. The results confirm that GRA is an excellent candidate for iontophoresis. The present study demonstrated the feasibility of GRA transdermal transport through the Lutrol F-127 gel by iontophoresis. Further in-vivo studies will be required to support in-vitro conclusions and develop in-vitro, in-vivo correlations.

  15. Enhancement and suppression of protein crystal nucleation due to electrically driven convection

    Science.gov (United States)

    Penkova, Anita; Gliko, Olga; Dimitrov, Ivaylo L.; Hodjaoglu, Feyzim V.; Nanev, Christo; Vekilov, Peter G.

    2005-02-01

    We investigated the effects of the constant electric fields from 2.0 to 6.0 kV cm -1 on the nucleation of ferritin, apoferritin and lysozyme crystals. For this, supersaturated solutions of the three proteins were held between electrodes separated by 1.0 cm in batch and sitting drop geometries without contact between electrodes and solutions. The nucleation rate was characterized by the number of crystals appearing after a certain time (1-3 days). We show that in sitting drop arrangements, weak electric fields (<4 kV cm -1) either suppress or have no effect on the nucleation rate of ferritin and apoferritin, while electric fields of 5 or 6 kV cm -1 reproducibly enhance crystal nucleation of both proteins. Electric fields of all tested strengths consistently enhance lysozyme crystal nucleation. All batch experiments showed no effect of the electric field on the nucleation rates. Since the solutions contain high electrolyte concentrations and are conductive, the electric field strengths within them are negligible. We show that the electric field causes solution stirring with rates of up to 100 μm s -1, depending of the field strength. Thus, our observations indicate that at slow solution flow rates, the rates of nucleation of ferritin and apoferritin crystal are suppressed, while faster stirring enhances crystal nucleation of these proteins. All solution flow rates enhance lysozyme crystal nucleation. Our results suggest that solution convection may strongly affect nucleation, and that for some systems, an optimal convection velocity, leading to fastest nucleation, exists.

  16. Enhanced North Atlantic deep convection preceding Heinrich 1 glacial ice sheet destabilization

    Science.gov (United States)

    Seidenkrantz, Marit-Solveig; Kuijpers, Antoon; Lindgreen, Holger

    2015-04-01

    The Labrador Sea is a crucial center of action for North Atlantic meridional overturning circulation. This region is characterized in winter by strong cold and dry winds from land or ice surfaces inducing large heat and moisture fluxes at the ocean-atmosphere interface. Particularly in late winter these conditions favor deep-convection processes leading to the formation of a relatively homogeneous and oxygen-rich intermediate water mass (Labrador Sea Water, LSW) spreading to other parts of the North Atlantic at water depths between about 1,000 and 2,000 m. Sedimentary records from the Labrador Sea have previously indicated here the presence of North Atlantic Deep Water during periods in between glacial ('Heinrich') ice-rafting events. The present sediment core investigation based on clay mineralogical analysis and study of the benthic foraminiferal fauna shows a significant oxygenation event at 18000 cal.yrs BP recorded both in the Labrador Sea and at the northern margin of Rockall Trough at 2381 m and 1286 m water depth, respectively. We conclude this ventilation pulse to be related to a period of enhanced deep convection and formation of glacial North Atlantic Intermediate Water occupying those parts of the water column presently affected under conditions of strong LSW formation. This ventilation event implies an early, significant re-activation of North Atlantic meridional overturning circulation after the Last Glacial Maximum immediately prior to Heinrich 1 large-scale ice-sheet destabilization. This scenario points to an oceanic trigger mechanism for large-scale glacial iceberg surges around the northern North Atlantic, which involves enhanced northward ocean (sub)surface heat transport and subsequent enhanced bottom melting of floating outlet glaciers and ice shelves.

  17. An Enhanced Convective Forecast (ECF) for the New York TRACON Area

    Science.gov (United States)

    Wheeler, Mark; Stobie, James; Gillen, Robert; Jedlovec, Gary; Sims, Danny

    2008-01-01

    In an effort to relieve summer-time congestion in the NY Terminal Radar Approach Control (TRACON) area, the FAA is testing an enhanced convective forecast (ECF) product. The test began in June 2008 and is scheduled to run through early September. The ECF is updated every two hours, right before the Air Traffic Control System Command Center (ATCSCC) national planning telcon. It is intended to be used by traffic managers throughout the National Airspace System (NAS) and airlines dispatchers to supplement information from the Collaborative Convective Forecast Product (CCFP) and the Corridor Integrated Weather System (CIWS). The ECF begins where the current CIWS forecast ends at 2 hours and extends out to 12 hours. Unlike the CCFP it is a detailed deterministic forecast with no aerial coverage limits. It is created by an ENSCO forecaster using a variety of guidance products including, the Weather Research and Forecast (WRF) model. This is the same version of the WRF that ENSCO runs over the Florida peninsula in support of launch operations at the Kennedy Space Center. For this project, the WRF model domain has been shifted to the Northeastern US. Several products from the NASA SPoRT group are also used by the ENSCO forecaster. In this paper we will provide examples of the ECF products and discuss individual cases of traffic management actions using ECF guidance.

  18. Gaussian process modelling for uncertainty quantification in convectively-enhanced dissolution processes in porous media

    Science.gov (United States)

    Crevillén-García, D.; Wilkinson, R. D.; Shah, A. A.; Power, H.

    2017-01-01

    Numerical groundwater flow and dissolution models of physico-chemical processes in deep aquifers are usually subject to uncertainty in one or more of the model input parameters. This uncertainty is propagated through the equations and needs to be quantified and characterised in order to rely on the model outputs. In this paper we present a Gaussian process emulation method as a tool for performing uncertainty quantification in mathematical models for convection and dissolution processes in porous media. One of the advantages of this method is its ability to significantly reduce the computational cost of an uncertainty analysis, while yielding accurate results, compared to classical Monte Carlo methods. We apply the methodology to a model of convectively-enhanced dissolution processes occurring during carbon capture and storage. In this model, the Gaussian process methodology fails due to the presence of multiple branches of solutions emanating from a bifurcation point, i.e., two equilibrium states exist rather than one. To overcome this issue we use a classifier as a precursor to the Gaussian process emulation, after which we are able to successfully perform a full uncertainty analysis in the vicinity of the bifurcation point.

  19. Nanoengineered drug delivery systems for enhancing antibiotic therapy.

    Science.gov (United States)

    Kalhapure, Rahul S; Suleman, Nadia; Mocktar, Chunderika; Seedat, Nasreen; Govender, Thirumala

    2015-03-01

    Formulation scientists are recognizing nanoengineered drug delivery systems as an effective strategy to overcome limitations associated with antibiotic drug therapy. Antibiotics encapsulated into nanodelivery systems will contribute to improved management of patients with various infectious diseases and to overcoming the serious global burden of antibiotic resistance. An extensive review of several antibiotic-loaded nanocarriers that have been formulated to target drugs to infectious sites, achieve controlled drug release profiles, and address formulation challenges, such as low-drug entrapment efficiencies, poor solubility and stability is presented in this paper. The physicochemical properties and the in vitro/in vivo performances of various antibiotic-loaded delivery systems, such as polymeric nanoparticles, micelles, dendrimers, liposomes, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanohybirds, nanofibers/scaffolds, nanosheets, nanoplexes, and nanotubes/horn/rods and nanoemulsions, are highlighted and evaluated. Future studies that will be essential to optimize formulation and commercialization of these antibiotic-loaded nanosystems are also identified. The review presented emphasizes the significant formulation progress achieved and potential that novel nanoengineered antibiotic drug delivery systems have for enhancing the treatment of patients with a range of infections.

  20. Heat transfer enhancement induced by wall inclination in turbulent thermal convection.

    Science.gov (United States)

    Kenjereš, Saša

    2015-11-01

    We present a series of numerical simulations of turbulent thermal convection of air in an intermediate range or Rayleigh numbers (10(6)≤Ra≤10(9)) with different configurations of a thermally active lower surface. The geometry of the lower surface is designed in such a way that it represents a simplified version of a mountain slope with different inclinations (i.e., "Λ"- and "V"-shaped geometry). We find that different wall inclinations significantly affect the local heat transfer by imposing local clustering of instantaneous thermal plumes along the inclination peaks. The present results reveal that significant enhancement of the integral heat transfer can be obtained (up to 32%) when compared to a standard Rayleigh-Bénard configuration with flat horizontal walls. This is achieved through combined effects of the enlargement of the heated surface and reorganization of the large-scale flow structures.

  1. Distinguishing the effects of convective and diffusive O₂ delivery on VO₂ on-kinetics in skeletal muscle contracting at moderate intensity.

    Science.gov (United States)

    Spires, Jessica; Gladden, L Bruce; Grassi, Bruno; Goodwin, Matthew L; Saidel, Gerald M; Lai, Nicola

    2013-09-01

    With current techniques, experimental measurements alone cannot characterize the effects of oxygen blood-tissue diffusion on muscle oxygen uptake (Vo₂) kinetics in contracting skeletal muscle. To complement experimental studies, a computational model is used to quantitatively distinguish the contributions of convective oxygen delivery, diffusion into cells, and oxygen utilization to Vo₂ kinetics. The model is validated using previously published experimental Vo₂ kinetics in response to slowed blood flow (Q) on-kinetics in canine muscle (τQ = 20 s, 46 s, and 64 s) [Goodwin ML, Hernández A, Lai N, Cabrera ME, Gladden LB. J Appl Physiol. 112:9-19, 2012]. Distinctive effects of permeability-surface area or diffusive conductance (PS) and Q on Vo₂ kinetics are investigated. Model simulations quantify the relationship between PS and Q, as well as the effects of diffusion associated with PS and Q dynamics on the mean response time of Vo₂. The model indicates that PS and Q are linearly related and that PS increases more with Q when convective delivery is limited by slower Q dynamics. Simulations predict that neither oxygen convective nor diffusive delivery are limiting Vo₂ kinetics in the isolated canine gastrocnemius preparation under normal spontaneous conditions during transitions from rest to moderate (submaximal) energy demand, although both operate close to the tipping point.

  2. Natural Terpenes as Penetration Enhancers for Transdermal Drug Delivery.

    Science.gov (United States)

    Chen, Jun; Jiang, Qiu-Dong; Chai, Ya-Ping; Zhang, Hui; Peng, Pei; Yang, Xi-Xiong

    2016-12-11

    The greatest hindrance for transdermal drug delivery (TDD) is the barrier property of skin, especially the stratum corneum (SC). Various methodologies have been investigated and developed to enhance the penetration of drugs through the skin. Among them, the most popular approach is the application of penetration enhancers (PEs), including natural terpenes, a very safe and effective class of PEs. In the present paper, we focused on terpenes as skin PEs for TDD. The mechanism of their action, the factors affecting their penetration enhancement effect, as well as their possible skin toxicity were discussed. Terpenes abundant in nature have great potential in the development of PEs. Compared to synthetic PEs, natural terpenes have been proved to possess higher enhancement activity. Interaction with SC intercellular lipids is the main mechanism of action for terpenes. The key factor affecting the enhancement effect is the lipophilicity of both terpenes and drug molecules. In addition, a lot of terpenes have also been proved to be much less toxic compared to azone, the classic synthetic PE. In summary, terpenes may be preferred over the chemically synthesized compounds as safe and effective PEs to promote the percutaneous absorption of drugs.

  3. A new model for analyzing laminar forced convective enhanced heat transfer in latent functionally thermal fluid

    Institute of Scientific and Technical Information of China (English)

    LU Wenqiang; BAI Fengwu

    2004-01-01

    In this paper, a new model to analyze laminar forced convective enhanced heat transfer in latent functionally thermal fluid is developed. The main characteristics of the model are: I) a new formula of the specific heat at constant pressure is used; ii) a real heat transfer process is considered; that is, heat transfer processes occur not only between working fluid and microcapsules, but also between the mixture and tube wall; iii) the new method, which combines the newly developed axisymmetrical dual reciprocity boundary element method (DRBEM) with finite difference method (FDM), is used to solve the control equations of this problem. The new model is validated by experimental data.Some new physical results on the variational characteristics of the specific heat at constant pressure with space and time during phase-change process, the time-marching history of the phase-change interfaces and so on are obtained. Several main physical factors that affect enhanced heat transfer in latent functionally thermal fluid are numerically analyzed.Some new understandings for the mechanism of enhanced heat transfer in the functionally fluid are obtained.

  4. Microneedle arrays as medical devices for enhanced transdermal drug delivery.

    Science.gov (United States)

    Garland, Martin J; Migalska, Katarzyna; Mahmood, Tuan Mazlelaa Tuan; Singh, Thakur Raghu Raj; Woolfson, A David; Donnelly, Ryan F

    2011-07-01

    In order to exploit the transdermal route for systemic delivery of a wide range of drug molecules, including peptide/protein molecules and genetic material, a means of disrupting the excellent barrier properties of the uppermost layer of the skin, the stratum corneum, must be sought. The use of microneedle (MN) arrays has been proposed as a method to temporarily disrupt the barrier function of the skin and thus enable enhanced transdermal drug delivery. MN arrays consist of a plurality of micron-sized needles, generally ranging from 25 to 2000 µm in height, of a variety of different shapes and composition (e.g., silicon, metal, sugars and biodegradable polymers). The application of such MN arrays to the skin results in the creation of aqueous channels that are orders of magnitude larger than molecular dimensions and, therefore, should readily permit the transport of macromolecules. This article will focus on recent and future developments for MN technology, focusing on the materials used for MN fabrication, the forces required for MN insertion and potential safety aspects that may be involved with the use of MN devices.

  5. Enhancing Endosomal Escape for Intracellular Delivery of Macromolecular Biologic Therapeutics.

    Science.gov (United States)

    Lönn, Peter; Kacsinta, Apollo D; Cui, Xian-Shu; Hamil, Alexander S; Kaulich, Manuel; Gogoi, Khirud; Dowdy, Steven F

    2016-09-08

    Bioactive macromolecular peptides and oligonucleotides have significant therapeutic potential. However, due to their size, they have no ability to enter the cytoplasm of cells. Peptide/Protein transduction domains (PTDs), also called cell-penetrating peptides (CPPs), can promote uptake of macromolecules via endocytosis. However, overcoming the rate-limiting step of endosomal escape into the cytoplasm remains a major challenge. Hydrophobic amino acid R groups are known to play a vital role in viral escape from endosomes. Here we utilize a real-time, quantitative live cell split-GFP fluorescence complementation phenotypic assay to systematically analyze and optimize a series of synthetic endosomal escape domains (EEDs). By conjugating EEDs to a TAT-PTD/CPP spilt-GFP peptide complementation assay, we were able to quantitatively measure endosomal escape into the cytoplasm of live cells via restoration of GFP fluorescence by intracellular molecular complementation. We found that EEDs containing two aromatic indole rings or one indole ring and two aromatic phenyl groups at a fixed distance of six polyethylene glycol (PEG) units from the TAT-PTD-cargo significantly enhanced cytoplasmic delivery in the absence of cytotoxicity. EEDs address the critical rate-limiting step of endosomal escape in delivery of macromolecular biologic peptide, protein and siRNA therapeutics into cells.

  6. Numerical Studies of Convective Mass Transfer Enhancement in a Membrane Channel by Rectangular Winglets☆

    Institute of Scientific and Technical Information of China (English)

    Jingchun Min; Bingqiang Zhang

    2014-01-01

    Numerical calculations were conducted to simulate the flow and mass transfer in narrow membrane channels with and without flow disturbers. The channel consists of an impermeable solid wall and a membrane surface with a spacing of 2.0 mm. The flow disturbers studied include rectangular winglets, which are often used as lon-gitudinal vortex generators to enhance heat transfer in heat exchanger applications, as wel as square prism, tri-angular prism, and circular cylinder, which are used here to mimic the traditional spacer filaments for comparison of their abilities in enhancing the convective mass transfer near the membrane surface to al eviate the concentration polarization. The disturber performance was evaluated in terms of concentration polarization factor versus consumed pumping power, with a larger factor meaning a more serious concentration polarization. Calculations were carried out for NaCl solution flow with Reynolds numbers ranging from 400 to 1000. The results show that the traditional flow disturbers can considerably reduce the concentration polarization but cause a substantial pressure drop, while the rectangular winglets can effectively reduce the concentration polarization with a much less pressure drop penalty. The rectangular winglets were optimized in geometry under equal pumping power condition.

  7. Nanoscale Delivery of Resveratrol towards Enhancement of Supplements and Nutraceuticals

    Science.gov (United States)

    Neves, Ana Rute; Martins, Susana; Segundo, Marcela A.; Reis, Salette

    2016-01-01

    Resveratrol was investigated in terms of its stability, biocompatibility and intestinal permeability across Caco-2 cell monolayers in its free form or encapsulated in solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). SLNs and NLCs presented a mean diameter between 160 and 190 nm, high negative zeta potential of −30 mV and resveratrol entrapment efficiency of 80%, suggesting they are suitable for resveratrol oral delivery. Nanoencapsulation effectively protected resveratrol from photodegradation, and MTT assays demonstrated that neither resveratrol nor lipid nanoparticles adversely affected cell viability and integrity of Caco-2 cell monolayers. The in vitro intestinal permeability of resveratrol was significantly increased by NLCs, and SLNs did not impair the absorption of resveratrol. Resveratrol oral absorption can be enhanced during meals, since the intestinal permeability was increased in the presence of fed-state intestinal juices. SLNs and NLCs constitute carrier systems for resveratrol oral administration, for further use as supplements or nutraceuticals. PMID:26950147

  8. Transcutaneous delivery of levodopa: enhancement by fatty acid synthesis inhibition.

    Science.gov (United States)

    Babita, Kumar; Tiwary, Ashok K

    2005-01-01

    The present investigation aimed at evaluating the role of fatty acid synthesis inhibition in enhancing transcutaneous delivery of levodopa (LD). Rat epidermis was treated with ethanol and various doses of cerulenin (an inhibitor of fatty acid synthase enzyme system) for reducing the normal level of fatty acids. Calcium chloride (0.1 mM) and/or verapamil (1 microM) were coapplied to cerulenin treated skin in order to modulate duration of epidermal perturbation. These treated skin portions were used for estimation of altered triglyceride content (an indicator of fatty acid synthesis), differential scanning calorimetry (DSC) analysis, and in vitro permeation of LD. Plasma concentration of LD was monitored in rats following topical application of various transdermal formulations. Application of cerulenin (0.1 or 0.15 mM/7 cm(2)) to viable rat skin inhibited approximately 60% triglyceride synthesis with respect to control at 2 h. Coapplication of calcium chloride (0.1 mM) significantly increased this inhibition, whereas verapamil application reduced this effect. The decrease in triglyceride content reduced the enthalpy of the lipid endothermic transition. The in vitro permeation of LD was enhanced 3-fold across skin excised after treatment with cerulenin. LD did not permeate across normal skin. The effective plasma concentration (C(eff)) of LD was achieved within 3 h and maintained till 10 h by a single topical application of a carbidopa-levodopa combination (1:4) to ethanol-perturbed cerulenin-treated skin. Coapplication of calcium chloride reduced the time lag to achieve C(eff) to 2 h and maintained it till 24 h. A single transdermal LD (64 mg) patch formulated with calcium chloride (0.1 mM) and cerulenin (0.1 mM) dissolved in a propylene glycol:ethanol (7:3) mixture seems to offer a noninvasive approach for transcutaneous delivery of levodopa.

  9. An investigation into keratinolytic enzymes to enhance ungual drug delivery.

    Science.gov (United States)

    Mohorcic, M; Torkar, A; Friedrich, J; Kristl, J; Murdan, S

    2007-03-06

    The topical therapy of nail diseases is limited by the low permeability of drugs through the nail plate. To increase drug penetration, the integrity of the nail plate must be compromised to a certain extent. We hypothesised that keratinolytic enzymes might decrease the barrier properties of the nail plate by hydrolysing the nail keratins, and thereby enhance ungual drug permeation. To determine enzyme action on nail plates, nail clippings were incubated at 35 degrees C, in the presence of keratinase at optimal pH for 48h, after which the nail plates were examined using scanning electron microscopy. It was found that the enzyme acted on the intercellular matrix which holds nail cells together, such that corneocytes on the dorsal surface separated from one another and 'lifted off' the nail plate. In addition, the surface of the corneocytes was corroded. Permeation studies using modified Franz diffusion cells and bovine hoof membranes as a model for the nail plate showed that the enzyme enhanced drug permeation through the hoof membrane. The permeability and partition coefficients, and the drug flux were found to be significantly increased in the presence of the enzyme. We can conclude that the enzyme, via its hydrolytic action on nail plate proteins, could increase ungual drug delivery.

  10. Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

    Science.gov (United States)

    Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

    2016-06-01

    The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

  11. Acoustic streaming induced by ultrasonic flexural vibrations and associated enhancement of convective heat transfer.

    Science.gov (United States)

    Loh, Byoung-Gook; Hyun, Sinjae; Ro, Paul I; Kleinstreuer, Clement

    2002-02-01

    Acoustic streaming induced by ultrasonic flexural vibrations and the associated convection enhancement are investigated. Acoustic streaming pattern, streaming velocity, and associated heat transfer characteristics are experimentally observed. Moreover, analytical analysis based on Nyborg's formulation is performed along with computational fluid dynamics (CFD) simulation using a numerical solver CFX 4.3. Two distinctive acoustic streaming patterns in half-wavelength of the flexural vibrations are observed, which agree well with the theory. However, acoustic streaming velocities obtained from CFD simulation, based on the incompressible flow assumption, exceed the theoretically estimated velocity by a factor ranging from 10 to 100, depending upon the location along the beam. Both CFD simulation and analytical analysis reveal that the acoustic streaming velocity is proportional to the square of the vibration amplitude and the wavelength of the vibrating beam that decreases with the excitation frequency. It is observed that the streaming velocity decreases with the excitation frequency. Also, with an open-ended channel, a substantial increase in streaming velocity is observed from CFD simulations. Using acoustic streaming, a temperature drop of 40 degrees C with a vibration amplitude of 25 microm at 28.4 kHz is experimentally achieved.

  12. Enhancing filling of interconnect deep trenches using forced convection magneto-electroplating

    Science.gov (United States)

    Said, R. A.

    2006-01-01

    Filling deep trenches and cavities is currently accomplished by copper electro-less plating technology utilizing super-conformal deposition methods. Unlike typical electrolyses processes, where an electric potential is applied between the anodes to activate the plating reaction, electro-less plating relies on chemical agents to activate deposition. To achieve super-conformal deposition, special electrolytic paths must be used. This poses a challenge to the fabrication of narrower trenches, and thus requires the development of other deposition schemes. This work proposes an alternative solution to the filling of deep trenches that avoids the difficulties outlined above, using a forced convection magneto-electroplating method. The technique operates as in typical electrolysis processes, however, with forcing the flow of the plating electrolyte, by hydro-dynamic means, in the presence of an externally applied magnetic field. This arrangement introduces a Lorentz type of force that enhances the transport of deposit species toward desired locations, such as deep regions in interconnect trenches. The proposed method is demonstrated by filling interconnect trenches with aspect ratio as high as 3:1. Quality of samples filled using the proposed magneto-electroplating method is compared with the quality of samples filled by typical electroplating method.

  13. Heat-transport enhancement in rotating turbulent Rayleigh-Bénard convection

    Science.gov (United States)

    Weiss, Stephan; Wei, Ping; Ahlers, Guenter

    2016-04-01

    We present new Nusselt-number (Nu) measurements for slowly rotating turbulent thermal convection in cylindrical samples with aspect ratio Γ =1.00 and provide a comprehensive correlation of all available data for that Γ . In the experiment compressed gasses (nitrogen and sulfur hexafluride) as well as the fluorocarbon C6F14 (3M Fluorinert FC72) and isopropanol were used as the convecting fluids. The data span the Prandtl-number (Pr) range 0.74 enhancement Nur ,max-1 due to rotation is about 0.02. With increasing Ra, Nur ,max-1 decreased further, and for Ra ≳2 ×109 heat-transport enhancement was no longer observed. For larger Pr the dependence of Nur on 1/Ro is qualitatively similar for all Pr. As noted before, there is a very small increase of Nur for small 1/Ro, followed by a decrease by a percent or so, before, at a critical value 1 /Roc , a sharp transition to enhancement by Ekman pumping takes place. While the data revealed no dependence of 1 /Roc on Ra, 1 /Roc decreased with increasing Pr. This dependence could be described by a power law with an exponent α ≃-0.41 . Power-law dependencies on Pr and Ra could be used to describe the slope SRo+=∂ Nur/∂ (1 /Ro ) just above 1 /Roc . The Pr and Ra exponents were β1=-0.16 ±0.08 and β2=-0.04 ±0.06 , respectively. Further increase of 1/Ro led to further increase of Nur until it reached a maximum value Nur ,max. Beyond the maximum, the Taylor-Proudman (TP) effect, which is expected to lead to reduced vertical fluid transport in the bulk region, lowered Nur. Nur ,max was largest for the largest Pr. For Pr =28.9 , for example, we measured an increase of the heat transport by up to 40% (Nur-1 =0.40 ) for the smallest Ra =2.2

  14. Enhanced azimuthal rotation of the large-scale flow through stochastic cessations in turbulent rotating convection with large Rossby numbers

    CERN Document Server

    Zhong, Jin-Qiang; Wang, Xue-ying

    2016-01-01

    We present measurements of the azimuthal orientation {\\theta}(t) and thermal amplitude {\\delta}(t) of the large-scale circulation (LSC) of turbulent rotating convection within an unprecedented large Rossby number range 170. We identify the mechanism through which the mean retrograde rotation speed can be enhanced by stochastic cessations in the presence of weak Coriolis force, and show that a low-dimensional, stochastic model provides predictions of the observed large-scale flow dynamics and interprets its retrograde rotation.

  15. Melatonin loaded ethanolic liposomes: physicochemical characterization and enhanced transdermal delivery.

    Science.gov (United States)

    Dubey, Vaibhav; Mishra, Dinesh; Jain, N K

    2007-09-01

    The current investigation aims to evaluate the transdermal potential of novel ethanolic liposomes (ethosomes) bearing Melatonin (MT), an anti-jet lag agent associated with poor skin permeation and long lag time. MT loaded ethosomes were prepared and characterized for vesicular shape and surface morphology, vesicular size, entrapment efficiency, stability, in vitro skin permeation and in vivo skin tolerability. Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), and Dynamic Light Scattering (DLS) defined ethosomes as spherical, unilamellar structures having low polydispersity (0.032+/-0.011) and nanometric size range (122+/-3.5 nm). % Entrapment efficiency of MT in ethosomal carrier was found to be 70.71+/-1.4. Stability profile of prepared system assessed for 120 days revealed very low aggregation and growth in vesicular size (7.6+/-1.2%). MT loaded ethosomal carriers also provided an enhanced transdermal flux of 59.2+/-1.22 microg/cm2/h and decreased lag time of 0.9 h across human cadaver skin. Fourier Transform-Infrared (FT-IR) data generated to assess the fluidity of skin lipids after application of formulation revealed a greater mobility of skin lipids on application of ethosomes as compared to that of ethanol or plain liposomes. Skin permeation profile of the developed formulation further assessed by confocal laser scanning microscopy (CLSM) revealed an enhanced permeation of Rhodamine Red (RR) loaded formulations to the deeper layers of the skin (240 microm). Further, a better skin tolerability of ethosomal suspension on rabbit skin suggested that ethosomes may offer a suitable approach for transdermal delivery of melatonin.

  16. Efficient production and enhanced tumor delivery of engineered extracellular vesicles.

    Science.gov (United States)

    Watson, Dionysios C; Bayik, Defne; Srivatsan, Avinash; Bergamaschi, Cristina; Valentin, Antonio; Niu, Gang; Bear, Jenifer; Monninger, Mitchell; Sun, Mei; Morales-Kastresana, Aizea; Jones, Jennifer C; Felber, Barbara K; Chen, Xiaoyuan; Gursel, Ihsan; Pavlakis, George N

    2016-10-01

    Extracellular vesicles (EV), including exosomes and microvesicles, are nano-sized intercellular communication vehicles that participate in a multitude of physiological processes. Due to their biological properties, they are also promising candidates for the systemic delivery of therapeutic compounds, such as cytokines, chemotherapeutic drugs, siRNAs and viral vectors. However, low EV production yield and rapid clearance of administered EV by liver macrophages limit their potential use as therapeutic vehicles. We have used a hollow-fiber bioreactor for the efficient production of bioactive EV bearing the heterodimeric cytokine complex Interleukin-15:Interleukin-15 receptor alpha. Bioreactor culture yielded ∼40-fold more EV per mL conditioned medium, as compared to conventional cell culture. Biophysical analysis and comparative proteomics suggested a more diverse population of EV in the bioreactor preparations, while serum protein contaminants were detectable only in conventional culture EV preparations. We also identified the Scavenger Receptor Class A family (SR-A) as a novel monocyte/macrophage uptake receptor for EV. In vivo blockade of SR-A with dextran sulfate dramatically decreased EV liver clearance in mice, while enhancing tumor accumulation. These findings facilitate development of EV therapeutic methods.

  17. Enhanced heat transfer of forced convective fin flow with transverse ribs

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Shyy Woei; Chiou, Shyr Fuu [Thermal Fluids Laboratory, National Kaohsiung Institute of Marine Technology, No. 142, Hai-Chuan Road, Nan-Tzu District, Post code 811, Kaohsiung, Taiwan (China); Su, Lo May [Department of Electrical Engineering, Tung Fang Institute of Technology, Taiwan (China); Yang, Tsun Lirng [Department of Electrical Engineering, Fortune Institute of Technology, Taiwan (China)

    2004-02-01

    This experimental study investigates the heat transfers in three side-opened and bottom-sealed rectangular channels with two opposite walls roughened by 90 staggered ribs, which simulate the enhanced cooling passages in the fin-type heat sinks of electronic chip-sets. The various degrees of interactive effects due to the surface ribs, side-profile leakage flows and stream-wise weakened coolant flow are functionally related with Reynolds number (Re) and channel length-to-gap ratio (L/B), which unravel the considerable impacts on local and spatially averaged heat transfers over the rib-roughened fin surfaces. A selection of detailed heat transfer measurements over the rib-roughened fin surfaces illustrates the manner by which the isolated and interactive influences of Re and L/B-ratio affect the local and spatially averaged heat transfers. Relative to the heat transfer results acquired from the smooth-walled test channels, the augmentations of spatially averaged heat transfers generated by the present surface ribs are in the range of 140-200% of the flat fin reference levels. In conformity with the experimentally revealed heat transfer physics, a regression-type analysis is performed to develop the correlation of spatially-averaged Nusselt number over rib-roughened fin surface, which permits the individual and interactive effect of Re and L/B on heat transfer to be evaluated. A criterion for selecting the optimal length-to-gap ratio of a fin channel, which provides the maximum convective heat flux from the rib-roughened fin surface, is formulated as an engineering tool to assist the design activity for the cooling device of electronic chip-sets. (authors)

  18. Strengthening Public Revenue and Expenditure Management to Enhance Service Delivery

    OpenAIRE

    2013-01-01

    To achieve higher growth and reduce poverty and inequality, Mexico needs to improve public service delivery. Mexico is a middle-income country with continuing high levels of poverty (46.2 percent of the population). To improve public sector service delivery, Mexico needs to ensure sufficient financial and human resources relative to the needs of the population, and effective and efficient ...

  19. Enhancements of magnetospheric convection electric field associated with sudden commencements in the inner magnetosphere and plasmasphere regions

    Science.gov (United States)

    Shinbori, A.; Ono, T.; Iizima, M.; Kumamoto, A.; Nishimura, Y.

    2006-01-01

    Electric field variations in the inner magnetosphere and plasmasphere regions associated with sudden commencements (SCs) are investigated by using the observation data of the Akebono satellite which has been carried out more than 15 years since 1989. 117 of 153 SC events in the low-latitude (MLAT bi-polar waveform due to the passage of fast-mode hydromagnetic (HM) waves. The increase of the convection electric field takes place in the entire magnetic local time sector in the inner magnetosphere. The amplitude does not depend on L-value and magnetic local time but is proportional to the SC amplitude measured at Kakioka. The majority of the electric field enhancements persist for about 4 14 min. The origin of the convection electric field in the inner magnetosphere is a plasma motion caused by the compression of the magnetosphere due to the solar wind shock and discontinuity.

  20. Nanoformulation for anticancer drug delivery: Enhanced pharmacokinetics and circulation

    Science.gov (United States)

    Parekh, Gaurav

    In this study, we have explored the application of the Layer-by-Layer (LbL) assembly technique for improving injectable drug delivery systems of low soluble anticancer drugs (e.g. Camptothecin (CPT), Paclitaxel (PTX) or Doxorubicin (DOX)). For this study, a polyelectrolyte shell encapsulates different types of drug nanocores (e.g. soft core, nanomicelle or solid lipid nanocores).The low soluble drugs tend to crystallize and precipitate in an aqueous medium. This is the reason they cannot be injected and may have low concentrations and low circulation time in the blood. Even though these drugs when present in the cancer microenvironment have high anti-tumor inhibition, the delivery to the tumor site after intravenous administration is a challenge. We have used FDA-approved biopolymers for the process and elaborated formation of 60-90 nm diameter initial cores, which was stabilized by multilayer LbL shells for controlled release and longer circulation. A washless LbL assembly process was applied as an essential advancement in nano-assembly technology using low density nanocore (lipids) and preventing aggregation. This advancement reduced the number of process steps, enhanced drug loading capacity, and prevented the loss of expensive polyelectrolytes. Finally, we elaborated a general nano-encapsulation process, which allowed these three important anticancer drug core-shell nanocapsules with diameters of ca. 100-130 nm (this small size is a record for LbL encapsulation technique) to be stable in the serum and the blood for at least one week, efficient for cancer cell culture studies, injectable to mice with circulation for 4 hrs, and effective in suppressing tumors. This work is divided into three studies. The first study (CHAPTER 4) explores the application of LbL assembly for encapsulating a soft core of albumin protein and CPT anticancer drug. In order to preserve the activity of drug in the core, a unique technique of pH reversal is employed where the first few

  1. Nanoemulsion Based Hydrogel for Enhanced Transdermal Delivery of Ketoprofen

    OpenAIRE

    2014-01-01

    The aim of the present study was to investigate the nanoemulgel as transdermal delivery system for poorly water soluble drug, ketoprofen, in order to overcome the troubles associated with its oral delivery. Different nanoemulsion components (oil, surfactant, and cosurfactant) were selected on the basis of solubility and emulsification ability. Pseudoternary phase diagrams were constructed using titration method to figure out the concentration range of components. Carbomer 940 was added as gel...

  2. Gold nanoparticles electroporation enhanced polyplex delivery to mammalian cells.

    Science.gov (United States)

    Huang, Shuyan; Deshmukh, Harshavardhan; Rajagopalan, Kartik Kumar; Wang, Shengnian

    2014-07-01

    Nonviral methods have been explored as the replacement of viral systems for their low toxicity and immunogenicity. However, they have yet to reach levels competitive to their viral counterparts. In this paper, we combined physical and chemical methods to improve the performance of polyplex delivery of DNA and small interfering RNA. Specifically, gold nanoparticles (AuNPs) were used to carry polyplex (a chemical approach) while electroporation (a physical approach) was applied for fast and direct cytosolic delivery. In this hybrid approach, cationic polymer molecules condense and/or protect genetic probes as usual while AuNPs help fix polycations to reduce their cytotoxicity and promote the transfection efficiency of electroporation. AuNPs of various sizes were first coated with polyethylenimine, which were further conjugated with DNA plasmids or small interfering RNA molecules to form AuNPs-polyplex. The hybrid nanoparticles were then mixed with cells and introduced into cell cytosol by electroporation. The delivery efficiency was evaluated with both model anchor cells (i.e., NIH/3T3) and suspension cells (i.e., K562), together with their impact on cell viability. We found that AuNP-polyplex showed 1.5∼2 folds improvement on the transfection efficiency with no significant increase of toxicity when compared to free plasmid delivery by electroporation alone. Such a combination of physical and chemical delivery concept may stimulate further exploration in the delivery of various therapeutic materials for both in vitro and in vivo applications.

  3. Indirect involvement of armorphous carbon layer on convective heat transfer enhancement using carbon nanofibers

    NARCIS (Netherlands)

    Taha, T.J.; Lefferts, L.; Meer, van der T.H.

    2015-01-01

    In this work, an experimental heat transfer investigation was carried out to investigate the combined influence of both amorphous carbon (a-C) layer thickness and carbon nanofibers (CNFs) on the convective heat transfer behavior. Synthesis of these carbon nanostructures was achieved using catalytic

  4. Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery.

    Science.gov (United States)

    Donnelly, Ryan F; Singh, Thakur Raghu Raj; Garland, Martin J; Migalska, Katarzyna; Majithiya, Rita; McCrudden, Cian M; Kole, Prashant Laxman; Mahmood, Tuan Mazlelaa Tuan; McCarthy, Helen O; Woolfson, A David

    2012-12-05

    Unique microneedle arrays prepared from crosslinked polymers, which contain no drug themselves, are described. They rapidly take up skin interstitial fluid upon skin insertion to form continuous, unblockable, hydrogel conduits from attached patch-type drug reservoirs to the dermal microcirculation. Importantly, such microneedles, which can be fabricated in a wide range of patch sizes and microneedle geometries, can be easily sterilized, resist hole closure while in place, and are removed completely intact from the skin. Delivery of macromolecules is no longer limited to what can be loaded into the microneedles themselves and transdermal drug delivery is now controlled by the crosslink density of the hydrogel system rather than the stratum corneum, while electrically modulated delivery is also a unique feature. This technology has the potential to overcome the limitations of conventional microneedle designs and greatly increase the range of the type of drug that is deliverable transdermally, with ensuing benefits for industry, healthcare providers and, ultimately, patients.

  5. Physical quantity synergy in laminar flow field of convective heat transfer and analysis of heat transfer enhancement

    Institute of Scientific and Technical Information of China (English)

    LIU Wei; LIU ZhiChun; GUO ZengYuan

    2009-01-01

    Based on the principle of field synergy for heat transfer enhancement, the concept of physical quantity synergy in the laminar flow field is proposed in the present study according to the physical mechanism of convective heat transfer between fluid and tube wall. The synergy regulation among physical quantities of fluid particle is revealed by establishing formulas reflecting the relation between synergy angles and heat transfer enhancement. The physical nature of enhancing heat transfer and reducing flow resistance, which is directly associated with synergy angles α,βγ,φ, θ and ψ, is also explained. Be-sides, the principle of synergy among physical quantities is numerically verified by the calculation of heat transfer and flow in a thin cylinder-interpolated tube, which may guide the optimum design for better heat transfer unit and high-efficiency heat exchanger.

  6. Enhancement of natural convection heat transfer from a fin by triangular perforation of bases parallel and toward its tip

    Institute of Scientific and Technical Information of China (English)

    Abdullah H. AlEssa; Mohamad I. Al-Widyan

    2008-01-01

    This study examines the heat transfer enhancement from a horizontal rect- angular fin embedded with triangular perforations (their bases parallel and toward the fin tip) under natural convection. The fin's heat dissipation rate is compared to that of an equivalent solid one. The parameters considered axe geometrical dimensions and thermal properties of the fin and the perforations. The gain in the heat transfer enhancement and the fin weight reduction due to the perforations are considered. The study shows that the heat dissipation from the perforated fin for a certain range of triangular perforation di- mensions and spaces between perforations result in improvement in the heat transfer over the equivalent solid fin. The heat transfer enhancement of the perforated fin increases as the fin thermal conductivity and its thickness are increased.

  7. NanoClusters Enhance Drug Delivery in Mechanical Ventilation

    Science.gov (United States)

    Pornputtapitak, Warangkana

    The overall goal of this thesis was to develop a dry powder delivery system for patients on mechanical ventilation. The studies were divided into two parts: the formulation development and the device design. The pulmonary system is an attractive route for drug delivery since the lungs have a large accessible surface area for treatment or drug absorption. For ventilated patients, inhaled drugs have to successfully navigate ventilator tubing and an endotracheal tube. Agglomerates of drug nanoparticles (also known as 'NanoClusters') are fine dry powder aerosols that were hypothesized to enable drug delivery through ventilator circuits. This Thesis systematically investigated formulations of NanoClusters and their aerosol performance in a conventional inhaler and a device designed for use during mechanical ventilation. These engineered powders of budesonide (NC-Bud) were delivered via a MonodoseRTM inhaler or a novel device through commercial endotracheal tubes, and analyzed by cascade impaction. NC-Bud had a higher efficiency of aerosol delivery compared to micronized stock budesonide. The delivery efficiency was independent of ventilator parameters such as inspiration patterns, inspiration volumes, and inspiration flow rates. A novel device designed to fit directly to the ventilator and endotracheal tubing connections and the MonodoseRTM inhaler showed the same efficiency of drug delivery. The new device combined with NanoCluster formulation technology, therefore, allowed convenient and efficient drug delivery through endotracheal tubes. Furthermore, itraconazole (ITZ), a triazole antifungal agent, was formulated as a NanoCluster powder via milling (top-down process) or precipitation (bottom-up process) without using any excipients. ITZ NanoClusters prepared by wet milling showed better aerosol performance compared to micronized stock ITZ and ITZ NanoClusters prepared by precipitation. ITZ NanoClusters prepared by precipitation methods also showed an amorphous state

  8. Peptide-enhanced oral delivery of therapeutic peptides and proteins

    DEFF Research Database (Denmark)

    Kristensen, Mie; Foged, Camilla; Berthelsen, Jens;

    2013-01-01

    throughout the gastrointestinal (GI) tract, chemical stability is an inherent challenge when employing amino acid-based excipients for oral delivery, and multiple approaches have been investigated to improve this. The exact mechanisms of transepithelial translocation are discussed, and it is believed......Systemic therapy upon oral delivery of biologics, such as peptide and protein drugs is limited due to their large molecular size, their low enzymatic stability and their inability to cross the intestinal epithelium. Ways to overcome the epithelial barrier include the use of peptide-based excipients...

  9. Transferosomes - A vesicular transdermal delivery system for enhanced drug permeation

    Directory of Open Access Journals (Sweden)

    Reshmy Rajan

    2011-01-01

    Full Text Available Transdermal administration of drugs is generally limited by the barrier function of the skin. Vesicular systems are one of the most controversial methods for transdermal delivery of active substances. The interest in designing transdermal delivery systems was relaunched after the discovery of elastic vesicles like transferosomes, ethosomes, cubosomes, phytosomes, etc. This paper presents the composition, mechanisms of penetration, manufacturing and characterization methods of transferosomes as transdermal delivery systems of active substances. For a drug to be absorbed and distributed into organs and tissues and eliminated from the body, it must pass through one or more biological membranes/barriers at various locations. Such a movement of drug across the membrane is called as drug transport. For the drugs to be delivered to the body, they should cross the membranous barrier. The concept of these delivery systems was designed in an attempt to concentrate the drug in the tissues of interest, while reducing the amount of drug in the remaining tissues. Hence, surrounding tissues are not affected by the drug. In addition, loss of drug does not happen due to localization of drug, leading to get maximum efficacy of the medication. Therefore, the phospholipid based carrier systems are of considerable interest in this era.

  10. Enhanced Remedial Amendment Delivery to Subsurface Using Shear Thinning Fluid and Aqueous Foam

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, Lirong; Szecsody, James E.; Oostrom, Martinus; Truex, Michael J.; Shen, Xin; Li, Xiqing

    2011-04-23

    A major issue with in situ subsurface remediation is the ability to achieve an even spatial distribution of remedial amendments to the contamination zones in an aquifer or vadose zone. Delivery of amendment to the aquifer using shear thinning fluid and to the vadose zone using aqueous foam has the potential to enhance the amendment distribution into desired locations and improve the remediation. 2-D saturated flow cell experiments were conducted to evaluate the enhanced sweeping, contaminant removal, and amendment persistence achieved by shear thinning fluid delivery. Bio-polymer xanthan gum solution was used as the shear thinning fluid. Unsaturated 1-D column and 2-D flow cell experiments were conducted to evaluate the mitigation of contaminant mobilization, amendment uniform distribution enhancement, and lateral delivery improvement by foam delivery. Surfactant sodium lauryl ether sulfate was used as the foaming agent. It was demonstrated that the shear thinning fluid injection enhanced the fluid sweeping over a heterogeneous system and increased the delivery of remedial amendment into low-permeability zones. The persistence of the amendment distributed into the low-perm zones by the shear thinning fluid was prolonged compared to that of amendment distributed by water injection. Foam delivery of amendment was shown to mitigate the mobilization of highly mobile contaminant from sediments under vadose zone conditions. Foam delivery also achieved more uniform amendment distribution in a heterogeneous unsaturated system, and demonstrated remarkable increasing in lateral distribution of the injected liquid compared to direct liquid injection.

  11. Currents and convection cause enhanced gas exchange in the ice–water boundary layer

    Directory of Open Access Journals (Sweden)

    Brice Loose

    2016-12-01

    Full Text Available The presence of sea ice acts as a physical barrier for air–sea exchange. On the other hand it creates additional turbulence due to current shear and convection during ice formation. We present results from a laboratory study that demonstrate how shear and convection in the ice–ocean boundary layer can lead to significant gas exchange. In the absence of wind, water currents beneath the ice of 0.23 m s−1 produced a gas transfer velocity (k of 2.8 m d−1, equivalent to k produced by a wind speed of 7 m s−1 over the open ocean. Convection caused by air–sea heat exchange also increased k of as much as 131 % compared to k produced by current shear alone. When wind and currents were combined, k increased, up to 7.6 m d−1, greater than k produced by wind or currents alone, but gas exchange forcing by wind produced mixed results in these experiments. As an aggregate, these experiments indicate that using a wind speed parametrisation to estimate k in the sea ice zone may underestimate k by ca. 50 % for wind speeds <8 m s−1.

  12. Nanoscale Delivery of Resveratrol towards Enhancement of Supplements and Nutraceuticals

    OpenAIRE

    Ana Rute Neves; Susana Martins; Segundo, Marcela A.; Salette Reis

    2016-01-01

    Resveratrol was investigated in terms of its stability, biocompatibility and intestinal permeability across Caco-2 cell monolayers in its free form or encapsulated in solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). SLNs and NLCs presented a mean diameter between 160 and 190 nm, high negative zeta potential of −30 mV and resveratrol entrapment efficiency of 80%, suggesting they are suitable for resveratrol oral delivery. Nanoencapsulation effectively protected resver...

  13. Round window membrane intracochlear drug delivery enhanced by induced advection.

    Science.gov (United States)

    Borkholder, David A; Zhu, Xiaoxia; Frisina, Robert D

    2014-01-28

    Delivery of therapeutic compounds to the inner ear via absorption through the round window membrane (RWM) has advantages over direct intracochlear infusions; specifically, minimizing impact upon functional hearing measures. However, previous reports show that significant basal-to-apical concentration gradients occur, with the potential to impact treatment efficacy. Here we present a new approach to inner ear drug delivery with induced advection aiding distribution of compounds throughout the inner ear in the murine cochlea. Polyimide microtubing was placed near the RWM niche through a bullaostomy into the middle ear cavity allowing directed delivery of compounds to the RWM. We hypothesized that a posterior semicircular canalostomy would induce apical flow from the patent cochlear aqueduct to the canalostomy due to influx of cerebral spinal fluid. To test this hypothesis, young adult CBA/CaJ mice were divided into two groups: bullaostomy approach only (BA) and bullaostomy+canalostomy (B+C). Cochlear function was evaluated by distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) thresholds during and after middle ear infusion of salicylate in artificial perilymph (AP), applied near the RWM. The mice recovered for 1week, and were re-tested. The results demonstrate there was no significant impact on auditory function utilizing the RWM surgical procedure with or without the canalostomy, and DPOAE thresholds were elevated reversibly during the salicylate infusion. Comparing the threshold shifts for both methods, the B+C approach had more of a physiological effect than the BA approach, including at lower frequencies representing more apical cochlear locations. Unlike mouse cochleostomies, there was no deleterious auditory functional impact after 1week recovery from surgery. The B+C approach had more drug efficacy at lower frequencies, underscoring potential benefits for more precise control of delivery of inner ear therapeutic compounds.

  14. Enhancement of therapeutic drug and DNA delivery into cells by electroporation* Enhancement of therapeutic drug and DNA delivery into cells by electroporation

    Science.gov (United States)

    Rabussay, Dietmar; Dev, Nagendu B.; Fewell, Jason; Smith, Louis C.; Widera, Georg; Zhang, Lei

    2003-02-01

    The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as `electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing `pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm-1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco

  15. Studying an effect of salt powder seeding used for precipitation enhancement from convective clouds

    Directory of Open Access Journals (Sweden)

    A. S. Drofa

    2010-08-01

    Full Text Available Experimental and theoretical studies of cloud microstructure modification with hygroscopic particles for obtaining additional precipitation amounts from convective clouds are performed. The experiment used salt powder with the particle sizes that gave the greatest effectiveness according to the simulations of Segal et al. (2004. The experiments were carried out in a cloud chamber at the conditions corresponding to the formation of convective clouds. The results have shown that the introduction of the salt powder before a cloud medium is formed in the chamber results in the formation on a "tail" of additional large drops. In this case seeding with the salt powder leads also to enlargement of the whole population of cloud drops and to a decrease of their total concentration as compared to a cloud medium that is formed on background aerosols. These results are the positive factors for stimulating coagulation processes in clouds and for subsequent formation of precipitation in them. An overseeding effect, which is characterized by increased droplet concentration and decreased droplet size, was not observed even at high salt powder concentrations.

    The results of numerical simulations have shown that the transformation of cloud drop spectra induced by the introduction of the salt powder results in more intense coagulation processes in clouds as compared to the case of cloud modification with hygroscopic particles with relatively narrow particle size distributions, and for the distribution of the South African hygroscopic flares. The calculation results obtained with a one-dimensional model of a warm convective cloud demonstrated that the effect of salt powder on clouds (total amounts of additional precipitation is significantly higher than the effect caused by the use of hygroscopic particles with narrow particle size distributions at comparable consumptions of seeding agents, or with respect to the hygroscopic flares. Here we show that

  16. 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.

  17. Enhanced rifampicin delivery to alveolar macrophages by solid lipid nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Chuan Junlan [West China School of Pharmacy, Sichuan University, Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education (China); Li Yanzhen [Tianjin Institute of Pharmaceutical Research, State Key Laboratory of Drug Delivery Technology and Pharmacokinetics (China); Yang Likai; Sun Xun [West China School of Pharmacy, Sichuan University, Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education (China); Zhang Qiang [Peking University, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences (China); Gong Tao, E-mail: gongtaoy@126.com; Zhang Zhirong, E-mail: zrzzl@vip.sina.com [West China School of Pharmacy, Sichuan University, Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education (China)

    2013-05-15

    The present study aimed at developing a drug delivery system targeting the densest site of tuberculosis infection, the alveolar macrophages (AMs). Rifampicin (RFP)-loaded solid lipid nanoparticles (RFP-SLNs) with an average size of 829.6 {+-} 16.1 nm were prepared by a modified lipid film hydration method. The cytotoxicity of RFP-SLNs to AMs and alveolar epithelial type II cells (AECs) was examined using MTT assays. The viability of AMs and AECs was above 80 % after treatment with RFP-SLNs, which showed low toxicity to both AMs and AECs. Confocal Laser Scanning Microscopy was employed to observe the interaction between RFP-SLNs and both AMs and AECs. After incubating the cells with RFP-SLNs for 2 h, the fluorescent intensity in AMs was more and remained longer (from 0.5 to 12 h) when compared with that in AECs (from 0.5 to 8 h). In vitro uptake characteristics of RFP-SLNs in AMs and AECs were also investigated by detection of intracellular RFP by High performance liquid chromatography. Results showed that RFP-SLNs delivered markedly higher RFP into AMs (691.7 ng/mg in cultured AMs, 662.6 ng/mg in primary AMs) than that into AECs (319.2 ng/mg in cultured AECs, 287.2 ng/mg in primary AECs). Subsequently, in vivo delivery efficiency and the selectivity of RFP-SLNs were further verified in Sprague-Dawley rats. Under pulmonary administration of RFP-SLNs, the amount of RFP in AMs was significantly higher than that in AECs at each time point. Our results demonstrated that solid lipid nanoparticles are a promising strategy for the delivery of rifampicin to alveolar macrophages selectively.

  18. Enhancing Oxidative Stability of Sunflower Oil during Convective and Microwave Heating Using Grape Seed Extract

    Directory of Open Access Journals (Sweden)

    Mariana-Atena Poiana

    2012-07-01

    Full Text Available This study was performed to investigate the effectiveness of grape seed extract (GSE compared to butylated hydroxytoluene (BHT on retarding lipid oxidation of sunflower oil subjected to convection and microwave heating up to 240 min under simulated frying conditions. The progress of lipid oxidation was assessed in terms of peroxide value (PV, p-anisidine value (p-AV, conjugated dienes and trienes (CD, CT, inhibition of oil oxidation (IO and TOTOX value. In addition, total phenolic content (TP was evaluated in samples before and after heating in order to assess the changes in these compounds relative to the extent of lipid oxidation. The results of this study highlight that GSE showed a significantly inhibitory effect on lipid oxidation during both treatments, although to a different extent. This ability was dose-dependent; therefore, the extent of lipid oxidation was inversely related to GSE level. Convective heating, respective microwave exposure for 240 min of samples supplemented by GSE to a level of 1000 ppm, resulted in significant decreases of investigated indices relative to the control values as follows: PV (48%; 30%, p-AV (29%; 40%, CD (45%; 30%, CT (41%; 36%, TOTOX (35%; 37%. GSE to a level of 600–800 ppm inhibited the lipid oxidation in a similar manner to BHT. These results suggested that GSE can be used as a potential natural extract for improving oxidative stability of sunflower oil during thermal applications.

  19. Enhancing oxidative stability of sunflower oil during convective and microwave heating using grape seed extract.

    Science.gov (United States)

    Poiana, Mariana-Atena

    2012-01-01

    This study was performed to investigate the effectiveness of grape seed extract (GSE) compared to butylated hydroxytoluene (BHT) on retarding lipid oxidation of sunflower oil subjected to convection and microwave heating up to 240 min under simulated frying conditions. The progress of lipid oxidation was assessed in terms of peroxide value (PV), p-anisidine value (p-AV), conjugated dienes and trienes (CD, CT), inhibition of oil oxidation (IO) and TOTOX value. In addition, total phenolic content (TP) was evaluated in samples before and after heating in order to assess the changes in these compounds relative to the extent of lipid oxidation. The results of this study highlight that GSE showed a significantly inhibitory effect on lipid oxidation during both treatments, although to a different extent. This ability was dose-dependent; therefore, the extent of lipid oxidation was inversely related to GSE level. Convective heating, respective microwave exposure for 240 min of samples supplemented by GSE to a level of 1000 ppm, resulted in significant decreases of investigated indices relative to the control values as follows: PV (48%; 30%), p-AV (29%; 40%), CD (45%; 30%), CT (41%; 36%), TOTOX (35%; 37%). GSE to a level of 600-800 ppm inhibited the lipid oxidation in a similar manner to BHT. These results suggested that GSE can be used as a potential natural extract for improving oxidative stability of sunflower oil during thermal applications.

  20. The experimental evaluation and molecular dynamics simulation of a heat-enhanced transdermal delivery system.

    Science.gov (United States)

    Otto, Daniel P; de Villiers, Melgardt M

    2013-03-01

    Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.

  1. Fluvastatin as a micropore lifetime enhancer for sustained delivery across microneedle-treated skin.

    Science.gov (United States)

    Ghosh, Priyanka; Brogden, Nicole K; Stinchcomb, Audra L

    2014-02-01

    Microneedles (MNs), a physical skin permeation enhancement technique, facilitate drug delivery across the skin, thus enhancing the number of drugs that can be delivered transdermally in therapeutically relevant concentrations. The micropores created in the skin by MNs reseal because of normal healing processes of the skin, thus limiting the duration of the drug delivery window. Pore lifetime enhancement strategies can increase the effectiveness of MNs as a drug delivery mechanism by prolonging the delivery window. Fluvastatin (FLU), a HMGCoA reductase inhibitor, was used in this study to enhance the pore lifetime by inhibiting the synthesis of cholesterol, a major component of the stratum corneum lipids. The study showed that using FLU as a pretreatment it is possible to enhance the pore lifetime of MN-treated skin and thus allow for sustained drug delivery. The skin recovered within a 30-45-min time period following the removal of occlusion, and there was no significant irritation observed due to the treatment compared to the control sites. Thus, it can be concluded that localized skin treatment with FLU can be used to extend micropore lifetime and deliver drugs for up to 7 days across MN-treated skin.

  2. Nanoemulsion Based Hydrogel for Enhanced Transdermal Delivery of Ketoprofen

    Directory of Open Access Journals (Sweden)

    Ritika Arora

    2014-01-01

    Full Text Available The aim of the present study was to investigate the nanoemulgel as transdermal delivery system for poorly water soluble drug, ketoprofen, in order to overcome the troubles associated with its oral delivery. Different nanoemulsion components (oil, surfactant, and cosurfactant were selected on the basis of solubility and emulsification ability. Pseudoternary phase diagrams were constructed using titration method to figure out the concentration range of components. Carbomer 940 was added as gel matrix to convert nanoemulsion into nanoemulgel. Drug loaded nanoemulsions and nanoemulgels were characterized for particle size, TEM, viscosity, conductivity, spreadability, rheological behavior, and permeation studies using Wistar rat skin and stability studies. Transdermal permeation of ketoprofen from nanoemulgels was determined by using Franz diffusion cell. Nanoemulgel containing 6% oleic acid as oil, 35% Tween 80, and Transcutol P as surfactant cosurfactant mixture, 56.5% water, 2.5% drug, and 0.6% carbomer was concluded as optimized formulation (NG6. The ex vivo permeation profile of optimized formulation was compared with nanoemulsion and marketed formulation (Fastum. Nanoemulgel showed significantly higher (P<0.05 cumulative amount of drug permeated and flux along with lower lag time and skin retention than marketed formulation. Thus, the study substantiated that nanoemulgel formulation can be used as a feasible alternative to conventional formulations of ketoprofen with advanced permeation characteristics for transdermal application.

  3. TranScreen-N: Method for rapid screening of trans-ungual drug delivery enhancers.

    Science.gov (United States)

    Murthy, S Narasimha; Vaka, Siva Ram Kiran; Sammeta, Srinivasa Murthy; Nair, Anroop B

    2009-11-01

    Topical monotherapy of nail diseases such as onychomycosis and nail psoriasis has been less successful due to poor permeability of the human nail plate to topically administered drugs. Chemical enhancers are utilized to improve the drug delivery across the nail plate. Choosing the most effective chemical enhancers for the given drug and formulation is highly critical in determining the efficacy of topical therapy of nail diseases. Screening the large pool of enhancers using currently followed diffusion cell experiments would be tedious and expensive. The main objective of this study is to develop TranScreen-N, a high throughput method of screening trans-ungual drug permeation enhancers. It is a rapid microwell plate based method which involves two different treatment procedures; the simultaneous exposure treatment and the sequential exposure treatment. In the present study, several chemicals were evaluated by TranScreen-N and by diffusion studies in the Franz diffusion cell (FDC). Good agreement of in vitro drug delivery data with TranScreen-N data provided validity to the screening technique. In TranScreen-N technique, the enhancers can be grouped according to whether they need to be applied before or simultaneously with drugs (or by either procedures) to enhance the drug delivery across the nail plate. TranScreen-N technique can significantly reduce the cost and duration required to screen trans-ungual drug delivery enhancers. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association

  4. SOFT MALLEABLE VESICLES TAILORED FOR ENHANCED DELIVERY OF ACTIVE AGENTS THROUGH THE SKIN: AN UPDATE

    OpenAIRE

    Sandeep Kumar Parihar*, Mithun Bhowmick, Rajeev Kumar and Balkrishna Dubey

    2013-01-01

    Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. These are soft, malleable vesicles tailored for enhanced delivery of active agents. They are composed mainly of phospholipids, high concentration of ethanol and water. The high concentration of ethanol makes the ethosomes unique, as ethanol is known for its disturbance of skin lipid bilayer organization; therefore, when integrated into ...

  5. Cell-penetrating peptides as tools to enhance non-injectable delivery of biopharmaceuticals

    DEFF Research Database (Denmark)

    Kristensen, Mie; Nielsen, Hanne Mørck

    2016-01-01

    Non-injectable delivery of peptide and protein drugs is hampered by their labile nature, hydrophilicity, and large molecular size; thus limiting their permeation across mucosae, which represent major biochemical and physical barriers to drugs administered via e.g. the oral, nasal, and pulmonary...... routes. However, in recent years cell-penetrating peptides (CPP) have emerged as promising tools to enhance mucosal delivery of co-administered or conjugated peptide and protein cargo and more advanced CPP-cargo formulations are emerging. CPPs act as transepithelial delivery vectors, but the mechanism...

  6. Enhanced transdermal delivery of salbutamol sulfate via ethosomes.

    Science.gov (United States)

    Bendas, Ehab R; Tadros, Mina I

    2007-12-14

    The main objective of the present work was to compare the transdermal delivery of salbutamol sulfate (SS), a hydrophilic drug used as a bronchodilator, from ethosomes and classic liposomes containing different cholesterol and dicetylphosphate concentrations. All the systems were characterized for shape, particle size, and entrapment efficiency percentage, by image analysis optical microscopy or transmission electron microscopy, laser diffraction, and ultracentrifugation, respectively. In vitro drug permeation via a synthetic semipermeable membrane or skin from newborn mice was studied in Franz diffusion cells. The selected systems were incorporated into Pluronic F 127 gels and evaluated for both drug permeation and mice skin deposition. In all systems, the presence of spherical-shaped vesicles was predominant. The vesicle size was significantly decreased (P ethosomal systems were much more efficient at delivering SS into mice skin (in terms of quantity and depth) than were liposomes or aqueous or hydroalcoholic solutions.

  7. Enhanced dermal delivery of acyclovir using solid lipid nanoparticles.

    Science.gov (United States)

    Jain, Sanyog; Mistry, Meghal A; Swarnakar, Nitin K

    2011-10-01

    The present investigation was enthused by the possibility to develop solid lipid nanoparticles (SLNs) of hydrophilic drug acyclovir (ACV) and evaluate their potential as the carrier for dermal delivery. ACV-loaded SLNs (ACV-SLNs) were prepared by the optimized double emulsion process using Compritol 888 ATO as solid lipid. The prepared SLNs were smooth and spherical in shape with average diameter, polydispersity index, and entrapment efficiency of 262 ± 13 nm, 0.280 ± 0.01, and 40.08 ± 4.39% at 10% (w/w) theoretical drug loading with respect to Compritol 888 ATO content. Differential scanning calorimetry and powder X-ray diffraction pattern revealed that ACV was present in the amorphous state inside the SLNs. In vitro skin permeation studies on human cadaver and Sprague-Dawley rat skin revealed 17.65 and 15.17 times higher accumulation of ACV-SLNs in the dermal tissues in comparison to commercially available ACV cream after 24 h. Mechanism of topical permeation and dermal distribution was studied qualitatively using confocal laser scanning microscopy. While free dye (calcein) failed to penetrate skin barrier, the same encapsulated in SLNs penetrated deeply into the dermal tissue suggesting that pilosebaceous route was followed by SLNs for skin penetration. Histological examination and transdermal epidermal water loss measurement suggested that no major morphological changes occurred on rat skin surface due to the application of SLNs. Overall, it was concluded that ACV-loaded SLNs might be beneficial in improving dermal delivery of antiviral agent(s) for the treatment of topical herpes simplex infection.

  8. The pretreatment effect of chemical skin penetration enhancers in transdermal drug delivery using iontophoresis.

    Science.gov (United States)

    Choi, E H; Lee, S H; Ahn, S K; Hwang, S M

    1999-01-01

    The transdermal drug delivery (TDD) system has largely been divided into physical, biochemical and chemical methods. Recently, combinations of these methods were introduced for more effective delivery with less side effects. We performed this study to identify the effectiveness and mechanism of TDD using the physical method, 'iontophoresis', plus the chemical method, 'pretreatment with chemical enhancer'. The action sites of chemical enhancers in the stratum corneum (SC) were observed by electron microscope. We also studied whether this combined method synergistically impaired the skin barrier. To confirm the synergistic effect on skin penetration by this combined method, we measured the blood glucose level after insulin iontophoresis following a chemical enhancer pretreatment in rabbits. The results were that (1) dilatation of the intercellular lipid layers of the SC and lacunae was prominent in pretreatment with chemical enhancers inducing high transepidermal water loss (TEWL); (2) the skin barrier impairment, with repeated treatments showing an increased TEWL and also epidermal proliferation, was increased with the chemical enhancers that showed a high TEWL immediately after treatment; (3) the combination of chemical enhancer pretreatment and iontophoresis showed no synergistic impairment of the skin barrier, and (4) the chemical enhancer pretreatment with greater impairment of the skin barrier could increase the delivery of insulin by iontophoresis. The results showed that a combination of chemical enhancer pretreatment and iontophoresis could deliver drugs more effectively than iontophoresis alone. Our proposed theory is that iontophoretic drug delivery may be easier through the dilated intercellular spaces of the SC which have a lower electrical impedance following the chemical enhancer pretreatment. Because the effect and the side effects in the combination are decided by the chemical enhancer rather than iontophoresis, the development of proper chemical

  9. Reactive Transport Modeling of the Enhancement of Density-Driven CO2 Convective Mixing in Carbonate Aquifers and its Potential Implication on Geological Carbon Sequestration.

    Science.gov (United States)

    Islam, Akand; Sun, Alexander Y; Yang, Changbing

    2016-01-01

    We study the convection and mixing of CO2 in a brine aquifer, where the spread of dissolved CO2 is enhanced because of geochemical reactions with the host formations (calcite and dolomite), in addition to the extensively studied, buoyancy-driven mixing. The nonlinear convection is investigated under the assumptions of instantaneous chemical equilibrium, and that the dissipation of carbonate rocks solely depends on flow and transport and chemical speciation depends only on the equilibrium thermodynamics of the chemical system. The extent of convection is quantified in term of the CO2 saturation volume of the storage formation. Our results suggest that the density increase of resident species causes significant enhancement in CO2 dissolution, although no significant porosity and permeability alterations are observed. Early saturation of the reservoir can have negative impact on CO2 sequestration.

  10. Enhancing Curriculum and Delivery: Linking Assessment to Learning Objectives

    Science.gov (United States)

    Combs, Kathryn L.; Gibson, Sharon K.; Hays, Julie M.; Saly, Jane; Wendt, John T.

    2008-01-01

    Typical university-wide course evaluations do not provide instructors with sufficient information on the effectiveness of their courses. This article describes a course assessment and enhancement model where student feedback can be used to improve courses and/or programs. The model employs an assessment tool that measures student perceptions of…

  11. Active enhancement methods for intra- and transdermal drug delivery: a review

    Directory of Open Access Journals (Sweden)

    Barbara Zorec

    2013-05-01

    Full Text Available Transdermal route has some advantages over other drug administration routes. These include avoidance of first pass effect (hepatic metabolism, better pharmacokinetic profile, reduction of side effects and good patient compliance. The greatest obstacle for the drugs to be delivered through the skin is overcoming the impermeable outermost layer of the skin – the stratum corneum. Quite a few enhancement techniques can be used to overcome the stratum corneum barrier and facilitate transdermal drug delivery. These include various passive (penetration enhancers, liposomes and active approaches (electroporation, iontophoresis, microneedles, which are of prime interest for transdermal drug delivery research area.

  12. CFD study of forced convective heat transfer enhancement in a 90° bend duct of square cross section using nanofluid

    Indian Academy of Sciences (India)

    ASHOK K BARIK; PRASANTA K SATAPATHY; SUDHANSU S SAHOO

    2016-07-01

    In this paper, the forced convective heat transfer enhancement with nanofluids in a 90° pipe bend has been presented. Numerical investigation is carried out for the turbulent flow through the pipe employing finite volume method. The governing differential equations are discretized using hexahedral cells, and theresulting algebraic equations are solved using Commercial solver Fluent 6.3. In order to close the time averaged Navier–Stokes equations, the two-equation k–e turbulence model with a standard wall function have been used.The duct Reynolds number is varied in the range of 2,500–6,000. It is observed that the heat transfer is enhanced significantly by varying the volume fraction of the nanofluid. It is also found that the heat transfer is increased with Reynolds number. A strong secondary flow is observed due to the presence of the wall. Turbulent kinetic energy near outer wall is found to be higher than the inner wall of the bend. A comparative assessment for the heat transfer enhancement with different types of nanofluids is also presented. The computed results of areaweighted average Nusselt numbers are validated with some of the existing literature

  13. Magnetically enhanced adeno-associated viral vector delivery for human neural stem cell infection.

    Science.gov (United States)

    Kim, Eunmi; Oh, Ji-Seon; Ahn, Ik-Sung; Park, Kook In; Jang, Jae-Hyung

    2011-11-01

    Gene therapy technology is a powerful tool to elucidate the molecular cues that precisely regulate stem cell fates, but developing safe vehicles or mechanisms that are capable of delivering genes to stem cells with high efficiency remains a challenge. In this study, we developed a magnetically guided adeno-associated virus (AAV) delivery system for gene delivery to human neural stem cells (hNSCs). Magnetically guided AAV delivery resulted in rapid accumulation of vectors on target cells followed by forced penetration of the vectors across the plasma membrane, ultimately leading to fast and efficient cellular transduction. To combine AAV vectors with the magnetically guided delivery, AAV was genetically modified to display hexa-histidine (6xHis) on the physically exposed loop of the AAV2 capsid (6xHis AAV), which interacted with nickel ions chelated on NTA-biotin conjugated to streptavidin-coated superparamagnetic iron oxide nanoparticles (NiStNPs). NiStNP-mediated 6xHis AAV delivery under magnetic fields led to significantly enhanced cellular transduction in a non-permissive cell type (i.e., hNSCs). In addition, this delivery method reduced the viral exposure times required to induce a high level of transduction by as much as to 2-10 min of hNSC infection, thus demonstrating the great potential of magnetically guided AAV delivery for numerous gene therapy and stem cell applications.

  14. Colon-targeted quercetin delivery using natural polymer to enhance its bioavailability.

    Science.gov (United States)

    Singhal, Anil; Jain, H; Singhal, Vipin; Elias, Edwin J; Showkat, Ahmad

    2011-01-01

    The aim of the present study is to develop a polymer (Guar Gum)-based matrix tablet (using quercetin as a model drug) with sufficient mechanical strength, and promising in vitro mouth-to-colon release profile. By definition, an oral colonic delivery system should retard drug release in the stomach and small intestine, and allow complete release in the colon. By drug delivery to the colon would therefore ensure direct treatment at the disease site, lower dosing, and fewer systemic side effects. Quercetin is antioxidant in nature and used to treat colon cancer, but they have poor absorption in the upper part of the gastrointestinal tract (GIT). As a site for drug delivery, the colon offers a near neutral pH, reduced digestive enzymatic activity, a long transit time, and an increased responsiveness to absorption enhancers. By achieving a colon-targeted drug delivery system, the absorption of quercetin may be increased, which leads to better bioactivity in fewer doses.

  15. Convective heat transfer enhancement of laminar flow of latent functionally thermal fluid in a circular tube with constant heat flux: internal heat source model and its application

    Institute of Scientific and Technical Information of China (English)

    张寅平; 胡先旭; 郝磬; 王馨

    2003-01-01

    This paper analyzes the convective heat transfer enhancement mechanism of latent heat functionally thermal fluid. By using the proposed internal heat source model, the influence of each factor affecting the heat transfer enhancement of laminar flow in a circular tube with constant heat flux is analyzed. The main influencing factors and the mechanisms of heat transfer enhancement are clarified, and the influences of the main factors on the heat transfer enhancement are quantitatively analyzed. A modified Nusselt number for internal flow is introduced to describe more effectively the degree of heat transfer enhancement for latent functionally thermal fluid.

  16. Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting

    Directory of Open Access Journals (Sweden)

    Brian C. Palmer

    2016-12-01

    Full Text Available Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

  17. SOFT MALLEABLE VESICLES TAILORED FOR ENHANCED DELIVERY OF ACTIVE AGENTS THROUGH THE SKIN: AN UPDATE

    Directory of Open Access Journals (Sweden)

    Sandeep Kumar Parihar*, Mithun Bhowmick, Rajeev Kumar and Balkrishna Dubey

    2013-01-01

    Full Text Available Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. These are soft, malleable vesicles tailored for enhanced delivery of active agents. They are composed mainly of phospholipids, high concentration of ethanol and water. The high concentration of ethanol makes the ethosomes unique, as ethanol is known for its disturbance of skin lipid bilayer organization; therefore, when integrated into a vesicle membrane, it gives that vesicle the ability to penetrate the stratum corneum. Also, because of their high ethanol concentration, the lipid membrane is packed less tightly than conventional vesicles but has equivalent stability, allowing a more malleable structure and improves drug distribution ability in stratum corneum lipids. The Ethosomes were found to be suitable for various applications within the pharmaceutical, biotechnology, veterinary, cosmetic, and nutraceutical markets. These “soft vesicles” represents novel vesicular carrier for enhanced delivery to/through skin.

  18. A steerable/distance enhanced penetrometer delivery system: Phase II. Topical report

    Energy Technology Data Exchange (ETDEWEB)

    Amini, A.; Shenhar, J.; Lum, K.D.

    1996-05-01

    This report summarizes the phase II work on the Position Location Device (POLO) for penetrometers. Phase II was carried out to generate an integrated design of a full-scale steerable/distance enhanced penetrometer delivery system. Steering provides for the controlled and directional use of the penetrometer, while vibratory thrusting can provide greater penetration ability.

  19. Enhancement of convective drying by application of airborne ultrasound - a response surface approach.

    Science.gov (United States)

    Beck, Svenja M; Sabarez, Henry; Gaukel, Volker; Knoerzer, Kai

    2014-11-01

    Drying is one of the oldest and most commonly used processes in the food manufacturing industry. The conventional way of drying is by forced convection at elevated temperatures. However, this process step often requires a very long treatment time, is highly energy consuming and detrimental to the product quality. Therefore, an investigation of whether the drying time and temperature can be reduced with the assistance of an airborne ultrasound intervention is of interest. Previous studies have shown that contact ultrasound can accelerate the drying process. It is assumed that mechanical vibrations, creating micro channels in the food matrix or keeping these channels from collapsing upon drying, are responsible for the faster water removal. In food samples, due to their natural origin, drying is also influenced by fluctuations in tissue structure, varying between different trials. For this reason, a model food system with thermo-physical properties and composition (water, cellulose, starch, fructose) similar to those of plant-based foods has been used in this study. The main objective was, therefore, to investigate the influence of airborne ultrasound conditions on the drying behaviour of the model food. The impact of airborne ultrasound at various power levels, drying temperature, relative humidity of the drying air, and the air speed was analysed. To examine possible interactions between these parameters, the experiments were designed with a Response Surface Method using Minitab 16 Statistical Software (Minitab Inc., State College, PA, USA). In addition, a first attempt at improving the process conditions and performance for better suitability and applicability in industrial scale processing was undertaken by non-continuous/intermittent sonication.

  20. Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil.

    Science.gov (United States)

    Mura, Simona; Manconi, Maria; Sinico, Chiara; Valenti, Donatella; Fadda, Anna Maria

    2009-10-01

    The aim of this work was to evaluate the ability of a few different penetration enhancers to produce elastic vesicles with soy lecithin and the influence of the obtained vesicles on in vitro (trans)dermal delivery of minoxidil. To this purpose, so-called Penetration Enhancer-containing Vesicles (PEVs) were prepared as dehydrated-rehydrated vesicles by using soy lecithin and different amounts of three penetration enhancers, 2-(2-ethoxyethoxy)ethanol (Transcutol), capryl-caproyl macrogol 8-glyceride (Labrasol), and cineole. Soy lecithin liposomes, without penetration enhancers, were used as control. Prepared formulations were characterized in terms of size distribution, morphology, zeta potential, and vesicle deformability. The influence of PEVs on (trans)dermal delivery of minoxidil was studied by in vitro diffusion experiments through newborn pig skin in comparison with traditional liposomes and ethanolic solutions of the drug also containing each penetration enhancer. A skin pre-treatment study using empty PEVs and conventional liposomes was also carried out. Results showed that all the used penetration enhancers were able to give more deformable vesicles than conventional liposomes with a good drug entrapment efficiency and stability. In vitro skin penetration data showed that PEVs were able to give a statistically significant improvement of minoxidil deposition in the skin in comparison with classic liposomes and penetration enhancer-containing drug ethanolic solutions without any transdermal delivery. Moreover, the most deformable PEVs, prepared with Labrasol and cineole, were also able to deliver to the skin a higher total amount of minoxidil than the PE alcoholic solutions thus suggesting that minoxidil delivery to the skin was strictly correlated to vesicle deformability, and therefore to vesicle composition.

  1. Ultrasound-enhanced drug delivery in prostate cancer xenografts by nanoparticles stabilizing microbubbles.

    Science.gov (United States)

    Eggen, Siv; Fagerland, Stein-Martin; Mørch, Ýrr; Hansen, Rune; Søvik, Kishia; Berg, Sigrid; Furu, Håkon; Bøhn, Audun Dybvik; Lilledahl, Magnus B; Angelsen, Anders; Angelsen, Bjørn; de Lange Davies, Catharina

    2014-08-10

    The delivery of nanoparticles to solid tumors is often ineffective due to the lack of specificity towards tumor tissue, limited transportation of the nanoparticles across the vascular wall and poor penetration through the extracellular matrix of the tumor. Ultrasound is a promising tool that can potentially improve several of the transportation steps, and the interaction between sound waves and microbubbles generates biological effects that can be beneficial for the successful delivery of nanocarriers and their contents. In this study, a novel platform consisting of nanoparticle-stabilized microbubbles has been investigated for its potential for ultrasound-enhanced delivery to tumor xenografts. Confocal laser scanning microscopy was used to study the supply of nanoparticles from the vasculature and to evaluate the effect of different ultrasound parameters at a microscopic level. The results demonstrated that although the delivery is heterogeneous within tumors, there is a significant improvement in the delivery and the microscopic distribution of both nanoparticles and a released model drug when the nanoparticles are combined with microbubbles and ultrasound. The mechanisms that underlie the improved delivery are discussed.

  2. Towards convective heat transfer enhancement: surface modification, characterization and measurement techniques

    NARCIS (Netherlands)

    Taha, T.J.; Thakur, D.B.; van der Meer, Theodorus H.

    2012-01-01

    In this work, heat transfer surface modification and heat transfer measurement technique is developed. Heat transfer investigation was aimed to study the effect of carbon nano fibers (extremely high thermal conductive material) on the enhancement level in heat transfer. Synthesis of these carbon nan

  3. Towards convective heat transfer enhancement: surface modification, characterization and measurement techniques

    NARCIS (Netherlands)

    Taha, T.J.; Thakur, D.B.; Meer, van der T.H.

    2012-01-01

    In this work, heat transfer surface modification and heat transfer measurement technique is developed. Heat transfer investigation was aimed to study the effect of carbon nano fibers (extremely high thermal conductive material) on the enhancement level in heat transfer. Synthesis of these carbon nan

  4. Lipid Nanocapsule-Based Gels for Enhancement of Transdermal Delivery of Ketorolac Tromethamine

    Directory of Open Access Journals (Sweden)

    Jaleh Varshosaz

    2011-01-01

    Full Text Available Previous reports show ineffective transdermal delivery of ketorolac by nanostructured lipid carriers (NLCs. The aim of the present work was enhancement of transdermal delivery of ketorolac by another colloidal carriers, lipid nanocapsules (LNCs. LNCs were prepared by emulsification with phase transition method and mixed in a Carbomer 934P gel base with oleic acid or propylene glycol as penetration enhancers. Permeation studies were performed by Franz diffusion cell using excised rat abdominal skin. Aerosil-induced rat paw edema model was used to investigate the in vivo performance. LNCs containing polyethylene glycol hydroxyl stearate, lecithin in Labrafac as the oily phase, and dilution of the primary emulsion with 3.5-fold volume of cold water produced the optimized nanoparticles. The 1% Carbomer gel base containing 10% oleic acid loaded with nanoparticles enhanced and prolonged the anti-inflammatory effects of this drug to more than 12 h in Aerosil-induced rat paw edema model.

  5. De Novo Design of Skin-Penetrating Peptides for Enhanced Transdermal Delivery of Peptide Drugs.

    Science.gov (United States)

    Menegatti, Stefano; Zakrewsky, Michael; Kumar, Sunny; De Oliveira, Joshua Sanchez; Muraski, John A; Mitragotri, Samir

    2016-03-09

    Skin-penetrating peptides (SPPs) are attracting increasing attention as a non-invasive strategy for transdermal delivery of therapeutics. The identification of SPP sequences, however, currently performed by experimental screening of peptide libraries, is very laborious. Recent studies have shown that, to be effective enhancers, SPPs must possess affinity for both skin keratin and the drug of interest. We therefore developed a computational process for generating and screening virtual libraries of disulfide-cyclic peptides against keratin and cyclosporine A (CsA) to identify SPPs capable of enhancing transdermal CsA delivery. The selected sequences were experimentally tested and found to bind both CsA and keratin, as determined by mass spectrometry and affinity chromatography, and enhance transdermal permeation of CsA. Four heptameric sequences that emerged as leading candidates (ACSATLQHSCG, ACSLTVNWNCG, ACTSTGRNACG, and ACSASTNHNCG) were tested and yielded CsA permeation on par with previously identified SPP SPACE (TM) . An octameric peptide (ACNAHQARSTCG) yielded significantly higher delivery of CsA compared to heptameric SPPs. The safety profile of the selected sequences was also validated by incubation with skin keratinocytes. This method thus represents an effective procedure for the de novo design of skin-penetrating peptides for the delivery of desired therapeutic or cosmetic agents.

  6. Convective Heat Transfer Enhancement of a Rectangular Flat Plate by an Impinging Jet in Cross Flow

    Institute of Scientific and Technical Information of China (English)

    李国能; 郑友取; 胡桂林; 张治国

    2014-01-01

    Experiments were carried out to study the heat transfer performance of an impinging jet in a cross flow. Several parameters including the jet-to-cross-flow mass ratio (X=2%-8%), the Reynolds number (Red=1434-5735) and the jet diameter (d=2-4 mm) were explored. The heat transfer enhancement factor was found to increase with the jet-to-cross-flow mass ratio and the Reynolds number, but decrease with the jet diameter when other parameters maintain fixed. The presence of a cross flow was observed to degrade the heat transfer performance in respect to the effect of impinging jet to the target surface only. In addition, an impinging jet was confirmed to be capable of en-hancing the heat transfer process in considerable amplitude even though the jet was not designed to impinge on the target surface.

  7. Convective heat transfer characters of nanoparticle enhanced latent functionally thermal fluid

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The latent heat of the microencapsulated phase change material(MPCM)increases the effective ther-mal capacity of latent functionally thermal fluid.However,researchers found that the heat transfer performance of such fluids was diminished due to the reduction of the low thermal conductivity of MPCM.For this reason,the nanoparticle enhanced latent functionally thermal fluids were formulated and the heat transfer behaviors of these fluids in a vertical circular tube at the laminar regime were conducted.The result showed that slurries containing 0.5% TiO2 nanoparticles by mass and 5%―20% MPCM by mass exhibited improved heat transfer rates in comparison with the conventional latent functionally thermal fluid and that the enhancement increased with the increasing MPCM concentration and up to 18.9% of the dimensionless wall temperature was reduced.

  8. Convective heat transfer characters of nanoparticle enhanced latent functionally thermal fluid

    Institute of Scientific and Technical Information of China (English)

    WANG Liang; LIN GuiPing; CHEN HaiSheng; DING YuLong

    2009-01-01

    The latent heat of the microencapsulated phase change material (MPCM) increases the effective ther-mal capacity of latent functionally thermal fluid. However, researchers found that the heat transfer performance of such fluids was diminished due to the reduction of the low thermal conductivity of MPCM. For this reason, the nanoparticle enhanced latent functionally thermal fluids were formulated and the heat transfer behaviors of these fluids in a vertical circular tube at the laminar regime were conducted. The result showed that slurries containing 0.5% TiO2 nanoparticles by mass and 5%-20% MPCM by mass exhibited improved heat transfer rates in comparison with the conventional latent functionally thermal fluid and that the enhancement increased with the increasing MPCM concentration and up to 18.9% of the dimensionless wall temperature was reduced.

  9. Towards convective heat transfer enhancement: surface modification, characterization and measurement techniques

    Science.gov (United States)

    Taha, T. J.; Thakur, D. B.; Van der Meer, T. H.

    2012-11-01

    In this work, heat transfer surface modification and heat transfer measurement technique is developed. Heat transfer investigation was aimed to study the effect of carbon nano fibers (extremely high thermal conductive material) on the enhancement level in heat transfer. Synthesis of these carbon nano structures is achieved using thermal catalytic chemical vapor deposition process (TCCVD) on a 50 μm pure nickel (Ni270) wire. The micro wire samples covered with CNF layers were subjected to a uniform flow from a nozzle. Heat transfer measurement was achieved by a controlled heat dissipation through the micro wire to attain a constant temperature during the flow. This measurement technique is adopted from hot wire anemometry calibration method. Synthesis of carbon nano structures, heat transfer surface characterization and measurement technique are evaluated. Preliminary results indicate that an average enhancement in Nusselt Number of 17% is achieved.

  10. Towards magnetic-enhanced cellular uptake, MRI and chemotherapeutics delivery by magnetic mesoporous silica nanoparticles.

    Science.gov (United States)

    Liu, Qian; Zhang, Jixi; Xia, Weiliang; Gu, Hongchen

    2012-10-01

    A type of nanoparticle with three functional modalities was prepared with the aim of providing a multifunctional drug delivery system. The nanoparticle was 50 nm in size, with 2.7 nm mesopores and a magnetic nanocrystal core, which was further doped with FITC to enable the tracking of cellular uptake. We demonstrated that the internalization of the nanoparticles in tumor cells could be enhanced by applying an external magnetic field and furthermore, this kind of nanoparticle could be used in magnetic targeted drug delivery. With high transverse relaxivity, the magnetic nanoparticles shortened proton relaxation time and induced high magnetic resonance imaging contrast in tumor cells. Studies on anticancer drug loading and delivery capacity of anticancer drugs also showed that this type of nanoparticles could load water-soluble doxorubicin, and produce a prominent inhibitive effect against tumor cells. Taken together, the presented nanoparticles could become a promising agent in cancer theranostics.

  11. Nanodiamond-DGEA peptide conjugates for enhanced delivery of doxorubicin to prostate cancer

    Directory of Open Access Journals (Sweden)

    Amanee D Salaam

    2014-07-01

    Full Text Available The field of nanomedicine has emerged as an approach to enhance the specificity and efficacy of cancer treatments as stand-alone therapies and in combination with standard chemotherapeutic treatment regimens. The current standard of care for metastatic cancer, doxorubicin (DOX, is presented with challenges, namely toxicity due to a lack of specificity and targeted delivery. Nano-enabled targeted drug delivery systems can provide an avenue to overcome these issues. Nanodiamonds (ND, in particular, have been researched over the past five years for use in various drug delivery systems but minimal work has been done that incorporates targeting capability. In this study, a novel targeted drug delivery system for bone metastatic prostate cancer was developed, characterized, and evaluated in vitro. NDs were conjugated with the Asp–Gly–Glu–Ala (DGEA peptide to target α2β1 integrins over-expressed in prostate cancers during metastasis. To facilitate drug delivery, DOX was adsorbed to the surface of the ND-DGEA conjugates. Successful preparation of the ND-DGEA conjugates and the ND-DGEA+DOX system was confirmed with transmission electron microscopy, hydrodynamic size, and zeta potential measurements. Since traditional DOX treatment regimens lack specificity and increased toxicity to normal tissues, the ND-DGEA conjugates were designed to distinguish between cells that overexpress α2β1 integrin, bone metastatic prostate cancers cells (PC3, and cells that do not, human mesenchymal stem cells (hMSC. Utilizing the ND-DGEA+DOX system, the efficacy of 1 µg/mL and 2 µg/mL DOX doses increased from 2.5% to 12% cell death and 11% to 34% cell death, respectively. These studies confirmed that the delivery and efficacy of DOX were enhanced by ND-DGEA conjugates. Thus, the targeted ND-DGEA+DOX system provides a novel approach for decreasing toxicity and drug doses.

  12. Modulating polymer chemistry to enhance non-viral gene delivery inside hydrogels with tunable matrix stiffness.

    Science.gov (United States)

    Keeney, Michael; Onyiah, Sheila; Zhang, Zhe; Tong, Xinming; Han, Li-Hsin; Yang, Fan

    2013-12-01

    Non-viral gene delivery holds great promise for promoting tissue regeneration, and offers a potentially safer alternative than viral vectors. Great progress has been made to develop biodegradable polymeric vectors for non-viral gene delivery in 2D culture, which generally involves isolating and modifying cells in vitro, followed by subsequent transplantation in vivo. Scaffold-mediated gene delivery may eliminate the need for the multiple-step process in vitro, and allows sustained release of nucleic acids in situ. Hydrogels are widely used tissue engineering scaffolds given their tissue-like water content, injectability and tunable biochemical and biophysical properties. However, previous attempts on developing hydrogel-mediated non-viral gene delivery have generally resulted in low levels of transgene expression inside 3D hydrogels, and increasing hydrogel stiffness further decreased such transfection efficiency. Here we report the development of biodegradable polymeric vectors that led to efficient gene delivery inside poly(ethylene glycol) (PEG)-based hydrogels with tunable matrix stiffness. Photocrosslinkable gelatin was maintained constant in the hydrogel network to allow cell adhesion. We identified a lead biodegradable polymeric vector, E6, which resulted in increased polyplex stability, DNA protection and achieved sustained high levels of transgene expression inside 3D PEG-DMA hydrogels for at least 12 days. Furthermore, we demonstrated that E6-based polyplexes allowed efficient gene delivery inside hydrogels with tunable stiffness ranging from 2 to 175 kPa, with the peak transfection efficiency observed in hydrogels with intermediate stiffness (28 kPa). The reported hydrogel-mediated gene delivery platform using biodegradable polyplexes may serve as a local depot for sustained transgene expression in situ to enhance tissue engineering across broad tissue types.

  13. Electrophoretic particle guidance significantly enhances olfactory drug delivery: a feasibility study.

    Directory of Open Access Journals (Sweden)

    Jinxiang Xi

    Full Text Available BACKGROUND: Intranasal olfactory drug delivery provides a non-invasive method that bypasses the Blood-Brain-Barrier and directly delivers medication to the brain and spinal cord. However, a device designed specifically for olfactory delivery has not yet been found. METHODS: In this study, a new delivery method was proposed that utilized electrophoretic forces to guide drug particles to the olfactory region. The feasibility of this method was numerically evaluated in both idealized 2-D and anatomically accurate 3-D nose models. The influence of nasal airflow, electrode strength, and drug release position were also studied on the olfactory delivery efficiency. FINDINGS: Results showed that by applying electrophoretic forces, the dosage to the olfactory region was significantly enhanced. In both 2-D and 3-D cases, electrophoretic-guided delivery achieved olfactory dosages nearly two orders of magnitude higher than that without electrophoretic forces. Furthermore, releasing drugs into the upper half of the nostril (i.e., partial release led to olfactory dosages two times higher than releasing drugs over the entire area of the nostril. By combining the advantages of pointed drug release and appropriate electrophoretic guidance, olfactory dosages of more than 90% were observed as compared to the extremely low olfactory dosage (<1% with conventional inhaler devices. CONCLUSION: Results of this study have important implications in developing personalized olfactory delivery protocols for the treatment of neurological disorders. Moreover, a high sensitivity of olfactory dosage was observed in relation to different pointed release positions, indicating the importance of precise particle guidance for effective olfactory delivery.

  14. Using networks to enhance health services delivery: perspectives, paradoxes and propositions.

    Science.gov (United States)

    Huerta, Timothy R; Casebeer, Ann; Vanderplaat, Madine

    2006-01-01

    There is a growing need to better understand and address the consequences of an increasing reliance on networks used to enhance health services delivery. Networks seem to have emerged as the definitive solution for tackling complex healthcare problems together that we have not been able to adequately address separately. Emphasizing the collective and the collaborative, networks are assumed to address healthcare issues in ways that are superior to previous service-delivery models. While this assumption would appear to be sound theoretically, we have little empirical information available to actually understand what networks are, what they do and whether they achieve their stated goals--truly making a difference in the delivery of care and the maintenance of health. With a diversity of networks within Canada focused on health services delivery, this paper offers a multi-dimensional framework for conceptualizing how these complex inter-organizational relationships generate both challenges and opportunities. We identify six paradoxes that the networks create when used to enhance the delivery of health services and posit several propositions concerning the evaluative work that needs to be done to enhance our understanding of and confidence in this inter-organizational form. Unless these paradoxes are adequately recognized and addressed, the value and costs associated with developing and using networks in healthcare contexts will remain unclear at best. Given the broad interest in and use of networks proliferating in health-related arenas, it is time to amass the evidence and than align the perspectives. Are networks here to stay in healthcare because they make a difference or because we got tired of talking about the need for greater collaboration and so gave it a new name and frame? At the very least, it will be important to build on what we have already learned through research into collaboration in healthcare and related fields, and even more critical to be mindful

  15. Acoustically active liposome-nanobubble complexes for enhanced ultrasonic imaging and ultrasound-triggered drug delivery.

    Science.gov (United States)

    Nguyen, An T; Wrenn, Steven P

    2014-01-01

    Ultrasound is well known as a safe, reliable imaging modality. A historical limitation of ultrasound, however, was its inability to resolve structures at length scales less than nominally 20 µm, which meant that classical ultrasound could not be used in applications such as echocardiography and angiogenesis where one requires the ability to image small blood vessels. The advent of ultrasound contrast agents, or microbubbles, removed this limitation and ushered in a new wave of enhanced ultrasound applications. In recent years, the microbubbles have been designed to achieve yet another application, namely ultrasound-triggered drug delivery. Ultrasound contrast agents are thus tantamount to 'theranostic' vehicles, meaning they can do both therapy (drug delivery) and imaging (diagnostics). The use of ultrasound contrast agents as drug delivery vehicles, however, is perhaps less than ideal when compared to traditional drug delivery vehicles (e.g., polymeric microcapsules and liposomes) which have greater drug carrying capacities. The drawback of the traditional drug delivery vehicles is that they are not naturally acoustically active and cannot be used for imaging. The notion of a theranostic vehicle is sufficiently intriguing that many attempts have been made in recent years to achieve a vehicle that combines the echogenicity of microbubbles with the drug carrying capacity of liposomes. The attempts can be classified into three categories, namely entrapping, tethering, and nesting. Of these, nesting is the newest-and perhaps the most promising.

  16. Remodeling Tumor Vasculature to Enhance Delivery of Intermediate-Sized Nanoparticles.

    Science.gov (United States)

    Jiang, Wen; Huang, Yuhui; An, Yi; Kim, Betty Y S

    2015-09-22

    Restoration of dysfunctional tumor vasculature can reestablish the pressure gradient between intravascular and interstitial space that is essential for transporting nanomedicines into solid tumors. Morphologic and functional normalization of tumor vessels improves tissue perfusion to facilitate intratumoral nanoparticle delivery. However, this remodeling process also reduces tumor vessel permeability, which can impair nanoparticle transport. Although nanoparticles sized below 10 nm maximally benefited from tumor vessel normalization therapy for enhanced nanomedicine delivery, the small particle size severely limits its applicability. Here, we show that intermediate-sized nanoparticles (20-40 nm) can also benefit from tumor vasculature remodeling. We demonstrate that a window of opportunity exists for a two-stage transport strategy of different nanoparticle sizes. Overall, tumor vessel remodeling enhances the transvascular delivery of intermediate-size nanoparticles of up to 40 nm. Once within the tumor matrix, however, smaller nanoparticles experience a significantly lesser degree of diffusional hindrance, resulting in a more homogeneous distribution within the tumor interstitium. These findings suggest that antiangiogenic therapy and nanoparticle design can be combined in a multistage fashion, with two sets of size-inclusion criteria, to achieve optimal nanomedicine delivery into solid tumors.

  17. Ultrasound-enhanced delivery of targeted echogenic liposomes in a novel ex vivo mouse aorta model.

    Science.gov (United States)

    Hitchcock, Kathryn E; Caudell, Danielle N; Sutton, Jonathan T; Klegerman, Melvin E; Vela, Deborah; Pyne-Geithman, Gail J; Abruzzo, Todd; Cyr, Peppar E P; Geng, Yong-Jian; McPherson, David D; Holland, Christy K

    2010-06-15

    The goal of this study was to determine whether targeted, Rhodamine-labeled echogenic liposomes (Rh-ELIP) containing nanobubbles could be delivered to the arterial wall, and whether 1-MHz continuous wave ultrasound would enhance this delivery profile. Aortae excised from apolipoprotein-E-deficient (n=8) and wild-type (n=8) mice were mounted in a pulsatile flow system through which Rh-ELIP were delivered in a stream of bovine serum albumin. Half the aortae from each group were treated with 1-MHz continuous wave ultrasound at 0.49 MPa peak-to-peak pressure, and half underwent sham exposure. Ultrasound parameters were chosen to promote stable cavitation and avoid inertial cavitation. A broadband hydrophone was used to monitor cavitation activity. After treatment, aortic sections were prepared for histology and analyzed by an individual blinded to treatment conditions. Delivery of Rh-ELIP to the vascular endothelium was observed, and sub-endothelial penetration of Rh-ELIP was present in five of five ultrasound-treated aortae and was absent in those not exposed to ultrasound. However, the degree of penetration in the ultrasound-exposed aortae was variable. There was no evidence of ultrasound-mediated tissue damage in any specimen. Ultrasound-enhanced delivery within the arterial wall was demonstrated in this novel model, which allows quantitative evaluation of therapeutic delivery.

  18. Enhanced laser thrombolysis with photomechanical drug delivery: an in vitro study.

    Science.gov (United States)

    Shangguan, H Q; Gregory, K W; Casperson, L W; Prahl, S A

    1998-01-01

    Current techniques for laser thrombolysis are limited because they can not completely clear thrombotic occlusions in arteries, typically leaving residual thrombus on the walls of the artery. The objective of this study was to investigate the possibility of using photomechanical drug delivery to enhance laser thrombolysis by delivering drugs into mural thrombus during laser thrombolysis. Three experimental protocols were performed in vitro to quantitatively compare the effectiveness of thrombolysis by 1) constant infusion of drug, 2) laser thrombolysis, and 3) photomechanical drug delivery. A fiber-optic flushing catheter delivered drug (a solution of 1 microm fluorescent microspheres) and light ( a 1 micros pulsed dye laser) into a gelatin-based thrombus model. The process of laser-thrombus interaction was visualized using flash photography and the laser-induced pressure waves were measured using an acoustic transducer. Lumen sizes generated by mechanically manipulating the catheter through the thrombus were smaller than those generated by laser ablation. The microspheres could be driven several hundred microns into the mural thrombus. Photomechanical drug delivery has potential for enhancement of laser thrombolysis. Two mechanisms seem to be involved in photomechanical drug delivery: 1) mural deposition of the drug at the ablation site and 2) increased exposure of the thrombus surface area to the drug.

  19. An experimental investigation of convective heat transfer enhancement in electronic module using curved deflector

    Science.gov (United States)

    Rosas, A. S.; Ali, R. K.; Abdel-Aziz, A. A.; Elshazly, K. M.

    2017-03-01

    This work investigated experimentally the heat transfer and pressure drop in electronic module using a curved deflector to direct the flow towards the recirculation zone enclosed between the two heat sources. The experiments were carried out to investigate the effect of deflector dimensionless radius ( R r ) and both horizontal and vertical distances ( R x , R y ) within a range of Reynolds number from 5223 to 11,380. The results show that larger deflector at small vertical distance enhances the heat transfer for upstream and downstream heat sources while the horizontal distance has a contrast effect. Correlations are obtained for the average Nusselt number of both upstream and downstream heat sources utilizing the present measurements within 5223 ≤ Re L ≤ 11,380, 0.02 ≤ R x ≤ 0.4, 0.3 ≤ R y ≤ 0.5 and 0.15 ≤ R r ≤ 0.35.

  20. An experimental investigation of convective heat transfer enhancement in electronic module using curved deflector

    Science.gov (United States)

    Rosas, A. S.; Ali, R. K.; Abdel-Aziz, A. A.; Elshazly, K. M.

    2016-07-01

    This work investigated experimentally the heat transfer and pressure drop in electronic module using a curved deflector to direct the flow towards the recirculation zone enclosed between the two heat sources. The experiments were carried out to investigate the effect of deflector dimensionless radius (R r ) and both horizontal and vertical distances (R x , R y ) within a range of Reynolds number from 5223 to 11,380. The results show that larger deflector at small vertical distance enhances the heat transfer for upstream and downstream heat sources while the horizontal distance has a contrast effect. Correlations are obtained for the average Nusselt number of both upstream and downstream heat sources utilizing the present measurements within 5223 ≤ Re L ≤ 11,380, 0.02 ≤ R x ≤ 0.4, 0.3 ≤ R y ≤ 0.5 and 0.15 ≤ R r ≤ 0.35.

  1. Enhanced Remedial Amendment Delivery through Fluid Viscosity Modifications: Experiments and numerical simulations

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, Lirong; Oostrom, Martinus; Wietsma, Thomas W.; Covert, Matthew A.

    2008-07-29

    Abstract Heterogeneity is often encountered in subsurface contamination characterization and remediation. Low-permeability zones are typically bypassed when remedial fluids are injected into subsurface heterogeneous aquifer systems. Therefore, contaminants in the bypassed areas may not be contacted by the amendments in the remedial fluid, which may significantly prolong the remediation operations. Laboratory experiments and numerical studies have been conducted to develop the Mobility-Controlled Flood (MCF) technology for subsurface remediation and to demonstrate the capability of this technology in enhancing the remedial amendments delivery to the lower permeability zones in heterogeneous systems. Xanthan gum, a bio-polymer, was used to modify the viscosity of the amendment-containing remedial solutions. Sodium mono-phosphate and surfactant were the remedial amendment used in this work. The enhanced delivery of the amendments was demonstrated in two-dimensional (2-D) flow cell experiments, packed with heterogeneous systems. The impact of polymer concentration, fluid injection rate, and permeability contract in the heterogeneous systems has been studied. The Subsurface Transport over Multiple Phases (STOMP) simulator was modified to include polymer-induced shear thinning effects. Shear rates of polymer solutions were computed from pore-water velocities using a relationship proposed in the literature. Viscosity data were subsequently obtained from empirical viscosity-shear rate relationships derived from laboratory data. The experimental and simulation results clearly show that the MCF technology is capable of enhancing the delivery of remedial amendments to subsurface lower permeability zones. The enhanced delivery significantly improved the NAPL removal from these zones and the sweeping efficiency on a heterogeneous system was remarkably increased when a polymer fluid was applied. MCF technology is also able to stabilize the fluid displacing front when there is a

  2. Impact of Focused Ultrasound-enhanced Drug Delivery on Survival in Rats with Glioma

    Science.gov (United States)

    Treat, Lisa Hsu; Zhang, Yongzhi; McDannold, Nathan; Hynynen, Kullervo

    2009-04-01

    Malignancies of the brain remain difficult to treat with chemotherapy because the selective permeability of the blood-brain barrier (BBB) blocks many potent agents from reaching their target. Previous studies have illustrated the feasibility of drug and antibody delivery across the BBB using MRI-guided focused ultrasound. In this study, we investigated the impact of focused ultrasound-enhanced delivery of doxorubicin on survival in rats with aggressive glioma. Sprague-Dawley rats were implanted with 9 L gliosarcoma cells in the brain. Eight days after implantation, each rat received one of the following: (1) no treatment (control), (2) a single treatment with microbubble-enhanced MRI-guided focused ultrasound (FUS only), (3) a single treatment with i.v. liposomal doxorubicin (DOX only), or (4) a single treatment with microbubble-enhanced MRI-guided focused ultrasound and concurrent i.v. injections of liposomal doxorubicin (FUS+DOX). The survival time from implantation to death or euthanasia was recorded. We observed a modest but significant increase in median survival time in rats treated with combined MRI-guided focused ultrasound chemotherapy, compared to chemotherapy alone (p0.10). Our study demonstrates for the first time a therapeutic benefit achieved with ultrasound-enhanced drug delivery across the blood-brain barrier. This confirmation of efficacy in an in vivo tumor model indicates that targeted drug delivery using MRI-guided focused ultrasound has the potential to have a major impact on the treatment of patients with brain tumors and other neurological disorders.

  3. Enhanced Amendment Delivery to Low Permeability Zones for Chlorinated Solvent Source Area Bioremediation

    Science.gov (United States)

    2014-09-01

    common carrier. 7) If a commercial courier service (e.g., Federal Express ) transports the samples to the laboratory, the chain-of-custody form will be... courier service will serve as chain-of custody documentation during shipment, because commercial couriers do not sign chain- of-custody forms...FINAL REPORT Enhanced Amendment Delivery to Low Permeability Zones for Chlorinated Solvent Source Area Bioremediation ESTCP Project ER

  4. Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement.

    Science.gov (United States)

    Rezhdo, Oljora; Speciner, Lauren; Carrier, Rebecca

    2016-10-28

    The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid in the understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented.

  5. Proposing a competitive intelligence (CI framework for Public Service departments to enhance service delivery

    Directory of Open Access Journals (Sweden)

    Nisha Sewdass

    2012-02-01

    Full Text Available Background: The aim of public service departments in South Africa is to improve service delivery through the transformation and improvement of human resources and the improvement of service delivery practices. Furthermore, it is important for the public service sector in South Africa to improve the quality of its service delivery, not only by comparing its performance with other sectors within South Africa but also by positioning itself amongst the best in the world. This can be achieved by benchmarking with other global industries and by implementing the most recent competitive intelligence strategies, tools and techniques. The environment of the public service organisations consists of competitive forces that impact the functioning of these organisations.Objectives: This article focuses on proposing competitive intelligence-related strategies, tools and techniques for gathering and analysing information in the public service departments in South Africa in order to enhance service delivery.Method: The study was qualitative in nature and was divided into two components, namely, (1 theoretical – through an extensive review of the literature and (2 empirical – an ethnographic study at the chosen public service department, the Department of Home Affairs (DHA. Ethnographic interviews with management-level staff, focus groups and document analysis were used to obtain adequate information to determine the current state of public service delivery in South Africa.Results: The results of the study was the development of a new competitive intelligencerelated framework for gathering and analysing information, and it represents a formal and systematic process of informing managers in public service departments about critical issues that these departments face or are likely to experience in future.Conclusion: The strategic planning tools and techniques of this framework will fill the gap that exists in public service departments. Once this framework has

  6. Transdermal drug delivery of labetalol hydrochloride: Feasibility and effect of penetration enhancers

    Directory of Open Access Journals (Sweden)

    Saqib Zafar

    2010-01-01

    Full Text Available Objectives : The objective of this study is to investigate the feasibility of transdermal drug delivery of Labetalol Hydrochloride (LHCl and to study the effect of different penetration enhancers on the skin permeability of LHCl. Methods : The permeability experiments were conducted using a horizontal glass diffusion cell with a diffusional area of 2.37 cm-2 on albino rat skin. The effect of various penetration enhancers namely turpentine oil, dimethyl formamide (DMF, menthol, dimethyl sulfoxide, pine oil, and 2-pyrollidone, and the effect of the concentration of drug and enhancer in the donor phase on the skin permeability of LHCl was studied. Results : The apparent partition coefficient of the drug was found to be 6.95, suggesting it to be a lipophilic drug. The preliminary skin permeation studies revealed that the permeation of LHCL through albino rat skin was moderate (Kp = 6.490 Χ 10 -2 cm hr -1 from isotonic phosphate buffer of pH 7.4. An appreciable increase in the LHCl permeability coefficient was observed on using a co-solvent (ethanol 95% with the penetration enhancers in the donor phase. DMSO (10% v/v was found to be the most effective enhancer for Labetalol hydrochloride (Enhancement Factor = 1.165. An increase in the concentration of drug and enhancer in the donor cell accentuated the permeability coefficient of LHCl. Conclusions : It was concluded that LHCl could be delivered via the dermal route with the use of 10% DMSO as the penetration enhancer.

  7. Colon-targeted quercetin delivery using natural polymer to enhance its bioavailability

    Directory of Open Access Journals (Sweden)

    Anil Singhal

    2011-01-01

    Full Text Available The aim of the present study is to develop a polymer (Guar Gum-based matrix tablet (using quercetin as a model drug with sufficient mechanical strength, and promising in vitro mouth-to-colon release profile. By definition, an oral colonic delivery system should retard drug release in the stomach and small intestine, and allow complete release in the colon. By drug delivery to the colon would therefore ensure direct treatment at the disease site, lower dosing, and fewer systemic side effects. Quercetin is antioxidant in nature and used to treat colon cancer, but they have poor absorption in the upper part of the gastrointestinal tract (GIT. As a site for drug delivery, the colon offers a near neutral pH, reduced digestive enzymatic activity, a long transit time, and an increased responsiveness to absorption enhancers. By achieving a colon-targeted drug delivery system, the absorption of quercetin may be increased, which leads to better bioactivity in fewer doses.

  8. Enhancement of nose-brain delivery of therapeutic agents for treating neurodegenerative diseases using peppermint oil.

    Science.gov (United States)

    Vaka, S R Kiran; Murthy, S Narasimha

    2010-09-01

    The nose-brain pathway is a potential route for drug delivery as it bypasses the brain barriers. The main objective of this study was to investigate the efficacy of peppermint oil in enhancing the bioavailability of intranasally administered neurotrophins like nerve growth factor (NGF). The effect of different concentrations of peppermint oil (PO) on the delivery of NGF across bovine olfactory epithelium was studied in vitro using Franz diffusion cells. Trans-olfactory epithelial electrical resistance (TEER) was measured to assess the permeability status of the bovine olfactory epithelium. The bioavailability of intranasally administered formulations in rat hippocampus was studied by carrying out brain microdialysis in male Sprague-Dawley rats. Peppermint oil at concentrations of 0.05, 0.1 and 0.5% v/v enhanced the in vitro transport of NGF by 5, 7 and 8 fold, respectively. In vivo studies employing brain microdialysis in rats demonstrated that intranasal administration of NGF formulation with 0.5% PO enhanced the bioavailability by approximately 8 fold compared to rats administered with NGF alone. The bioavailability of NGF in the brain could be enhanced by intranasal administration of peppermint oil.

  9. Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery.

    Science.gov (United States)

    Guo, Jianwei; Gao, Xiaoling; Su, Lina; Xia, Huimin; Gu, Guangzhi; Pang, Zhiqing; Jiang, Xinguo; Yao, Lei; Chen, Jun; Chen, Hongzhuan

    2011-11-01

    Targeted delivery of therapeutic nanoparticles in a disease-specific manner represents a potentially powerful technology especially when treating infiltrative brain tumors such as gliomas. We developed a nanoparticulate drug delivery system decorated with AS1411 (Ap), a DNA aptamer specifically binding to nucleolin which was highly expressed in the plasma membrane of both cancer cells and endothelial cells in angiogenic blood vessels, as the targeting ligand to facilitate anti-glioma delivery of paclitaxel (PTX). Ap was conjugated to the surface of PEG-PLGA nanoparticles (NP) via an EDC/NHS technique. With the conjugation confirmed by Urea PAGE and XPS, the resulting Ap-PTX-NP was uniformly round with particle size at 156.0 ± 54.8 nm and zeta potential at -32.93 ± 3.1 mV. Ap-nucleolin interaction significantly enhanced cellular association of nanoparticles in C6 glioma cells, and increased the cytotoxicity of its payload. Prolonged circulation and enhanced PTX accumulation at the tumor site was achieved for Ap-PTX-NP, which eventually obtained significantly higher tumor inhibition on mice bearing C6 glioma xenografts and prolonged animal survival on rats bearing intracranial C6 gliomas when compared with PTX-NP and Taxol(®). The results of this contribution demonstrated the potential utility of AS1411-functionalized nanoparticles for a therapeutic application in the treatment of gliomas.

  10. Custom fractional factorial designs to develop atorvastatin self-nanoemulsifying and nanosuspension delivery systems--enhancement of oral bioavailability

    National Research Council Canada - National Science Library

    Hashem, Fahima M; Al-Sawahli, Majid M; Nasr, Mohamed; Ahmed, Osama A A

    2015-01-01

    ...) and solid nanosuspensions (NS) in order to enhance the oral delivery of atorvastatin (ATR). According to the design, 14 experimental runs of ATR SNEDDS were formulated utilizing the highly ATR solubilizing SNEDDS components...

  11. Paracellular permeation-enhancing effect of AT1002 C-terminal amidation in nasal delivery

    Directory of Open Access Journals (Sweden)

    Song KH

    2015-03-01

    Full Text Available Keon-Hyoung Song,1 Sang-Bum Kim,2 Chang-Koo Shim,2 Suk-Jae Chung,2 Dae-Duk Kim,2 Sang-Ki Rhee,1 Guang J Choi,1 Chul-Hyun Kim,3 Kiyoung Kim4 1Department of Pharmaceutical Engineering, Soonchunhyang University, Asan, Republic of Korea; 2College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; 3Department of Sports Medicine, 4Department of Medical Biotechnology, Soonchunhyang University, Asan, Republic of Korea Background: The identification of permeation enhancers has gained interest in the development of drug delivery systems. A six-mer peptide, H-FCIGRL-OH (AT1002, is a tight junction modulator with promising permeation-enhancing activity. AT1002 enhances the transport of molecular weight markers or agents with low bioavailability with no cytotoxicity. However, AT1002 is not stable in neutral pH or after incubation under physiological conditions, which is necessary to fully uncover its permeation-enhancing effect. Thus, we increased the stability or mitigated the instability of AT1002 by modifying its terminal amino acids and evaluated its subsequent biological activity.Methods: C-terminal-amidated (FCIGRL-NH2, Pep1 and N-terminal-acetylated (Ac-FCIGRL, Pep2 peptides were analyzed by liquid chromatography–mass spectrometry. We further assessed cytotoxicity on cell monolayers, as well as the permeation-enhancing activity following nasal administration of the paracellular marker mannitol.Results: Pep1 was nontoxic to cell monolayers and showed a relatively low decrease in peak area compared to AT1002. In addition, administration of mannitol with Pep1 resulted in significant increases in the area under the plasma concentration–time curve and peak plasma concentration at 3.63-fold and 2.68-fold, respectively, compared to mannitol alone. In contrast, no increase in mannitol concentration was shown with mannitol/AT1002 or mannitol/Pep2 compared to the control. Thus, Pep1 increased

  12. Enhanced skin delivery of aceclofenac via hydrogel-based solid lipid nanoparticles.

    Science.gov (United States)

    Raj, Rakesh; Mongia, Pooja; Ram, Alpana; Jain, N K

    2016-09-01

    The aim of the present study was to develop solid lipid nanoparticles (SLN) and formulate a hydrogel for enhanced topical delivery of aceclofenac (ACF). The SLN were prepared by the ultrasonic emulsification method and optimized on the basis of stirring speed and lipid content. The optimized formulation was characterized for particle size (189 ± 9.2 nm), polydispersity index (PDI) (0.162 ± 0.02), zeta potential (-32.51 ± 0.12 mV), entrapment efficiency (86.51 ± 2.46%), surface morphology, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In vivo performance of ACF-loaded SLN hydrogel showed prolonged inhibition of edema, as compared to that observed using plain ACF hydrogel, after 24 h. The results demonstrated that the ACF-SLN formulation for skin targeting could be a promising carrier for topical delivery of ACF.

  13. Transdermal delivery of lercanidipine hydrochloride: effect of chemical enhancers and ultrasound.

    Science.gov (United States)

    Shetty, Pallavi K; Suthar, Neelam A; Menon, Jyothsna; Deshpande, Praful B; Avadhani, Kiran; Kulkarni, Raghavendra V; Mutalik, Srinivas

    2013-08-01

    The effects of permeation enhancers and sonophoresis on the transdermal permeation of lercanidipine hydrochloride (LRDP) across mouse skin were investigated. Parameters including drug solubility, partition coefficient, drug degradation and drug permeation in skin were determined. Tween-20, dimethyl formamide, propylene glycol, poly ethylene glycol (5% v/v) and different concentration of ethanol were used for permeation enhancement. Low frequency ultrasound was also applied in the presence and absence of permeation enhancers to assess its effect on augmenting the permeation of drug. All the permeation enhancers, except propylene glycol, increased the transdermal permeation of LRDP. Sonophoresis significantly increased the cumulative amount of LRDP permeating through the skin in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in presence of permeation enhancers. The results suggest that the formulation of LRDP with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver LRDP across the skin for a prolonged period (i.e., 24 h). The application of ultrasound in association with permeation enhancers could further serve as non-oral and non-invasive drug delivery modality for the immediate therapeutic effect.

  14. A combined approach of chemical enhancers and sonophoresis for the transdermal delivery of tizanidine hydrochloride.

    Science.gov (United States)

    Mutalik, Srinivas; Parekh, Harendra S; Davies, Nigel M; Udupa, Nayanabhirama

    2009-02-01

    The effects of chemical enhancers and sonophoresis on the transdermal permeation of tizanidine hydrochloride (TIZ) across mouse skin were investigated. Parameters including drug solubility, apparent partition coefficient (APC), drug permeation, and degradation in skin were determined. Low frequency ultrasound was also applied in the presence and absence of chemical enhancers to assess whether drug permeation improved. APC values indicated that TIZ preferentially partitions into intercellular spaces and does not form a reservoir, with the drug also exhibiting good enzymatic stability in skin. Most of the enhancers studied significantly increased the permeation rate of TIZ through full thickness mouse skin in comparison with TIZ formulated in phosphate buffer. Maximum enhancement was observed for TIZ formulated as a suspension in 50% v/v aqueous ethanol containing 5% v/v citral. Sonophoresis significantly (p synergistic effect was noted when sonophoresis was applied in the presence of chemical enhancers. The results suggest that the formulation of TIZ with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver TIZ across the skin for a prolonged period, i.e. 24 hr. The application of ultrasound in association with chemical enhancers, such as the combination of 5% v/v citral in 50% v/v aqueous ethanol, could further serve as a non-oral and non-invasive drug delivery modality for the immediate therapeutic effect of muscle relaxants such as TIZ.

  15. Convective heat transfer

    CERN Document Server

    Kakac, Sadik; Pramuanjaroenkij, Anchasa

    2014-01-01

    Intended for readers who have taken a basic heat transfer course and have a basic knowledge of thermodynamics, heat transfer, fluid mechanics, and differential equations, Convective Heat Transfer, Third Edition provides an overview of phenomenological convective heat transfer. This book combines applications of engineering with the basic concepts of convection. It offers a clear and balanced presentation of essential topics using both traditional and numerical methods. The text addresses emerging science and technology matters, and highlights biomedical applications and energy technologies. What’s New in the Third Edition: Includes updated chapters and two new chapters on heat transfer in microchannels and heat transfer with nanofluids Expands problem sets and introduces new correlations and solved examples Provides more coverage of numerical/computer methods The third edition details the new research areas of heat transfer in microchannels and the enhancement of convective heat transfer with nanofluids....

  16. A Framework to Enhance Quality of Service for Content Delivery Network Using Web Services: A Review

    Directory of Open Access Journals (Sweden)

    K.Manivannan

    2011-09-01

    Full Text Available Content Delivery Networks (CDNs is anticipated to provide better performance delivery of content in internet through worldwide coverage, which would be a fence for new content delivery network providers. The appearance of Web as a omnipresent media for sharing content and services has led to the rapid growth of the Internet. At the same time, the number of users accessing Web-based content and services are growing exponentially. This has placed a heavy demand on Internet bandwidth and Web systems hosting content and application services. As a result, many Web sites are unable to manage this demand and offer their services in a timely manner. Content Delivery Networks (CDNs have emerged to overcome these limitations by offering infrastructure and mechanisms to deliver content and services in a scalable manner, and enhancing users Web experience. The planned research provides a framework designed to enhance QoS of Web service processes for real time servicing. QoS parameters of various domains can be combined to provide differentiated services, and allocating dynamically available resources in the midst of customers while delivering high-quality real time multimedia content. While accessing the service by a customer, it is possible to adapt real time streams to vastly changeable network conditions to give suitable quality in spite of factors upsetting Quality of service. To reach these intentions, adaptive web service processes to supply more information for determining the quality and size of the delivered object. The framework includes a section for QoS monitoring and adaptation and QoS faults prediction possibility and convalesce actions in case of failure. The aim of this research is to encourage research about quality of composite services in service-oriented architectures with security measures.

  17. Control of the Free Convective Flow around the Human Body for Enhanced Inhaled Air Quality: Application to a Seat-Incorporated Personalized Ventilation Unit

    DEFF Research Database (Denmark)

    Bolashikov, Zhecho Dimitrov; Melikov, Arsen Krikor; Krenek, M.

    2010-01-01

    This paper reports on methods for control of the free convective flow around the human body, with the aim of improving inhaled air quality. The methods were studied with sea-incorporated personalized ventilation (PV)-two PV nozzles placed sideways at the head level of a seated occupant supplied...... the clean air. Another pair of control nozzles below the P V nozzles, the height of the shoulders, either provided an additional amount of clean PV air or exhausted part of the air from the free convective flow. The effectiveness of the methods for enhancing the quality of the inhaled air was studied...... of the supplied PV flows and of the control flows, etc., were performed under isothermal conditions at 20 degrees C (68 degrees F) and 26 degrees C (78.8 degrees F). The methods of control proved to be efficient and made it possible to increase the amount of clean air into inhalation at reduced personalized flow...

  18. Enhancement of oral bioavailability of cyclosporine A: comparison of various nanoscale drug-delivery systems

    Directory of Open Access Journals (Sweden)

    Wang K

    2014-10-01

    Full Text Available Kai Wang,1–3 Jianping Qi,1 Tengfei Weng,1,2 Zhiqiang Tian,1 Yi Lu,1 Kaili Hu,4 Zongning Yin,2 Wei Wu1 1School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery of Ministry of Education, Shanghai, People’s Republic of China; 2West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Tropical Crops Genetic Resources Institute, Hainan Provincial Engineering Research Center for Blumea Balsamifera, Chinese Academy of Tropical Agricultural Sciences, Danzhou, Hainan, People’s Republic of China; 4Murad Research Center for Modernized Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaAbstract: A variety of nanoscale delivery systems have been shown to enhance the oral absorption of poorly water-soluble and poorly permeable drugs. However, the performance of these systems has seldom been evaluated simultaneously. The aim of this study was to compare the bioavailability enhancement effect of lipid-based nanocarriers with poly(lactic-co-glycolic acid (PLGA nanoparticles (NPs to highlight the importance of the lipid composition, with cyclosporine A (CyA as a model drug. CyA-loaded PLGA NPs, nanostructured lipid carriers (NLCs, and self-microemulsifying drug-delivery systems (SMEDDS were prepared. The particle size of PLGA NPs (182.2±12.8 nm was larger than that of NLCs (89.7±9.0 nm and SMEDDS (26.9±1.9 nm. All vehicles are charged negatively. The entrapment efficiency of PLGA NPs and NLCs was 87.6%±1.6% and 80.3%±0.6%, respectively. In vitro release tests indicated that the cumulative release of CyA was lower than 4% from all vehicles, including Sandimmun Neoral®, according to the dialysis method. Both NLCs and SMEDDS showed high relative oral bioavailability, 111.8% and 73.6%, respectively, after oral gavage administration to beagle dogs, which was not statistically different from commercial Sandimmun Neoral®. However, PLGA NPs

  19. Enhancement of oral bioavailability of cyclosporine A: comparison of various nanoscale drug-delivery systems.

    Science.gov (United States)

    Wang, Kai; Qi, Jianping; Weng, Tengfei; Tian, Zhiqiang; Lu, Yi; Hu, Kaili; Yin, Zongning; Wu, Wei

    2014-01-01

    A variety of nanoscale delivery systems have been shown to enhance the oral absorption of poorly water-soluble and poorly permeable drugs. However, the performance of these systems has seldom been evaluated simultaneously. The aim of this study was to compare the bioavailability enhancement effect of lipid-based nanocarriers with poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to highlight the importance of the lipid composition, with cyclosporine A (CyA) as a model drug. CyA-loaded PLGA NPs, nanostructured lipid carriers (NLCs), and self-microemulsifying drug-delivery systems (SMEDDS) were prepared. The particle size of PLGA NPs (182.2 ± 12.8 nm) was larger than that of NLCs (89.7 ± 9.0 nm) and SMEDDS (26.9 ± 1.9 nm). All vehicles are charged negatively. The entrapment efficiency of PLGA NPs and NLCs was 87.6%± 1.6% and 80.3%± 0.6%, respectively. In vitro release tests indicated that the cumulative release of CyA was lower than 4% from all vehicles, including Sandimmun Neoral(®), according to the dialysis method. Both NLCs and SMEDDS showed high relative oral bioavailability, 111.8% and 73.6%, respectively, after oral gavage administration to beagle dogs, which was not statistically different from commercial Sandimmun Neoral(®). However, PLGA NPs failed to achieve efficient absorption, with relative bioavailability of about 22.7%. It is concluded that lipid-based nanoscale drug-delivery systems are superior to polymeric NPs in enhancing oral bioavailability of poorly water-soluble and poorly permeable drugs.

  20. Root Effect Haemoglobins in Fish May Greatly Enhance General Oxygen Delivery Relative to Other Vertebrates.

    Directory of Open Access Journals (Sweden)

    Jodie L Rummer

    Full Text Available The teleost fishes represent over half of all extant vertebrates; they occupy nearly every body of water and in doing so, occupy a diverse array of environmental conditions. We propose that their success is related to a unique oxygen (O2 transport system involving their extremely pH-sensitive haemoglobin (Hb. A reduction in pH reduces both Hb-O2 affinity (Bohr effect and carrying capacity (Root effect. This, combined with a large arterial-venous pH change (ΔpHa-v relative to other vertebrates, may greatly enhance tissue oxygen delivery in teleosts (e.g., rainbow trout during stress, beyond that in mammals (e.g., human. We generated oxygen equilibrium curves (OECs at five different CO2 tensions for rainbow trout and determined that, when Hb-O2 saturation is 50% or greater, the change in oxygen partial pressure (ΔPO2 associated with ΔpHa-v can exceed that of the mammalian Bohr effect by at least 3-fold, but as much as 21-fold. Using known ΔpHa-v and assuming a constant arterial-venous PO2 difference (Pa-vO2, Root effect Hbs can enhance O2 release to the tissues by 73.5% in trout; whereas, the Bohr effect alone is responsible for enhancing O2 release by only 1.3% in humans. Disequilibrium states are likely operational in teleosts in vivo, and therefore the ΔpHa-v, and thus enhancement of O2 delivery, could be even larger. Modeling with known Pa-vO2 in fish during exercise and hypoxia indicates that O2 release from the Hb and therefore potentially tissue O2 delivery may double during exercise and triple during some levels of hypoxia. These characteristics may be central to performance of athletic fish species such as salmonids, but may indicate that general tissue oxygen delivery may have been the incipient function of Root effect Hbs in fish, a trait strongly associated with the adaptive radiation of teleosts.

  1. Degradable terpolymers with alkyl side chains demonstrate enhanced gene delivery potency and nanoparticle stability.

    Science.gov (United States)

    Eltoukhy, Ahmed A; Chen, Delai; Alabi, Christopher A; Langer, Robert; Anderson, Daniel G

    2013-03-13

    Degradable, cationic poly(β-amino ester)s (PBAEs) with alkyl side chains are developed for non-viral gene delivery. Nanoparticles formed from these PBAE terpolymers exhibit significantly enhanced DNA transfection potency and resistance to aggregation. These hydrophobic PBAE terpolymers, but not PBAEs lacking alkyl side chains, support interaction with PEG-lipid conjugates, facilitating their functionalization with shielding and targeting moieties and accelerating the in vivo translation of these materials. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Doxorubicin conjugated functionalizable carbon dots for nucleus targeted delivery and enhanced therapeutic efficacy

    Science.gov (United States)

    Yang, Lei; Wang, Zheran; Wang, Ju; Jiang, Weihua; Jiang, Xuewei; Bai, Zhaoshi; He, Yunpeng; Jiang, Jianqi; Wang, Dongkai; Yang, Li

    2016-03-01

    Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared with free DOX. Thus, the DOX-CD conjugates may be exploited as promising drug delivery vehicles in cancer therapy.Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared

  3. Modification of palm kernel oil esters nanoemulsions with hydrocolloid gum for enhanced topical delivery of ibuprofen

    Directory of Open Access Journals (Sweden)

    Abdullah DK

    2012-09-01

    Full Text Available Norazlinaliza Salim,1 Mahiran Basri,1,2 Mohd BA Rahman,1 Dzulkefly K Abdullah,1 Hamidon Basri31Department of Chemistry, Faculty of Science, 2Laboratory of Biomolecular Medicine, Institute of Bioscience, 3Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, MalaysiaIntroduction: During recent years, there has been growing interest in the use of nanoemulsion as a drug-carrier system for topical delivery. A nanoemulsion is a transparent mixture of oil, surfactant and water with a very low viscosity, usually the product of its high water content. The present study investigated the modification of nanoemulsions with different hydrocolloid gums, to enhanced drug delivery of ibuprofen. The in vitro characterization of the initial and modified nanoemulsions was also studied.Methods: A palm kernel oil esters nanoemulsion was modified with different hydrocolloid gums for the topical delivery of ibuprofen. Three different hydrocolloids (gellan gum, xanthan gum, and carrageenan were selected for use. Ternary phase diagrams were constructed using palm kernel oil esters as the oil, Tween 80 as the surfactant, and water. Nanoemulsions were prepared by phase inversion composition, and were gradually mixed with the freshly prepared hydrocolloids. The initial nanoemulsion and modified nanoemulsions were characterized. The abilities of the nanoemulsions to deliver ibuprofen were assessed in vitro, using a Franz diffusion cell fitted with rat skin.Results: No significant changes were observed in droplet size (~16–20 nm but a significant difference in polydispersity indexes were observed before and after the modification of nanoemulsions using gellan gum, carrageenan, and xanthan gum. The zeta potentials of the initial nanoemulsions (–11.0 mV increased to –19.6 mV, –13.9 mV, and –41.9 mV, respectively. The abilities of both the initial nanoemulsion (T802 and the modified nanoemulsion to deliver ibuprofen

  4. Convective heat transfer enhancement using Carbon nanofibers (CNFs): influence of amorphous carbon layer on heat transfer performance

    NARCIS (Netherlands)

    Taha, T.J.; Lefferts, Leonardus; van der Meer, Theodorus H.

    2013-01-01

    In this work, an experimental heat transfer investigation was carried out to investigate the combined influence of both amorphous carbon (a-C) layer thickness and carbon nanofibers (CNFs) on the convective heat transfer behavior. Synthesis of these carbon nano structures was achieved using catalytic

  5. Convective heat transfer enhancement using Carbon nanofibers (CNFs): influence of amorphous carbon layer on heat transfer performance

    NARCIS (Netherlands)

    Taha, T.J.; Lefferts, L.; Meer, van der T.H.

    2013-01-01

    In this work, an experimental heat transfer investigation was carried out to investigate the combined influence of both amorphous carbon (a-C) layer thickness and carbon nanofibers (CNFs) on the convective heat transfer behavior. Synthesis of these carbon nano structures was achieved using catalytic

  6. Cavitation-enhanced delivery of insulin in agar and porcine models of human skin.

    Science.gov (United States)

    Feiszthuber, Helga; Bhatnagar, Sunali; Gyöngy, Miklós; Coussios, Constantin-C

    2015-03-21

    Ultrasound-assisted transdermal insulin delivery offers a less painful and less invasive alternative to subcutaneous insulin injections. However, ultrasound-based drug delivery, otherwise known as sonophoresis, is a highly variable phenomenon, in part dependent on cavitation. The aim of the current work is to investigate the role of cavitation in transdermal insulin delivery. Fluorescently stained, soluble Actrapid insulin was placed on the surface of human skin-mimicking materials subjected to 265 kHz, 10% duty cycle focused ultrasound. A confocally and coaxially aligned 5 MHz broadband ultrasound transducer was used to detect cavitation. Two different skin models were used. The first model, 3% agar hydrogel, was insonated with a range of pressures (0.25-1.40 MPa peak rarefactional focal pressure-PRFP), with and without cavitation nuclei embedded within the agar at a concentration of 0.05% w/v. The second, porcine skin was insonated at 1.00 and 1.40 MPa PRFP. In both models, fluorescence measurements were used to determine penetration depth and concentration of delivered insulin. Results show that in agar gel, both insulin penetration depth and concentration only increased significantly in the presence of inertial cavitation, with up to a 40% enhancement. In porcine skin the amount of fluorescent insulin was higher in the epidermis of those samples that were exposed to ultrasound compared to the control samples, but there was no significant increase in penetration distance. The results underline the importance of instigating and monitoring inertial cavitation during transdermal insulin delivery.

  7. Modeling the coupling between free and forced convection in a vertical permeable slot: Implications for the heat production of an Enhanced Geothermal System

    Energy Technology Data Exchange (ETDEWEB)

    Bataille, Arnaud; Genthon, Pierre; Rabinowicz, Michel [Laboratoire de Dynamique Terrestre et Planetaire, UMR 5562, Observatoire Midi-Pyrenees, 14 Avenue Edouard Belin, 31400 Toulouse (France); Fritz, Bertrand [Centre de Geochimie de Surface, UMR 7517, Ecole de l' Observatoire des Sciences de la Terre, 1 rue Blessig, F-67084 Strasbourg (France)

    2006-10-15

    The aim of the hydraulic stimulations in the Soultz-sous-Forets, France, Enhanced Geothermal System (EGS) project was to create, in crystalline rocks, a fractured reservoir 750 m high, 750 m long and 35 m thick interconnecting the injection and production wells. Increasing the permeability in a zone with a high geothermal gradient will trigger free convection, which will interact with the forced flow driven by pumping. A systematic numerical study of the coupling between forced and free convective flows has been performed by considering a large range of injection rates and Rayleigh numbers. The simulations showed that if there is weak or no free convection in an EGS reservoir, economic exploitation of the system will rapidly end because of a decrease in produced fluid temperature. The maximum injection rate preventing such a temperature drop increases with the Rayleigh number and the height of the stimulated domain. The model establishes constraints on the conditions for achieving optimal heat extraction at the Soultz-sous-Forets EGS site. It was also shown that, although mineral precipitation may partially close or heal some open fissures, it does not lead to a major decrease of the hydraulic conductivity in the stimulated reservoir. (author)

  8. Diffusion, Convection and Erosion on SE(3)/({0} \\times SO(2)) and their Application to the Enhancement of Crossing Fibers

    CERN Document Server

    Duits, Remco; Ghosh, Arpan; Haije, Tom Dela

    2011-01-01

    In this article we study both left-invariant (convection-)diffusions and left-invariant Hamilton-Jacobi equations on the space SE(3)/({0} \\times SO(2)) of 3D-positions and orientations naturally embedded in the group SE(3) of 3D-rigid body movements. The general motivation for these (convection-)diffusions and erosions is to obtain crossing-preserving fiber enhancement on probability densities defined on the space of positions and orientations. The linear left-invariant (convection-)diffusions are forward Kolmogorov equations of Brownian motions on SE(3)/({0}\\timesSO(2)) and can be solved by convolution with the corresponding Green's functions or by a finite difference scheme. The left-invariant Hamilton-Jacobi equations are Bellman equations of cost processes on SE(3)/({0}\\timesSO(2)) and they are solved by a morphological convolution with the corresponding Green's functions. Furthermore, we consider pseudo-linear scale spaces on the space of positions and orientations that combines dilation and diffusion in...

  9. HIV-TAT enhances the transdermal delivery of NSAID drugs from liquid crystalline mesophases.

    Science.gov (United States)

    Cohen-Avrahami, Marganit; Shames, Alexander I; Ottaviani, M Francesca; Aserin, Abraham; Garti, Nissim

    2014-06-12

    Sodium diclofenac (Na-DFC) and celecoxib (CLXB) are common nonsteroidal anti-inflammatory (NSAID) drugs which suffer from poor bioavailability and severe side effects when consumed orally, and their transdermal delivery might present important advantages. In this study, the drugs were solubilized in cubic and lamellar mesophases as transdermal delivery vehicles, and a cell-penetrating peptide, HIV-TAT (TAT), was examined as a skin penetration enhancer. SD-NMR, ATR-FTIR, and EPR measurements revealed that, in the cubic mesophase (which is rich in water content), TAT populates the aqueous cores and binds water, while in the dense lamellar system (with the lower water content) TAT is bound also to the glycerol monooleate (GMO) and increases the microviscosity and the order degree. TAT secondary structure in the cubic system was found to be a random coil while once it was embedded in the closely packed lamellar system it transforms to a more ordered compact state of β-turns arranged around the GMO headgroups. TAT remarkably increased the diffusion of Na-DFC and CLXB from the cubic systems by 6- and 9-fold enhancement, respectively. TAT effect on drug diffusion from the lamellar systems was limited to an increase of 1.3- and 1.7-fold, respectively. The dense packing and strong binding in the lamellar phase led to slow diffusion rates and slower drug release in controlled pattern. These effects of the chemical composition and vehicle geometry on drug diffusion are demonstrated with the impacts of TAT which can be specifically utilized for controlling skin delivery of drugs as required.

  10. Tumor priming enhances siRNA delivery and transfection in intraperitoneal tumors.

    Science.gov (United States)

    Wang, Jie; Lu, Ze; Yeung, Bertrand Z; Wientjes, M Guillaume; Cole, David J; Au, Jessie L-S

    2014-03-28

    Cancers originating from the digestive system account for 290,000 or ~20% of all new cancer cases annually in the US. We previously developed paclitaxel-loaded tumor-penetrating microparticles (TPM) for intraperitoneal (IP) treatment of peritoneal tumors (Lu et al., 2008; Tsai et al., 2007; Tsai et al., 2013). TPM is undergoing NIH-supported IND-enabling studies for clinical evaluation. The present study evaluated the hypothesis that TPM, via inducing apoptosis and expanding the interstitial space, promotes the delivery and transfection of lipid vectors containing siRNA. The in vivo model was the metastatic human Hs766T pancreatic tumor that, upon IP injection, produced widely distributed solid tumors and ascites in the peritoneal cavity in 100% of animals. The target gene was survivin, an anti-apoptotic protein induced by chemotherapy and associated with metastases and poor prognosis of patients with gastric and colorectal cancers. The siRNA carrier was pegylated liposomes comprising cationic and neutral lipids plus a fusogenic lipid (PCat). PCat-loaded with survivin siRNA (PCat-siSurvivin) was active in cultured cells (decreased survivin mRNA and protein levels, reduced cell clonogenicity, enhanced paclitaxel activity), but lost its activity in vivo; this difference is consistent with the well-known problem of inadequate delivery and transfection of siRNA in vivo. In comparison, single agent TPM prolonged animal survival and, as expected, induced survivin expression in tumors. Addition of PCat-siSurvivin reversed the TPM-induced survivin expression and enhanced the antitumor activity of TPM. The finding that in vivo survivin knockdown by PCat-siSurvivin was successful only when it was given in combination with TPM provides the proof-of-concept that tumor priming promotes the delivery and transfection of liposomal siRNA. The data further suggest the TPM/PCat-siSurvivin combination as a potentially useful chemo-gene therapy for peritoneal cancer.

  11. Formulation and optimization of nano-sized ethosomes for enhanced transdermal delivery of cromolyn sodium

    Directory of Open Access Journals (Sweden)

    R Rakesh

    2012-01-01

    Full Text Available Aim: The current study was aimed to investigate the feasibility of transdermal delivery of cromolyn sodium using a novel lipid vesicular carrier, ethosomes. Materials And Methods: Ethosomes of cromolyn sodium was prepared, optimized, and characterized for vesicle shape, vesicle size and size distribution, zeta potential, entrapment efficiency, in vitro drug release, in vitro skin permeation, in vitro skin deposition and vesicle stability. Histological examination of porcine ear skin treated with optimized ethosomal formulation was performed to study the change of skin morphologies. Results: The optimized cromolyn sodium ethosomes showed reasonable entrapment efficiency (49.88±1.84%, optimum nanometric size range (133.8 ± 7.5 nm, and high zeta potential (-69.82 ± 1.2 mV. In vitro drug release studies of optimized ethosomal formulation through cellophane membrane showed an enhanced and sustained delivery of drug compared to conventional liposomes, hydroethanolic, (45% v/v and phosphate buffer saline PBS pH 7.4 drug solutions. The optimized ethosomal formulation showed significantly-enhanced transdermal flux (18.49 ± 0.08 mg/cm 2 /h across porcine ear skin as compared to liposome (1.80 ± 0.12 mg/cm 2 /h, hydroethanolic drug solution (4.45 ± 0.71 mg/cm 2 /h, and PBS pH 7.4 drug solution (1.18 ± 0.35 mg/cm 2 /h. Moreover, ethosomal formulation showed better skin drug deposition (10.28 ± 0.67% and shortest lag time (0.11 ± 0.09 h for cromolyn sodium. Conclusion: Our significant results suggest that ethosomes can be a promising tool for transdermal delivery of cromolyn sodium.

  12. DNA Tetrahedron Delivery Enhances Doxorubicin-Induced Apoptosis of HT-29 Colon Cancer Cells

    Science.gov (United States)

    Zhang, Guiyu; Zhang, Zhiyong; Yang, Junen

    2017-08-01

    As a nano-sized drug carrier with the advantage of modifiability and proper biocompatibility, DNA tetrahedron (DNA tetra) delivery is hopeful to enhance the inhibitory efficiency of nontargeted anticancer drugs. In this investigation, doxorubicin (Dox) was assembled to a folic acid-modified DNA tetra via click chemistry to prepare a targeted antitumor agent. Cellular uptake efficiency was measured via fluorescent imaging. Cytotoxicity, inhibition efficiency, and corresponding mechanism on colon cancer cell line HT-29 were evaluated by MTT assay, cell proliferation curve, western blot, and flow cytometry. No cytotoxicity was induced by DNA tetra, but the cellular uptake ratio increased obviously resulting from the DNA tetra-facilitated penetration through cellular membrane. Accordingly, folic acid-DNA tetra-Dox markedly increased the antitumor efficiency with increased apoptosis levels. In details, 100 μM was the effective concentration and a 6-h incubation period was needed for apoptosis induction. In conclusion, nano-sized DNA tetrahedron was a safe and effective delivery system for Dox and correspondingly enhanced the anticancer efficiency.

  13. Permeability enhancement for transdermal delivery of large molecule using low-frequency sonophoresis combined with microneedles.

    Science.gov (United States)

    Han, Tao; Das, Diganta Bhusan

    2013-10-01

    Transdermal drug delivery is limited by the high resistance of skin towards diffusion of high-molecular-weight drugs. This is mainly because of the fact that the outer layer of the skin, that is the stratum corneum, can prevent diffusion of molecules whose molecular weight is greater than 500 Da. Sonophoresis can be used to enhance the permeability of the skin. However, in the delivery of large molecules, ultrasound alone cannot provide sufficient permeability enhancement. In addressing this issue, we propose optimised ultrasound combined with microneedles to further increase the permeation rates. In this paper, we use porcine ear skin to simulate human skin and treat the skin samples with both ultrasound and microneedles. Further, bovine serum albumin (BSA) is used as a model of larger molecular weight molecule. Our results show that the permeability of BSA is increased to 1 μm/s with the combination of 1.5 mm microneedles patch and 15-W ultrasound output which is about 10 times higher than the permeability obtained in passive diffusion. Diffusion with only microneedles or ultrasound pre-treatment is also tested. The maximum permeability from microneedles and ultrasound treatment reached 0.43 and 0.4 μm/s, respectively. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

  14. Enhanced transdermal delivery of 5-aminolevulinic acid and a dipeptide by iontophoresis.

    Science.gov (United States)

    Krishnan, Gayathri; Roberts, Michael S; Grice, Jeffrey; Anissimov, Yuri G; Benson, Heather A E

    2011-01-01

    Poor skin permeability limits the application of peptides to the skin. Enhanced skin permeation could facilitate the development of new therapies for dermatologic and cosmeceutical applications. The aim of this study was to investigate the application of iontophoresis to the delivery of small peptide model compounds (5-aminolevulinic acid and L-alanine-L-tryptophan) across human skin. Under the conditions tested, iontophoresis increased the in vitro permeability coefficient of ALA.HCl across human epidermis from 7 X 10(-5) cm/h with passive diffusion to 110 x 10(-5) cm/h with iontophoresis. D-Glucose permeation elucidated the iontophoretic electrotransport of ALA.HCl to have contributions of both electrorepulsion and electroosmosis. The L-alanine-L-tryptophan permeability coefficient was increased from 1.5 x 10(-5) cm/h to 35 x 10(-5) cm/h with iontophoretic application. Iontophoretic delivery of the dipeptide increased markedly at lower pH because of an increase in electrorepulsive transport. The study demonstrates that iontophoresis can enhance epidermal permeation of a small peptide and peptide-like drug by up to 15- and 22-fold under the conditions tested.

  15. Localized Co-delivery of Doxorubicin, Cisplatin, and Methotrexate by Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment.

    Science.gov (United States)

    Ma, Hecheng; He, Chaoliang; Cheng, Yilong; Yang, Zhiming; Zang, Junting; Liu, Jianguo; Chen, Xuesi

    2015-12-16

    Localized cancer treatments with combination drugs have recently emerged as crucial approaches for effective inhibition of tumor growth and reoccurrence. In this study, we present a new strategy for the osteosarcoma treatment by localized co-delivery of multiple drugs, including doxorubicin (DOX), cisplatin (CDDP) and methotraxate (MTX), using thermosensitive PLGA-PEG-PLGA hydrogels. The release profiles of the drugs from the hydrogels were investigated in vitro. It was found that the multidrug coloaded hydrogels exhibited synergistic effects on cytotoxicity against osteosarcoma Saos-2 and MG-63 cells in vitro. After a single peritumoral injection of the drug-loaded hydrogels into nude mice bearing human osteosarcoma Saos-2 xenografts, the hydrogels coloaded with DOX, CDDP, and MTX displayed the highest tumor suppression efficacy in vivo for up to 16 days, as well as led to enhanced tumor apoptosis and increased regulation of the expressions of apoptosis-related genes. Moreover, the monitoring on the mice body change and the ex vivo histological analysis of the key organs indicated that the localized treatments caused less systemic toxicity and no obvious damage to the normal organs. Therefore, the approach of localized co-delivery of DOX, CDDP, and MTX by the thermosensitive hydrogels may be a promising approach for enhanced osteosarcoma treatment.

  16. Enhanced topical delivery of tetrandrine by ethosomes for treatment of arthritis.

    Science.gov (United States)

    Fan, Chao; Li, Xinru; Zhou, Yanxia; Zhao, Yong; Ma, Shujin; Li, Wenjing; Liu, Yan; Li, Guiling

    2013-01-01

    The purpose of this work was to explore the feasibility of ethosomes for improving the antiarthritic efficacy of tetrandrine by topical application. It was found that tetrandrine was a weak base (pK(a) = 7.06) with pH-dependent partition coefficient. The spherical-shaped ethosomes were prepared by pH gradient loading method. Ex vivo permeation and deposition behavior demonstrated that the drug flux across rat skin and deposition of the drug in rat skin for ethosomes was 2.1- and 1.7-fold higher than that of liposomes, respectively. Confocal laser scanning microscopy confirmed that ethosomes could enhance the topical delivery of the drug in terms of depth and quantity compared with liposomes. The ethosomes were shown to generate substantial enhancement of therapeutic efficacy of tetrandrine on Freund's complete adjuvant-induced arthritis with regard to liposomes. These results indicated that ethosomes would be a promising carrier for topical delivery of tetrandrine into and across the skin.

  17. Enhanced Topical Delivery of Tetrandrine by Ethosomes for Treatment of Arthritis

    Directory of Open Access Journals (Sweden)

    Chao Fan

    2013-01-01

    Full Text Available The purpose of this work was to explore the feasibility of ethosomes for improving the antiarthritic efficacy of tetrandrine by topical application. It was found that tetrandrine was a weak base (pKa=7.06 with pH-dependent partition coefficient. The spherical-shaped ethosomes were prepared by pH gradient loading method. Ex vivo permeation and deposition behavior demonstrated that the drug flux across rat skin and deposition of the drug in rat skin for ethosomes was 2.1- and 1.7-fold higher than that of liposomes, respectively. Confocal laser scanning microscopy confirmed that ethosomes could enhance the topical delivery of the drug in terms of depth and quantity compared with liposomes. The ethosomes were shown to generate substantial enhancement of therapeutic efficacy of tetrandrine on Freund’s complete adjuvant-induced arthritis with regard to liposomes. These results indicated that ethosomes would be a promising carrier for topical delivery of tetrandrine into and across the skin.

  18. Ethosomes - novel vesicular carriers for enhanced delivery: characterization and skin penetration properties.

    Science.gov (United States)

    Touitou, E; Dayan, N; Bergelson, L; Godin, B; Eliaz, M

    2000-04-03

    This work describes a novel carrier for enhanced skin delivery, the ethosomal system, which is composed of phospholipid, ethanol and water. Ethosomal systems were much more efficient at delivering a fluorescent probe to the skin in terms of quantity and depth, than either liposomes or hydroalcoholic solution. The ethosomal system dramatically enhanced the skin permeation of minoxidil in vitro compared with either ethanolic or hydroethanolic solution or phospholipid ethanolic micellar solution of minoxidil. In addition, the transdermal delivery of testosterone from an ethosomal patch was greater both in vitro and in vivo than from commercially available patches. Skin permeation of ethosomal components, ethanol and phospholipid, was demonstrated in diffusion-cell experiments. Ethosomal systems composed of soy phosphatidylcholine 2%, ethanol 30% and water were shown by electron microscopy to contain multilamellar vesicles. 31P-NMR studies confirmed the bilayer configuration of the lipids. Calorimetry and fluorescence measurements suggested that the vesicular bilayers are flexible, having a relatively low T(m) and fluorescence anisotropy compared with liposomes obtained in the absence of ethanol. Dynamic light scattering measurements indicated that ethanol imparted a negative charge to the vesicles. The average vesicle size, as measured by dynamic light scattering, was modulated by altering the ethosome composition. Experiments using fluorescent probes and ultracentrifugation showed that the ethosomes had a high entrapment capacity for molecules of various lyophilicities.

  19. Convection-Enhanced Delivery (CED) in an Animal Model of Malignant Peripheral Nerve Sheath Tumors and Plexiform Neurofibromas

    Science.gov (United States)

    2013-02-01

    sheath tumors or plexiform neurofibromas. References: Perrin GQ, Fishbein L, Thomson SA, et al., Plexiform-like neurofibromas develop in the...mouse by intraneural xenograft of an NF1 tumor-derived Schwann cell line. J Neurosci Res, 2007. 85(6): p. 1347-1357. 3 Perrin GQ, Li H, Fishbein L

  20. Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats

    OpenAIRE

    Tianyao Huo; Barth, Rolf F.; Weilian Yang; Nakkula, Robin J.; Rumiana Koynova; Boris Tenchov; Abhik Ray Chaudhury; Lawrence Agius; Teni Boulikas; Helene Elleaume; Lee, Robert J.

    2012-01-01

    International audience; 12 Hide Figures Abstract Introduction Materials and Methods Results Discussion Acknowledgments Author Contributions References Reader Comments (0) Figures Abstract The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (...

  1. Enhancement of Natural Convection by Carbon Nanotube Films Covered Microchannel-Surface for Passive Electronic Cooling Devices.

    Science.gov (United States)

    Zhang, Guang; Jiang, Shaohui; Yao, Wei; Liu, Changhong

    2016-11-16

    Owing to the outstanding properties of thermal conduction, lightweight, and chemical durability, carbon nanotubes (CNTs) have revealed promising applications in thermal management materials. Meanwhile, the increasingly popular portable electronics and the rapid development of space technology need lighter weight, smaller size, and more effective thermal management devices. Here, a novel kind of heat dissipation devices based on the superaligned CNT films and underlying microchannels is proposed, and the heat dissipation properties are measured at the natural condition. Distinctive from previous studies, by combining the advantages of microchannels and CNTs, such a novel heat dissipation device enables superior natural convection heat transfer properties. Our findings prove that the novel CNT-based devices could show an 86.6% larger total natural heat dissipation properties than bare copper plate. Further calculations of the radiation and natural convection heat transfer properties demonstrate that the excellent passive cooling properties of these CNT-based devices are primarily caused by the reinforcement of the natural convection heat transfer properties. Furthermore, the heat dissipation mechanisms are briefly discussed, and we propose that the very high heat transfer coefficients and the porous structures of superaligned CNT films play critical roles in reinforcing the natural convection. The novel CNT-based heat dissipation devices also have advantages of energy-saving, free-noise, and without additional accessories. So we believe that the CNT-based heat dissipation devices would replace the traditional metal-finned heat dissipation devices and have promising applications in electronic devices, such as photovoltaic devices, portable electronic devices, and electronic displays.

  2. PLGA-soya lecithin based micelles for enhanced delivery of methotrexate: Cellular uptake, cytotoxic and pharmacokinetic evidences.

    Science.gov (United States)

    Singh, Anupama; Thotakura, Nagarani; Kumar, Rajendra; Singh, Bhupinder; Sharma, Gajanand; Katare, Om Prakash; Raza, Kaisar

    2017-02-01

    Biocompatible and biodegradable polymers like PLGA have revolutionized the drug delivery approaches. However, poor drug loading and substantially high lipophilicity, pave a path for further tailing of this promising agent. In this regard, PLGA was feathered with biocompatible phospholipid and polymeric micelles were developed for delivery of Methotrexate (MTX) to cancer cells. The nanocarriers (114.6nm±5.5nm) enhanced the cytotoxicity of MTX by 2.13 folds on MDA-MB-231 cells. Confocal laser scanning microscopy confirmed the increased intracellular delivery. The carrier decreased the protein binding potential and enhanced the bioavailable fraction of MTX. Pharmacokinetic studies vouched substantial enhancement in AUC and bioresidence time, promising an ideal carrier to effectively deliver the drug to the site of action. The developed nanocarriers offer potential to deliver the drug in the interiors of cancer cells in an effective manner for improved therapeutic action. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Experimental investigation of forced convective heat transfer enhancement of γ-Al{sub 2}O{sub 3}/water nanofluid in a tube

    Energy Technology Data Exchange (ETDEWEB)

    Noghrehabadi, Aminreza; Pourrajab, Rashid [Shahid Chamran University of Ahvaz, Ahvaz (Iran, Islamic Republic of)

    2016-02-15

    The effect of nanofluids on heat transfer inside circular tubes under uniform constant heat flux boundary condition was investigated. The working nanofluid was a suspension of γ-Al{sub 2}O{sub 3} nanoparticles of average diameter 20 nm. The heat transfer coefficients were calculated experimentally in the range of 1057 < Re < 2070 with different particle volume concentrations of 0.1%, 0.3% and 0.9%. Increasing the particle volume fraction led to enhancement of the convective heat transfer coefficient. The results show that the average heat transfer coefficient increased 16.8% at 0.9% volume concentration and Reynolds number of 2070 compared with distilled water. In addition, the enhancement of the convective heat transfer was particularly significant in the entrance region and decreased with axial distance. Finally, an empirical correlation for Nusselt number has been proposed for the present range of nanofluids. The mean deviation between the predicted Nusselt number and experimental values for the new correlation is 3.57%.

  4. Spray-freeze-dried dry powder inhalation of insulin-loaded liposomes for enhanced pulmonary delivery.

    Science.gov (United States)

    Bi, Ru; Shao, Wei; Wang, Qun; Zhang, Na

    2008-11-01

    Nowadays, growing attention has been paid to the pulmonary region as a target for the delivery of peptide and protein drugs, especially macromolecules with systemic effect like insulin, since the pulmonary route exhibits numerous benefits to be an alternative for repeated injection. Furthermore, encapsulation of insulin into liposomal carriers is an attractive way to increase drug retention time and control the drug release in the lung; however, its long-term stability during storage in the reservoir and the process of aerosolization might be suspected when practically applied. Thus, the aim of this study was to design and characterize dry powder inhalation of insulin-loaded liposomes prepared by novel spray-freeze-drying method for enhanced pulmonary delivery. Process variables such as compressed air pressure, pump speed, and concentration were optimized for parameters such as mean particle diameter, moisture content, and fine particle fraction of the produced powders. Influence of different kinds and amounts of lyoprotectants was also evaluated for the best preservation of the drug entrapped in the liposome bilayers after the dehydration-rehydration cycle. The in vivo study of intratracheal instillation of insulin-loaded liposomes to diabetic rats showed successful hypoglycemic effect with low blood glucose level and long-lasting period and a relative pharmacological bioavailability as high as 38.38% in the group of 8 IU/kg dosage.

  5. Enhancing the nurses' role in healthcare delivery through strategic management: recognizing its importance or not?

    Science.gov (United States)

    Carney, Marie

    2009-09-01

    To determine the importance of strategy in nursing management and to establish if strategic management has entered the lexicon of nurses' vocabulary. Developing and managing strategy is a critical success factor for health care managers. It remains unclear if nurse managers view strategy development as their role. A review of scholarly International nursing and management literature, available through CINAHL and PUBMED Data Bases was undertaken. The titles of 1063 articles, published between 1997 and 2007 were examined in order to determine the profile of strategy in those titles. Documentary analysis was undertaken on a random sample of 250 of those articles and on the full text of a further 100. Less than 10% of journal titles contained the word strategy. What was presented as strategy was in the majority of cases describing policy, administration or management. Little formal strategy theory was evident. The nursing profession does not appear to have adopted the terms strategy or strategic management to any great extent. Nurse Managers could play a greater role in enhancing healthcare delivery if an understanding of, and acceptance of the importance of strategy in health care delivery was promoted.

  6. Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

    Directory of Open Access Journals (Sweden)

    Jan Hoyer

    2012-10-01

    Full Text Available Over the past 20 years, cell-penetrating peptides (CPPs have gained tremendous interest due to their ability to deliver a variety of therapeutically active molecules that would otherwise be unable to cross the cellular membrane due to their size or hydrophilicity. Recently, we reported on the identification of a novel CPP, sC18, which is derived from the C-terminus of the 18 kDa cationic antimicrobial protein. Furthermore, we demonstrated successful application of sC18 for the delivery of functionalized cyclopentadienyl manganese tricarbonyl (cymantrene complexes to tumor cell lines, inducing high cellular toxicity. In order to increase the potential of the organometallic complexes to kill tumor cells, we were looking for a way to enhance cellular uptake. Therefore, we designed a branched dimeric variant of sC18, (sC182, which was shown to have a dramatically improved capacity to internalize into various cell lines, even primary cells, using flow cytometry and fluorescence microscopy. Cell viability assays indicated increased cytotoxicity of the dimer presumably caused by membrane leakage; however, this effect turned out to be dependent on the specific cell type. Finally, we could show that conjugation of a functionalized cymantrene with (sC182 leads to significant reduction of its IC50 value in tumor cells compared to the respective sC18 conjugate, proving that dimerization is a useful method to increase the drug-delivery potential of a cell-penetrating peptide.

  7. SOLUBILITY ENHANCEMENT OF FENOFIBRATE, A BCS CLASS II DRUG, BY SELF EMULSIFYING DRUG DELIVERY SYSTEMS

    Directory of Open Access Journals (Sweden)

    M.Sunitha Reddy

    2011-11-01

    Full Text Available The present work was aimed at the enhancement of solubility of Fenofibrate a BCS class II drug by Self Emulsifying Drug Delivery systems (SEDDS. The solubility of Fenofibrate in various excipients was determined. The excipients were screened for maximum solubility and compatibility. SEDDS formulations of Fenofibrate were developed using different Oils, Surfactants and Co-Surfactant combinations. Pseudoternary phase diagrams were drawn using Triplot software and by applying Pseudoternary phase diagrams, microemulsification area was evaluated.Formulations were screened based on visual observances and phase diagrams. Seven formulations were selected for further evaluations like stability, effect of dilution, freeze-thawing, emulsion droplet size and zeta potential. Among the seven formulations three were optimized and In-Vitro dissolution was performed. The dissolution rate of SEDDS was compared with plain Fenofibrate (API. The study confirmed that the solubility and dissolution rate of Fenofibrate were remarkably increased when compared to that of plain drug. Hence SEDDS formulations can be a potential alternative to traditional oral drug delivery systems of Fenofibrate to improve its bioavailability.

  8. Silica-Based Carbon Source Delivery for In-situ Bioremediation Enhancement

    Science.gov (United States)

    Zhong, L.; Lee, M. H.; Lee, B.; Yang, S.

    2015-12-01

    Colloidal silica aqueous suspensions undergo viscosity increasing and gelation over time under favorable geochemical conditions. This property of silica suspension can potentially be applied to deliver remedial amendments to the subsurface and establish slow release amendment sources for enhanced remediation. In this study, silica-based delivery of carbon sources for in-situ bioremediation enhancement is investigated. Sodium lactate, vegetable oil, ethanol, and molasses have been studied for the interaction with colloidal silica in aqueous suspensions. The rheological properties of the carbon source amendments and silica suspension have been investigated. The lactate-, ethanol-, and molasses-silica suspensions exhibited controllable viscosity increase and eventually became gels under favorable geochemical conditions. The gelation rate was a function of the concentration of silica, salinity, amendment, and temperature. The vegetable oil-silica suspensions increased viscosity immediately upon mixing, but did not perform gelation. The carbon source release rate from the lactate-, ethanol-, and molasses-silica gels was determined as a function of silica, salinity, amendment concentration. The microbial activity stimulation and in-situ bioremediation enhancement by the slow-released carbon from the amendment-silica gels will be demonstrated in future investigations planned in this study.

  9. Electrokinetically Enhanced Delivery for ERD Remediation of Chlorinated Ethenes in a Fractured Limestone Aquifer

    DEFF Research Database (Denmark)

    Broholm, Mette Martina; Hansen, Bente H.; With Nedergaard, Lærke;

    Leakage of the chlorinated solvents PCE and TCE into limestone aquifers from contaminated overburden and the long-lasting back diffusion from the secondary source in the limestone matrix pose a severe risk for contamination of drinking water resources. Dechlorination of PCE and TCE in limestone...... often accumulates cis-DCE due to incomplete dechlorination in the limestone aquifers, as observed downgradient of a PCE and TCE DNAPL source area at Naverland in Denmark. A microcosm study with limestone core material and groundwater from the Naverland site source area spiked with PCE showed...... that enhanced reductive dechlorination (ERD) by the addition of donor and specific degraders (KB1® culture) can lead to complete dechlorination of PCE and TCE in the limestone aquifer, provided sufficient contact between specific degraders, donor and specific degraders, is obtained. Advection-based delivery...

  10. Triphenyl Phosphine-Functionalized Chitosan Nanoparticles Enhanced Antitumor Efficiency Through Targeted Delivery of Doxorubicin to Mitochondria

    Science.gov (United States)

    Hou, Jiahui; Yu, Xiwei; Shen, Yaping; Shi, Yijie; Su, Chang; Zhao, Liang

    2017-02-01

    Mitochondria as an important organ in eukaryotic cells produced energy through oxidative phosphorylation and also played an important role in regulating the apoptotic signal transduction process. Importantly, mitochondria like nuclei also contained the functional DNA and were very sensitive to anticancer drugs which could effectively inhibit the synthesis of nucleic acid, especially the production of DNA. In this work, we designed novel triphenyl phosphine (TPP)-conjugated chitosan (CS) nanoparticles (NPs) for efficient drug delivery to cell mitochondria. The results showed that compared with free doxorubicin (Dox), Dox-loaded TPP-NPs were specifically distributed in mitochondria of tumor cells and interfered with the function of mitochondria, thus resulted in the higher cytotoxicity and induced the significant cell apoptosis effect. Taken together, triphenyl phosphine-conjugated chitosan nanoparticles may become a promising mitochondria-targeting nanocarrier candidate for enhancing antitumor effects.

  11. Polymeric micelles as a drug delivery system enhance cytotoxicity of vinorelbine through more intercellular accumulation.

    Science.gov (United States)

    Lu, Xiaoyan; Zhang, Fayun; Qin, Lei; Xiao, Fengying; Liang, Wei

    2010-05-01

    Polymeric micelles had been used as an efficacious carrier system for anti-cancer drug delivery. However, it is not clear whether the molecular mechanism of drug encapsulated in micelles is same as free drug. In this study, the mechanism of vinorelbine loaded in glycol-phosphatidylethanolamine (PEG-PE) micelles (M-Vino) on tumor cells was investigated. Compared with free vinorelbine (Free Vino), M-Vino was more effective in inhibiting the growth of tumor cells in vitro, inducing G(2)/M phase arrest and apoptosis of tumor cells. M-Vino showed a faster entry and higher accumulation in 4T1 cells than free vinorelbine. Therefore, M-Vino destabilized microtubules, induced cell death, and enhanced its cytotoxicity through more intercellular accumulation of vinorelbine.

  12. Microencapsulation in alginate and chitosan microgels to enhance viability of Bifidobacterium longum for oral delivery

    Directory of Open Access Journals (Sweden)

    Timothy W. Yeung

    2016-04-01

    Full Text Available Probiotic microorganisms are incorporated into a wide variety of foods, supplements, and pharmaceuticals to promote human health and wellness. However, maintaining bacterial cell viability during storage and gastrointestinal transit remains a challenge. Encapsulation of bifidobacteria within food-grade hydrogel particles potentially mitigates their sensitivity to environmental stresses. In this study, Bifidobacterium longum subspecies and strains were encapsulated in core-shell microgels consisting of an alginate core and a microgel shell. Encapsulated obligate anaerobes Bifidobacterium longum subsp. infantis and Bifidobacterium longum subsp. longum exhibited differences in viability in a strain-dependent manner, without a discernable relationship to subspecies lineage. This includes viability under aerobic storage conditions and modeled gastrointestinal tract conditions. Coating alginate microgels with chitosan did not improve viability compared to cells encapsulated in alginate microgels alone, suggesting that modifying the surface charge alone does not enhance delivery. Thus hydrogel beads have great potential for improving the stability and efficacy of bifidobacterial probiotics in various nutritional interventions.

  13. Microencapsulation in Alginate and Chitosan Microgels to Enhance Viability of Bifidobacterium longum for Oral Delivery

    Science.gov (United States)

    Yeung, Timothy W.; Üçok, Elif F.; Tiani, Kendra A.; McClements, David J.; Sela, David A.

    2016-01-01

    Probiotic microorganisms are incorporated into a wide variety of foods, supplements, and pharmaceuticals to promote human health and wellness. However, maintaining bacterial cell viability during storage and gastrointestinal transit remains a challenge. Encapsulation of bifidobacteria within food-grade hydrogel particles potentially mitigates their sensitivity to environmental stresses. In this study, Bifidobacterium longum subspecies and strains were encapsulated in core-shell microgels consisting of an alginate core and a microgel shell. Encapsulated obligate anaerobes Bifidobacterium longum subsp. infantis and Bifidobacterium longum subsp. longum exhibited differences in viability in a strain-dependent manner, without a discernable relationship to subspecies lineage. This includes viability under aerobic storage conditions and modeled gastrointestinal tract conditions. Coating alginate microgels with chitosan did not improve viability compared to cells encapsulated in alginate microgels alone, suggesting that modifying the surface charge alone does not enhance delivery. Thus hydrogel beads have great potential for improving the stability and efficacy of bifidobacterial probiotics in various nutritional interventions. PMID:27148184

  14. Chitosan wound dressing with hexagonal silver nanoparticles for hyperthermia and enhanced delivery of small molecules.

    Science.gov (United States)

    Levi-Polyachenko, Nicole; Jacob, Reuben; Day, Cynthia; Kuthirummal, Narayanan

    2016-06-01

    Chitosan films were synthesized with hexagonal silver nanoparticles (Ag NP). The unique shape and size of the Ag NP shift the optical absorption into the infrared. Stimulation of the nanoparticles with infrared light was used to generate heat and facilitate intracellular delivery of fluorescently-labeled dextran molecules. Chitosan films prepared with hexagonal or spherical Ag NP were characterized by optical and thermal analyses, and X-ray diffraction. There were found to be slight differences between how the chitosan molecular chains interface with the Ag NP depending upon shape of the nanoparticle. Viability of cells associated with dermal wound healing was evaluated on chitosan films prepared with hexagonal or spherical Ag NP, with both keratinocytes and fibroblasts having normal or moderately enhanced growth on films containing hexagonally-shaped nanoparticles.

  15. Mixed-micellar proliposomal systems for enhanced oral delivery of progesterone.

    Science.gov (United States)

    Potluri, Praveen; Betageri, Guru V

    2006-01-01

    The objective of our study was to develop a mixed-micellar proliposomal formulation of poorly water-soluble drug progesterone and evaluate the dissolution profile and membrane transport. Several formulations of proliposomes were prepared by mixing different concentrations of lipid, progesterone, polysorbate 80, and microcrystalline cellulose. The mixed-micellar formulation of drug:dimyristoyl-phosphatidycholine:polysorbate 80 (1:20:3.3) exhibited the maximum dissolution (75.27%), while pure progesterone resulted in low dissolution. The above formulation showed a 4-fold increase in transport in Caco-2 cells and a 6-fold increase in transport across the everted rat intestinal sac experiments compared with control. Proliposomal formulations enhance the extent of dissolution and membrane transport of progesterone and serve as ideal carriers for oral delivery of drugs with low water solubility.

  16. Enhanced transdermal delivery of indomethacin-loaded PLGA nanoparticles by iontophoresis.

    Science.gov (United States)

    Tomoda, Keishiro; Terashima, Hiroto; Suzuki, Kenichi; Inagi, Toshio; Terada, Hiroshi; Makino, Kimiko

    2011-12-01

    Nanoparticles effectively deliver therapeutic agent by penetrating into the skin. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100 nm. IM and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis with 3 V/cm was applied, permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal delivery of therapeutic agents.

  17. Enhanced transdermal delivery of indomethacin using combination of PLGA nanoparticles and iontophoresis in vivo.

    Science.gov (United States)

    Tomoda, Keishiro; Terashima, Hiroto; Suzuki, Kenichi; Inagi, Toshio; Terada, Hiroshi; Makino, Kimiko

    2012-04-01

    Nanoparticles effectively deliver therapeutic agent by penetrating into the rat skin in vivo. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100 nm. Indomethacin (IM) and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied in vivo. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis was applied at 0.05 mA/cm(2), permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal systemic delivery of therapeutic agents.

  18. Blood-Brain Barrier Transport of Cationized Immunoglobulin G: Enhanced Delivery Compared to Native Protein

    Science.gov (United States)

    Triguero, Domingo; Buciak, Jody B.; Yang, Jing; Pardridge, William M.

    1989-06-01

    IgG molecules are potential neuropharmaceuticals that may be used for therapeutic or diagnostic purposes. However, IgG molecules are excluded from entering brain, owing to a lack of transport of these plasma proteins through the brain capillary wall, or blood-brain barrier (BBB). The possibility of enhanced IgG delivery through the BBB by cationization of the proteins was explored in the present studies. Native bovine IgG molecules were cationized by covalent coupling of hexamethylenediamine and the isoelectric point was raised to >10.7 based on isoelectric focusing studies. Native and cationized IgG molecules were radiolabeled with 125I and chloramine T. Cationized IgG, but not native IgG, was rapidly taken up by isolated bovine brain microvessels, which were used as an in vitro model system of the BBB. Cationized IgG binding was time and temperature dependent and was saturated by increasing concentrations of unlabeled cationized IgG (dissociation constant of the high-affinity binding site, 0.90 ± 0.37 μ M; Bmax, 1.4 ± 0.4 nmol per mg of protein). In vivo studies documented enhanced brain uptake of 125I-labeled cationized IgG relative to [3H]albumin, and complete transcytosis of the 125I-labeled cationized IgG molecule through the BBB and into brain parenchyma was demonstrated by thaw-mount autoradiography of frozen sections of rat brain obtained after carotid arterial infusions of 125I-labeled cationized IgG. These studies demonstrate that cationization of IgG molecules greatly facilitates the transport of these plasma proteins through the BBB in vivo, and this process may provide a new strategy for IgG delivery through the BBB.

  19. Blood-brain barrier transport of cationized immunoglobulin G: Enhanced delivery compared to native protein

    Energy Technology Data Exchange (ETDEWEB)

    Triguero, D.; Buciak, J.B.; Yang, J.; Pardridge, W.M.

    1989-06-01

    IgG molecules are potential neuropharmaceuticals that may be used for therapeutic or diagnostic purposes. However, IgG molecules are excluded from entering brain, owing to a lack of transport of these plasma proteins through the brain capillary wall, or blood-brain barrier (BBB). The possibility of enhanced IgG delivery through the BBB by cationization of the proteins was explored in the present studies. Native bovine IgG molecules were cationized by covalent coupling of hexamethylenediamine and the isoelectric point was raised to greater than 10.7 based on isoelectric focusing studies. Native and cationized IgG molecules were radiolabeled with /sup 125/I and chloramine T. Cationized IgG, but not native IgG, was rapidly taken up by isolated bovine brain microvessels, which were used as an in vitro model system of the BBB. Cationized IgG binding was time and temperature dependent and was saturated by increasing concentrations of unlabeled cationized IgG (dissociation constant of the high-affinity binding site, 0.90 +/- 0.37 microM; Bmax, 1.4 +/- 0.4 nmol per mg of protein). In vivo studies documented enhanced brain uptake of 125I-labeled cationized IgG relative to (3H)albumin, and complete transcytosis of the 125I-labeled cationized IgG molecule through the BBB and into brain parenchyma was demonstrated by thaw-mount autoradiography of frozen sections of rat brain obtained after carotid arterial infusions of 125I-labeled cationized IgG. These studies demonstrate that cationization of IgG molecules greatly facilitates the transport of these plasma proteins through the BBB in vivo, and this process may provide a new strategy for IgG delivery through the BBB.

  20. Thermal safety of ultrasound-enhanced ocular drug delivery: A modeling study

    Energy Technology Data Exchange (ETDEWEB)

    Nabili, Marjan, E-mail: mnabili@gwmail.gwu.edu [Department of Electrical and Computer Engineering, The George Washington University, 800 22nd Street NW, Room 5000, Washington, DC 20052 (United States); Geist, Craig, E-mail: cgeist@mfa.gwu.edu, E-mail: zderic@gwu.edu [Department of Ophthalmology, The George Washington University, 2150 Pennsylvania Avenue NW, Floor 2A, Washington, DC 20037 (United States); Zderic, Vesna, E-mail: cgeist@mfa.gwu.edu, E-mail: zderic@gwu.edu [Department of Biomedical Engineering, The George Washington University, 800 22nd Street NW, Room 6670, Washington, DC 20052 (United States)

    2015-10-15

    Purpose: Delivery of sufficient amounts of therapeutic drugs into the eye for treatment of various ocular diseases is often a challenging task. Ultrasound was shown to be effective in enhancing ocular drug delivery in the authors’ previous in vitro and in vivo studies. Methods: The study reported here was designed to investigate the safety of ultrasound application and its potential thermal effects in the eye using PZFlex modeling software. The safety limit in this study was set as a temperature increase of no more than 1.5 °C based on regulatory recommendations and previous experimental safety studies. Acoustic and thermal specifications of different human eye tissues were obtained from the published literature. The tissues of particular interest in this modeling safety study were cornea, lens, and the location of optic nerve in the posterior eye. Ultrasound application was modeled at frequencies of 400 kHz–1 MHz, intensities of 0.3–1 W/cm{sup 2}, and exposure duration of 5 min, which were the parameters used in the authors’ previous drug delivery experiments. The baseline eye temperature was 37 °C. Results: The authors’ results showed that the maximal tissue temperatures after 5 min of ultrasound application were 38, 39, 39.5, and 40 °C in the cornea, 39.5, 40, 42, and 43 °C in the center of the lens, and 37.5, 38.5, and 39 °C in the back of the eye (at the optic nerve location) at frequencies of 400, 600, 800 kHz, and 1 MHz, respectively. Conclusions: The ocular temperatures reached at higher frequencies were considered unsafe based on current recommendations. At a frequency of 400 kHz and intensity of 0.8 W/cm{sup 2} (parameters shown in the authors’ previous in vivo studies to be optimal for ocular drug delivery), the temperature increase was small enough to be considered safe inside different ocular tissues. However, the impact of orbital bone and tissue perfusion should be included in future modeling efforts to determine the safety

  1. Inulin Derivatives Obtained Via Enhanced Microwave Synthesis for Nucleic Acid Based Drug Delivery.

    Science.gov (United States)

    Sardo, Carla; Craparo, Emanuela Fabiola; Fiorica, Calogero; Giammona, Gaetano; Cavallaro, Gennara

    2015-01-01

    A new class of therapeutic agents with a high potential for the treatment of different socially relevant human diseases is represented by Nucleic Acid Based Drugs (NABD), including small interfering RNAs (siRNA), decoy oligodeoxynucleotides (decoy ODN) and antisense oligonucleotides (ASOs). Although NABD can be engineered to be specifically directed against virtually any target, their susceptibility to nuclease degradation and the difficulty of delivery into target tissues severely limit their use in clinical practice and require the development of an appropriate nanostructured delivery system. For delivery of NABD, Inulin (Inu), a natural, water soluble and biocompatible polysaccharide, was derivatized by Spermine (Spm), a flexible molecule with four amine groups that, having pKa values in the range between 8-11, is mainly in the protonated form at pH 7.4. The synthesis of related copolymers (Inu-Spm) was performed by a two step reaction, using a method termed Enhanced Microwave Synthesis (EMS) which has the advantage, compared to conventional microwave reaction, that high amount of energy can be applied to the reaction system, by administering microwave irradiation and simultaneously controlling the temperature in the reaction vessel with cooled air. The synthesized inulin derivatives were characterized by FT-IR spectra and (1)H-NMR. INU-Spm derivatives with a degree of derivatization of about 14 % mol/mol were obtained. These polycations were tested to evaluate their ability to form non covalent complexes with genetic material (polyplexes). Agarose gel retardation assays showed that the obtained copolymers are able to electrostatically interact with DNA duplex to form polyplexes at different c/p weight ratios. Moreover, light scattering studies, performed to analyze size and z-potential of polyplexes, evidenced that copolymers are able to interact with genetic material leading to the formation of nanoscaled systems. In addition, biocompatibility of polyplexes

  2. Dynamic characterization of hydrophobic and hydrophilic solutes in oleic-acid enhanced transdermal delivery using two-photon fluorescence microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Tseng, Te-Yu; Yang, Chiu-Sheng; Chen, Yang-Fang [Department of Physics, National Taiwan University, Taipei, Taiwan (China); Tsai, Tsung-Hua [Department of Dermatology, Far Eastern Memorial Hospital, New Taipei City, Taiwan (China); Dong, Chen-Yuan, E-mail: cydong@phys.ntu.edu.tw [Department of Physics, National Taiwan University, Taipei, Taiwan (China); Center for Quantum Science and Engineering, National Taiwan University, Taipei, Taiwan (China); Center for Optoelectronic Biomedicine, National Taiwan University, Taipei, Taiwan (China)

    2014-10-20

    In this letter, we propose an efficient methodology of investigating dynamic properties of sulforhodamine B and rhodamine B hexyl ester molecules transporting across ex-vivo human stratum corneum with and without oleic acid enhancement. Three-dimensional, time-lapse fluorescence images of the stratum corneum can be obtained using two-photon fluorescence microscopy. Furthermore, temporal quantifications of transport enhancements in diffusion parameters can be achieved with the use of Fick's second law. Dynamic characterization of solutes transporting across the stratum corneum is an effective method for understanding transient phenomena in transdermal delivery of probe molecules, leading to improved delivery strategies of molecular species for therapeutic purposes.

  3. Effect of penetration enhancers on the permeability characteristics of lisinopril transdermal delivery systems

    Directory of Open Access Journals (Sweden)

    Suja Chathoth

    2012-01-01

    Full Text Available Lisinopril is an ACE inhibitor used in the treatment of hypertension and heart failure, prophylactically after myocardial infarction and in diabetic nephropathy. Lisinopril is slowly and incompletely absorbed following oral administration. On an average about 25% of the drug is absorbed after administration of a single dose. Thus, a controlled drug delivery formulation of lisinopril for transdermal absorption would be more advantageous and beneficial for improving the bioavailability and reducing the frequency of administration for long-term treatment. Matrix type transdermal films were prepared by solvent casting technique using a combination of ammonia methacrylate copolymer, type A. USP/NF( EudragitRL100 and poly vinyl pyrrolidone (PVP as polymers. Propylene glycol was used as plasticizer. Glycerine, dimethyl sulphoxide (DMSO and span-60 were used as penetration enhancers. The physicochemical parameters like thickness, folding endurance, drug content, tensile strength and stability were evaluated. In- vitro drug release and in-vitro skin permeation studies were carried out using modified Keshary-Chien permeation cell. Infra-red spectroscopy (IR and differential scanning colorimetry (DSC were performed to follow drug carrier interactions. In- vitro drug permeation profile of the formulated films showed that formulations containing span-60 as penetration enhancer (F4, F8, F12, F16, F20 showed highest drug permeation. From the results of this study it indicated that the permeation of lisinopril from films containing span-60 as penetration enhancer was the best at all polymer ratios as compared to the films containing DMSO and glycerine. The order of permeability enhancement from the films was found to be span-60 > DMSO > glycerine. There was no significant difference in the physicochemical characters and drug content for a period of 3 months.

  4. Self-assembling micelle-like nanoparticles with detachable envelopes for enhanced delivery of nucleic acid therapeutics.

    Science.gov (United States)

    Battogtokh, Gantumur; Ko, Young Tag

    2014-03-01

    In spite of the great potential of nucleic acids as therapeutic agents, the clinical application of nucleic acid therapeutics requires the development of effective systemic delivery strategies. In an effort to develop effective nucleic acid delivery systems suitable for clinical application, we previously reported a self-assembling micelle-like nanoparticle that was based on phospholipid-polyethylenimine conjugates, i.e., "micelle-like nanoparticles" (MNPs). In this study, we aimed to improve the system by enhancing the efficiency of intracellular delivery of the payload via pH-responsive detachment of the monolayer envelope and release of the nucleic acid therapeutics upon reaching the target tissues with an acidic pH, e.g., tumors. The acid-cleavable phospholipid-polyethylenimine conjugate was synthesized via hydrazone bond, and acid-cleavable MNPs were then prepared and characterized as before. We evaluated the acid-cleavable MNP construct for in vitro and in vivo nucleic acid delivery efficiency using cultured tumor cells and tumor-bearing mice. The acid-cleavable nanocarrier showed an enhanced cellular delivery at pH 6.5 as compared to pH 7.4, whereas the noncleavable nanocarrier did not show any differences. Tail vein injections also led to enhanced intracellular uptake of the acid-cleavable nanocarrier compared to the noncleavable nanocarrier into tumor cells of tumor-bearing mice although no significant difference was observed in total tumor accumulation.

  5. Intestine-Specific Delivery of Hydrophobic Bioactives from Oxidized Starch Microspheres with an Enhanced Stability.

    Science.gov (United States)

    Wang, Shanshan; Chen, Yuying; Liang, Hao; Chen, Yiming; Shi, Mengxuan; Wu, Jiande; Liu, Xianwu; Li, Zuseng; Liu, Bin; Yuan, Qipeng; Li, Yuan

    2015-10-01

    An intestine-specific delivery system for hydrophobic bioactives with improved stability was developed. It consists of oxidized potato starch polymers, where the carboxyl groups were physically cross-linked via ferric ions. The model hydrophobic ingredients (β-carotene) were incorporated inside the starch microspheres via a double-emulsion method. Confocal laser scanning microscopy images showed that β-carotene were distributed homogeneously in the inner oil phase of the starch microspheres. The negative value of the ζ-potential of microspheres increased with increasing pH and decreasing ionic strength. In vitro release experiments showed that the microspheres were stable at acidic stomach conditions (pH intestinal conditions (pH 7.0), they rupture to release the loaded β-carotene. The 1,1-diphenyl-2-picrylhydrazyl radical, 2,2-diphenyl-1-(2,4,6-trinitriphenyl), scavenging activity results suggested that microsphere-encapsulated β-carotene had an improved activity after thermal treatment at 80 °C. The storage stability of encapsulated β-carotene at room temperature was also enhanced. The starch microspheres showed potential as intestine-specific carriers with an enhanced stability.

  6. Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae.

    Science.gov (United States)

    Ioannou, Petros; Andrianaki, Aggeliki; Akoumianaki, Tonia; Kyrmizi, Irene; Albert, Nathaniel; Perlin, David; Samonis, George; Kontoyiannis, Dimitrios P; Chamilos, Georgios

    2015-12-07

    The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae.

  7. Skin lipid synthesis inhibition: a possible means for enhancing percutaneous delivery of levodopa.

    Science.gov (United States)

    Babita, Kumar; Tiwary, Ashok Kumar

    2004-10-01

    Skin perturbation with ethanol followed by application of beta-chloroalanine (beta-CA) or atorvastatin (AVN) was employed for delaying the recovery of sphingosine (a precursor of ceramide) and cholesterol, respectively in epidermis of rats. Dose optimization studies revealed 600 microg of beta-CA and 750 microg of AVN significantly (p<0.05) inhibited the synthesis of sphingosine and cholesterol, respectively and prevented their replenishment to normal levels till 48 hr in viable rat skin. Co-application of calcium chloride (0.1 mM) inhibited the synthesis of both micro constituents of epidermis to a greater magnitude, whereas verapamil reduced this effect. The in vitro permeation of levodopa across treated skin portions was directly correlated with percentage of sphingosine and cholesterol inhibited by the treatments. The in vitro permeation of levodopa across skin excised after treatment with beta-CA or AVN was enhanced 3-fold. Effective plasma concentration (1.58 microg/ml) of levodopa in rats was achieved within 2 hr and maintained till 12 hr after AVN treatment, and increased to 36 hr with the co-application of calcium chloride. However, when the skin was treated with beta-CA, Ceff was achieved after 4 hr and was maintained till 36 hr. The inclusion of calcium chloride maintained Ceff for 48 hr. Hence, synthesis inhibition of skin lipids seems to offer a feasible means to enhance the systemic delivery of polar drugs like levodopa.

  8. Diatom silica microparticles for sustained release and permeation enhancement following oral delivery of prednisone and mesalamine.

    Science.gov (United States)

    Zhang, Hongbo; Shahbazi, Mohammad-Ali; Mäkilä, Ermei M; da Silva, Tiago H; Reis, Rui L; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

    2013-12-01

    Diatoms are porous silica-based materials obtained from single cell photosynthetic algae. Despite low cost, easy purification process, environmentally safe properties, and rapidly increasing potentials for medical applications, the cytotoxicity of diatoms and the effect on drug permeation of oral formulations have not been studied so far. Herein, we have evaluated the potential of diatom silica microparticles (DSMs) for the delivery of mesalamine and prednisone, which are two commonly prescribed drugs for gastrointestinal (GI) diseases. Transmission electron microscopy analysis of the morphological surface changes of Caco-2/HT-29 monolayers and the cell viability data in colon cancer cells (Caco-2, HT-29 and HCT-116) showed very low toxicity of diatoms at concentrations up to 1000 μg/mL. The mesalamine and prednisone release under simulated GI conditions indicated prolonged release of both drugs from the diatoms. Furthermore, drug permeation across Caco-2/HT-29 co-culture monolayers demonstrated that diatoms are capable to enhance the drug permeability. Overall, this study evaluated DSMs' cytotoxicity in colon cancer cells and the effect of DSMs on drug permeability across Caco-2/HT-29 monolayers. Our results demonstrate that DSMs can be considered as a non-cytotoxic biomaterial with high potential to improve the mesalamine and prednisone bioavailability by sustaining the drug release and enhancing drug permeability.

  9. Parameterizing convective organization

    Directory of Open Access Journals (Sweden)

    Brian Earle Mapes

    2011-06-01

    Full Text Available Lateral mixing parameters in buoyancy-driven deep convection schemes are among the most sensitive and important unknowns in atmosphere models. Unfortunately, there is not a true optimum value for plume mixing rate, but rather a dilemma or tradeoff: Excessive dilution of updrafts leads to unstable stratification bias in the mean state, while inadequate dilution allows deep convection to occur too easily, causing poor space and time distributions and variability. In this too-small parameter space, compromises are made based on competing metrics of model performance. We attempt to escape this “entrainment dilemma” by making bulk plume parameters (chiefly entrainment rate depend on a new prognostic variable (“organization,” org meant to reflect the rectified effects of subgrid-scale structure in meteorological fields. We test an org scheme in the Community Atmosphere Model (CAM5 with a new unified shallow-deep convection scheme (UW-ens, a 2-plume version of the University of Washington scheme. Since buoyant ascent involves natural selection, subgrid structure makes convection systematically deeper and stronger than the pure unorganized case: plumes of average (or randomly sampled air rising in the average environment. To reflect this, org is nonnegative, but we leave it dimensionless. A time scale characterizes its behavior (here ∼3 h for a 2o model. Currently its source is rain evaporation, but other sources can be added easily. We also let org be horizontally transported by advection, as a mass-weighted mean over the convecting layer. Linear coefficients link org to a plume ensemble, which it assists via: 1 plume base warmth above the mean temperature 2 plume radius enhancement (reduced mixing, and 3 increased probability of overlap in a multi-plume scheme, where interactions benefit later generations (this part has only been implemented in an offline toy column model. Since rain evaporation is a source for org, it functions as a time

  10. School-Related Factors Contributing to the Delivery Enhancement of the Special Science Program in Western Visayas, Philippines

    Science.gov (United States)

    Bangcaya, Porferio S.; Alejandro, Grecebio Jonathan D.

    2015-01-01

    In this mixed-method study, the secondary schools in Western Visayas, Philippines offering special science program (SSP) were assessed as basis for delivery enhancement. The SSP along student-related factors and the extent of implementation in the areas of curriculum and instruction, laboratory facilities, and administration in terms of the…

  11. Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery

    Science.gov (United States)

    Shen, Haifa; Rodriguez-Aguayo, Cristian; Xu, Rong; Gonzalez-Villasana, Vianey; Mai, Junhua; Huang, Yi; Zhang, Guodong; Guo, Xiaojing; Bai, Litao; Qin, Guoting; Deng, Xiaoyong; Li, Qingpo; Erm, Donald R.; Liu, Xuewu; Sakamoto, Jason; Chavez-Reyes, Arturo; Han, Hee-Dong; Sood, Anil K.; Ferrari, Mauro; Lopez-Berestein, Gabriel

    2013-01-01

    Purpose RNA interference has the potential to specifically knock down the expression of target genes, and thereby transform cancer therapy. However, lack of effective delivery of small inhibitory RNA (siRNA) has dramatically limited its in vivo applications. We have developed a multistage vector (MSV) system, composed of discoidal porous silicon particles loaded with nanotherapeutics, that directs effective delivery and sustained release of siRNA in tumor tissues. In this study, we evaluated therapeutic efficacy of MSV-loaded EphA2 siRNA (MSV/EphA2) with murine orthotopic models of metastatic ovarian cancers as a first step towards development of a new class of nanotherapeutics for the treatment of ovarian cancer. Experimental design Tumor accumulation of MSV/EphA2 and sustained release of siRNA from MSV were analyzed after i.v. administration of MSV/siRNA. Nude mice with metastatic SKOV3ip2 tumors were treated with MSV/EphA2 and paclitaxel, and therapeutic efficacy was assessed. Mice with chemotherapy-resistant HeyA8 ovarian tumors were treated with a combination of MSV/EphA2 and docetaxel, and enhanced therapeutic efficacy was evaluated. Results Treatment of SKOV3ip2 tumor mice with MSV/EphA2 biweekly for 6 weeks resulted in dose-dependent (5, 10 and 15 μg/mice) reduction of tumor weight (36%, 64%, and 83%) and number of tumor nodules compared with the control groups. In addition, tumor growth was completely inhibited when mice were treated with MSV/EphA2 in combination with paclitaxel. Furthermore, combination treatment with MSV/EphA2 and docetaxel inhibited growth of HeyA8-MDR tumors, which were otherwise resistant to docetaxel treatment. Conclusion These findings indicate that MSV/EphA2 merits further development as a novel therapeutic agent for ovarian cancer. PMID:23386691

  12. Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

    Directory of Open Access Journals (Sweden)

    Pan W

    2016-08-01

    Full Text Available Wenhui Pan, Mengyao Qin, Guoguang Zhang, Yueming Long, Wenyi Ruan, Jingtong Pan, Zushuai Wu, Tao Wan, Chuanbin Wu, Yuehong Xu Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China Abstract: Tacrolimus (FK506, an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC and nanoparticles (NPs encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA was chemically conjugated with cholesterol (Chol to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 µg/cm2 and penetration through the skin (13.38±2.26 µg/cm2. The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced

  13. Enhancement of heat transfer and entropy generation analysis of nanofluids turbulent convection flow in square section tubes

    Directory of Open Access Journals (Sweden)

    Bianco Vincenzo

    2011-01-01

    Full Text Available Abstract In this article, developing turbulent forced convection flow of a water-Al2O3 nanofluid in a square tube, subjected to constant and uniform wall heat flux, is numerically investigated. The mixture model is employed to simulate the nanofluid flow and the investigation is accomplished for particles size equal to 38 nm. An entropy generation analysis is also proposed in order to find the optimal working condition for the given geometry under given boundary conditions. A simple analytical procedure is proposed to evaluate the entropy generation and its results are compared with the numerical calculations, showing a very good agreement. A comparison of the resulting Nusselt numbers with experimental correlations available in literature is accomplished. To minimize entropy generation, the optimal Reynolds number is determined.

  14. Enhancement of heat transfer and entropy generation analysis of nanofluids turbulent convection flow in square section tubes.

    Science.gov (United States)

    Bianco, Vincenzo; Nardini, Sergio; Manca, Oronzio

    2011-03-24

    In this article, developing turbulent forced convection flow of a water-Al2O3 nanofluid in a square tube, subjected to constant and uniform wall heat flux, is numerically investigated. The mixture model is employed to simulate the nanofluid flow and the investigation is accomplished for particles size equal to 38 nm.An entropy generation analysis is also proposed in order to find the optimal working condition for the given geometry under given boundary conditions. A simple analytical procedure is proposed to evaluate the entropy generation and its results are compared with the numerical calculations, showing a very good agreement.A comparison of the resulting Nusselt numbers with experimental correlations available in literature is accomplished. To minimize entropy generation, the optimal Reynolds number is determined.

  15. Transdermal Iontophoretic Delivery of Atenolol in Combination with Penetration Enhancers: Optimization and Evaluation on Solution and Gels

    Directory of Open Access Journals (Sweden)

    Nandy B. C.

    2009-07-01

    Full Text Available In the present investigation, we prepared Atenolol (1.5 % w/w solution and various polymer formulations by incorporating the tween-20 or L-menthol, as a penetration enhancers and its effect on permeation of the drug through the excised abdominal rat skin were used to examined by using the vertical Franz-type diffusion cell. The physicochemical interactions between Atenolol and various polymers were investigated by performing the assay, ultra violet absorption maxima, Fourier transform infrared spectroscopy and it was further confirmed by thin layer chromatography studies, from which drug did not show any evidence of interaction with the polymers. We found that, L-menthol was superior than tween-20 to iontophoresis [current density applied 0.5 mA/cm2 and 90:10 (on: off ratio], in enhancing the transdermal permeation of Atenolol; it enhanced the flux of Atenolol by more than 2-folds, comparison to the preparations without penetration enhancer via passive diffusion, and 3 folds increased using iontophoresis alone with a shorter lag time. Atenolol also showed good stability in gel formulations. The basic parameters like % loading dose released at the end of the study, permeation coefficient and steady state flux (Jss were calculated and showed statistically significant difference (p<0.05. The results indicated that suitable iontophoretic delivery with desired permeability could be appeared and the cumulative amount-time curves were suitable to fit by a zero order equations which indicated a steady state permeation rate or sustained effect could be achieved from hydrogel; when it is combined with penetration enhancer, L-menthol. The results demonstrate that the semisolid gel formulations are more applicable than solution as a transdermal iontophoretic delivery system to administer clinically. Electrically assisted transdermal delivery of Atenolol significantly increased transport compared to passive delivery. Also, rapid and modulated delivery was

  16. Hydroxycamptothecin-loaded nanoparticles enhance target drug delivery and anticancer effect

    Directory of Open Access Journals (Sweden)

    Li Su

    2008-05-01

    Full Text Available Abstract Background Hydroxycamptothecin (HCPT has been shown to have activity against a broad spectrum of cancers. In order to enhance its tissue-specific delivery and anticancer activity, we prepared HCPT-loaded nanoparticles made from poly(ethylene glycol-poly(γ-benzyl-L-glutamate (PEG-PBLG, and then studied their release characteristics, pharmacokinetic characteristics, and anticancer effects. PEG-PBLG nanoparticles incorporating HCPT were prepared by a dialysis method. Scanning electron microscopy (SEM was used to observe the shape and diameter of the nanoparticles. The HCPT release characteristics in vitro were evaluated by ultraviolet spectrophotometry. A high-performance liquid chromatography (HPLC detection method for determining HCPT in rabbit plasma was established. The pharmacokinetic parameters of HCPT/PEG-PBLG nanoparticles were compared with those of HCPT. Results The HCPT-loaded nanoparticles had a core-shell spherical structure, with a core diameter of 200 nm and a shell thickness of 30 nm. Drug-loading capacity and drug encapsulation were 7.5 and 56.8%, respectively. The HCPT release profile was biphasic, with an initial abrupt release, followed by sustained release. The terminal elimination half-lives (t 1/2 β of HCPT and HCPT-loaded nanoparticles were 4.5 and 10.1 h, respectively. Peak concentrations (Cmax of HCPT and HCPT-loaded nanoparticles were 2627.8 and 1513.5 μg/L, respectively. The apparent volumes of distribution of the HCPT and HCPT-loaded nanoparticles were 7.3 and 20.0 L, respectively. Compared with a blank control group, Lovo cell xenografts or Tca8113 cell xenografts in HCPT or HCPT-loaded nanoparticle treated groups grew more slowly and the tumor doubling times were increased. The tumor inhibition effect in the HCPT-loaded nanosphere-treated group was significantly higher than that of the HCPT-treated group (p 0.05. Conclusion Compared to the HCPT- and control-treated groups, the HCPT-loaded nanoparticle

  17. Effects of Chemical and Physical Enhancement Techniques on Transdermal Delivery of Cyanocobalamin (Vitamin B12 In Vitro

    Directory of Open Access Journals (Sweden)

    Ajay K. Banga

    2011-08-01

    Full Text Available Vitamin B12 deficiency, which may result in anemia and nerve damage if left untreated, is currently treated by administration of cyanocobalamin via oral or intramuscular routes. However, these routes are associated with absorption and compliance issues which have prompted us to investigate skin as an alternative site of administration. Delivery through skin, however, is restricted to small and moderately lipophilic molecules due to the outermost barrier, the stratum corneum (SC. In this study, we have investigated the effect of different enhancement techniques, chemical enhancers (ethanol, oleic acid, propylene glycol, iontophoresis (anodal iontophoresis and microneedles (soluble maltose microneedles, which may overcome this barrier and improve cyanocobalamin delivery. Studies with different chemical enhancer formulations indicated that ethanol and oleic acid decreased the lag time while propylene glycol based formulations increased the lag time. The formulation with ethanol (50%, oleic acid (10% and propylene glycol (40% showed the maximum improvement in delivery. Iontophoresis and microneedle treatments resulted in enhanced permeation levels compared to passive controls. These enhancement approaches can be explored further to develop alternative treatment regimens.

  18. Self-enhanced targeted delivery of a cell wall– and membrane-active antibiotics, daptomycin, against staphylococcal pneumonia

    Directory of Open Access Journals (Sweden)

    Hong Jiang

    2016-07-01

    Full Text Available Considering that some antibacterial agents can identify the outer structure of pathogens like cell wall and/or cell membrane, we explored a self-enhanced targeted delivery strategy by which a small amount of the antibiotic molecules were modified on the surface of carriers as targeting ligands of certain bacteria while more antibiotic molecules were loaded inside the carriers, and thus has the potential to improve the drug concentration at the infection site, enhance efficacy and reduce potential toxicity. In this study, a novel targeted delivery system against methicillin-resistant Staphylococcus aureus (MRSA pneumonia was constructed with daptomycin, a lipopeptide antibiotic, which can bind to the cell wall of S. aureus via its hydrophobic tail. Daptomycin was conjugated with N-hydroxysuccinimidyl–polyethylene glycol–1,2-distearoyl-sn-glycero-3-phosphoethanolamine to synthesize a targeting compound (Dapt–PEG–DSPE which could be anchored on the surface of liposomes, while additional daptomycin molecules were encapsulated inside the liposomes. These daptomycin-modified, daptomycin-loaded liposomes (DPD-L[D] showed specific binding to MRSA as detected by flow cytometry and good targeting capabilities in vivo to MRSA-infected lungs in a pneumonia model. DPD-L[D] exhibited more favorable antibacterial efficacy against MRSA than conventional PEGylated liposomal daptomycin both in vitro and in vivo. Our study demonstrates that daptomycin-modified liposomes can enhance MRSA-targeted delivery of encapsulated antibiotic, suggesting a novel drug delivery approach for existing antimicrobial agents.

  19. Fabrication of doxorubicin nanoparticles by controlled antisolvent precipitation for enhanced intracellular delivery.

    Science.gov (United States)

    Tam, Yu Tong; To, Kenneth Kin Wah; Chow, Albert Hee Lum

    2016-03-01

    Over-expression of ATP-binding cassette transporters is one of the most important mechanisms responsible for multidrug resistance. Here, we aimed to develop a stable polymeric nanoparticle system by flash nanoprecipitation (FNP) for enhanced anticancer drug delivery into drug resistant cancer cells. As an antisolvent precipitation process, FNP works best for highly lipophilic solutes (logP>6). Thus we also aimed to evaluate the applicability of FNP to drugs with relatively low lipophilicity (logP=1-2). To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate with a logP of 1.3, was selected as a model drug for the assessment. DOX was successfully incorporated into the amphiphilic diblock copolymer, polyethylene glycol-b-polylactic acid (PEG-b-PLA), by FNP using a four-stream multi-inlet vortex mixer. Optimization of key processing parameters and co-formulation with the co-stabilizer, polyvinylpyrrolidone, yielded highly stable, roughly spherical DOX-loaded PEG-b-PLA nanoparticles (DOX.NP) with mean particle size below 100nm, drug loading up to 14%, and drug encapsulation efficiency up to 49%. DOX.NP exhibited a pH-dependent drug release profile with higher cumulative release rate at acidic pHs. Surface analysis of DOX.NP by XPS revealed an absence of DOX on the particle surface, indicative of complete drug encapsulation. While there were no significant differences in cytotoxic effect on P-gp over-expressing LCC6/MDR cell line between DOX.NP and free DOX in buffered aqueous media, DOX.NP exhibited a considerably higher cellular uptake and intracellular retention after efflux. The apparent lack of cytotoxicity enhancement with DOX.NP may be attributable to its slow DOX release inside the cells.

  20. Enhancement of drug delivery: enzyme-replacement therapy for murine Morquio A syndrome.

    Science.gov (United States)

    Tomatsu, Shunji; Montaño, Adriana M; Dung, Vu Chi; Ohashi, Amiko; Oikawa, Hirotaka; Oguma, Toshihiro; Orii, Tadao; Barrera, Luis; Sly, William S

    2010-06-01

    Mucopolysaccharidosis IVA (MPS IVA, Morquio A disease) is an inherited lysosomal storage disorder that features skeletal chondrodysplasia caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Human GALNS was bioengineered with the N-terminus extended by the hexaglutamate sequence (E6) to improve targeting to bone (E6-GALNS). We initially assessed blood clearance and tissue distribution. Next, to assess the effectiveness of storage clearance and reversal of pathological phenotype, a dose of 250 U/g of enzyme was given weekly to Morquio A mice (adults: 12 or 24 weeks, newborn: 8 weeks). Sulfatase modifier factor 1 (SUMF1) was co-transfected to activate the enzyme fully. The E6-GALNS tagged enzyme had markedly prolonged clearance from circulation, giving over 20 times exposure time in blood, compared to untagged enzyme. The tagged enzyme was retained longer in bone, with residual enzyme activity demonstrable at 48 hours after infusion. The pathological findings in adult mice treated with tagged enzyme showed substantial clearance of the storage materials in bone, bone marrow, and heart valves, especially after 24 weekly infusions. Mice treated from the newborn period showed marked reduction of storage materials in tissues investigated. These findings indicate the feasibility of using tagged enzyme to enhance delivery and pathological effectiveness in Morquio A mice.

  1. Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Green, Damian J.; Pagel, John M.; Nemecek, Eneida R.; Lin, Yukang; Kenoyer, Aimee L.; Pantelias, Anastasia; Hamlin, Donald K.; Wilbur, D. S.; Fisher, Darrell R.; Rajendran, Joseph G.; Gopal, Ajay K.; Park, Steven I.; Press, Oliver W.

    2009-08-06

    Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in nineteen nonhuman primates (M. fascicularis) the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation when compared to directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)4SA] produced markedly lower concentrations of radiation in non-target tissues when compared to conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung and liver (10.3:1, 18.9:1 and 9.9:1 respectively) when compared to the conventional RIT controls (2.6:1, 6.4:1 and 2.9:1 respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time-point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.

  2. Enhancement of Drug Delivery: Enzyme-replacement Therapy for Murine Morquio A Syndrome

    Science.gov (United States)

    Tomatsu, Shunji; Montaño, Adriana M; Dung, Vu Chi; Ohashi, Amiko; Oikawa, Hirotaka; Oguma, Toshihiro; Orii, Tadao; Barrera, Luis; Sly, William S

    2010-01-01

    Mucopolysaccharidosis IVA (MPS IVA, Morquio A disease) is an inherited lysosomal storage disorder that features skeletal chondrodysplasia caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Human GALNS was bioengineered with the N-terminus extended by the hexaglutamate sequence (E6) to improve targeting to bone (E6-GALNS). We initially assessed blood clearance and tissue distribution. Next, to assess the effectiveness of storage clearance and reversal of pathological phenotype, a dose of 250 U/g of enzyme was given weekly to Morquio A mice (adults: 12 or 24 weeks, newborn: 8 weeks). Sulfatase modifier factor 1 (SUMF1) was co-transfected to activate the enzyme fully. The E6-GALNS tagged enzyme had markedly prolonged clearance from circulation, giving over 20 times exposure time in blood, compared to untagged enzyme. The tagged enzyme was retained longer in bone, with residual enzyme activity demonstrable at 48 hours after infusion. The pathological findings in adult mice treated with tagged enzyme showed substantial clearance of the storage materials in bone, bone marrow, and heart valves, especially after 24 weekly infusions. Mice treated from the newborn period showed marked reduction of storage materials in tissues investigated. These findings indicate the feasibility of using tagged enzyme to enhance delivery and pathological effectiveness in Morquio A mice. PMID:20332769

  3. Enhanced Oral Delivery of Docetaxel Using Thiolated Chitosan Nanoparticles: Preparation, In Vitro and In Vivo Studies

    Science.gov (United States)

    Saremi, Shahrooz; Kebriaeezadeh, Abbas; Ostad, Seyed Nasser; Atyabi, Fatemeh

    2013-01-01

    The aim of this study was to evaluate a nanoparticulate system with mucoadhesion properties composed of a core of polymethyl methacrylate surrounded by a shell of thiolated chitosan (Ch-GSH-pMMA) for enhancing oral bioavailability of docetaxel (DTX), an anticancer drug. DTX-loaded nanoparticles were prepared by emulsion polymerization method using cerium ammonium nitrate as an initiator. Physicochemical properties of the nanoparticles such as particle size, size distribution, morphology, drug loading, and entrapment efficiency were characterized. The pharmacokinetic study was carried out in vivo using wistar rats. The half-life of DTX-loaded NPs was about 9 times longer than oral DTX used as positive control. The oral bioavailability of DTX was increased to 68.9% for DTX-loaded nanoparticles compared to 6.5% for positive control. The nanoparticles showed stronger effect on the reduction of the transepithelial electrical resistance (TEER) of Caco-2 cell monolayer by opening the tight junctions. According to apparent permeability coefficient (Papp) results, the DTX-loaded NPs showed more specific permeation across the Caco-2 cell monolayer in comparison to the DTX. In conclusion, the nanoparticles prepared in this study showed promising results for the development of an oral drug delivery system for anticancer drugs. PMID:23971023

  4. Enhanced Oral Delivery of Docetaxel Using Thiolated Chitosan Nanoparticles: Preparation, In Vitro and In Vivo Studies

    Directory of Open Access Journals (Sweden)

    Shahrooz Saremi

    2013-01-01

    Full Text Available The aim of this study was to evaluate a nanoparticulate system with mucoadhesion properties composed of a core of polymethyl methacrylate surrounded by a shell of thiolated chitosan (Ch-GSH-pMMA for enhancing oral bioavailability of docetaxel (DTX, an anticancer drug. DTX-loaded nanoparticles were prepared by emulsion polymerization method using cerium ammonium nitrate as an initiator. Physicochemical properties of the nanoparticles such as particle size, size distribution, morphology, drug loading, and entrapment efficiency were characterized. The pharmacokinetic study was carried out in vivo using wistar rats. The half-life of DTX-loaded NPs was about 9 times longer than oral DTX used as positive control. The oral bioavailability of DTX was increased to 68.9% for DTX-loaded nanoparticles compared to 6.5% for positive control. The nanoparticles showed stronger effect on the reduction of the transepithelial electrical resistance (TEER of Caco-2 cell monolayer by opening the tight junctions. According to apparent permeability coefficient (Papp results, the DTX-loaded NPs showed more specific permeation across the Caco-2 cell monolayer in comparison to the DTX. In conclusion, the nanoparticles prepared in this study showed promising results for the development of an oral drug delivery system for anticancer drugs.

  5. Cholesterol-Enhanced Polylactide-Based Stereocomplex Micelle for Effective Delivery of Doxorubicin

    Directory of Open Access Journals (Sweden)

    Jixue Wang

    2015-01-01

    Full Text Available Nanoscale micelles as an effective drug delivery system have attracted increasing interest in malignancy therapy. The present study reported the construction of the cholesterol-enhanced doxorubicin (DOX-loaded poly(D-lactide-based micelle (CDM/DOX, poly(L-lactide-based micelle (CLM/DOX, and stereocomplex micelle (CSCM/DOX from the equimolar enantiomeric 4-armed poly(ethylene glycol–polylactide copolymers in aqueous condition. Compared with CDM/DOX and CLM/DOX, CSCM/DOX showed the smallest hydrodynamic size of 96 ± 4.8 nm and the slowest DOX release. The DOX-loaded micelles exhibited a weaker DOX fluorescence inside mouse renal carcinoma cells (i.e., RenCa cells compared to free DOX·HCl, probably because of a slower DOX release. More importantly, all the DOX-loaded micelles, especially CSCM/DOX, exhibited the excellent antiproliferative efficacy that was equal to or even better than free DOX·HCl toward RenCa cells attributed to their successful internalization. Furthermore, all of the DOX-loaded micelles exhibited the satisfactory hemocompatibility compared to free DOX·HCl, indicating the great potential for systemic chemotherapy through intravenous injection.

  6. SOLUBILITY ENHANCEMENT OF CANDESARTAN CILEXETIL BY SELF EMULSIFYING DRUG DELIVERY SYSTEMS

    Directory of Open Access Journals (Sweden)

    M. Sunitha Reddy*, P. Srinivas Goud and S.S. Apte

    2012-07-01

    Full Text Available The present research work was aimed at the enhancement of solubility of Candesartan by Self Emulsifying Drug Delivery Systems (SEDDS. Candesartan is a BCS class II drug having low aqueous solubility and high permeability; hence its bioavailability is solubility rate limited. The saturated solubility of Candesartan in various oils and surfactants was determined. The excipients were screened and selected showing maximum solubility and compatibility for Candesartan. SEDDS formulations of Candesartan were developed using different Oils, Surfactants and Co-Surfactant combinations. Pseudoternary phase diagrams were constructed using Triplot V 4.1.2 software and applying Pseudoternary phase diagrams, microemulsification area was evaluated. Formulations were prepared based on phase diagrams using various proportions of oil, surfactants and co-surfactants. The formulations were screened visually for stability and phase separation. Seven formulations were selected for further evaluations like effect of dilution, freeze-thawing, emulsion droplet size and zeta potential. Among the seven formulations three were optimized and filled in hard gelatin capsules. The in-vitro dissolution studies of the SEDDS formulation were performed and the dissolution rate of SEDDS was compared with plain Candesartan (API. The results indicated that the solubility and dissolution rate of Candesartan was significantly higher than that of plain drug (API. The results of the present studies demonstrate that SEDDS can be used as a potential means for improving solubility, dissolution and bioavailability of Candesartan.

  7. Perfluorochemical Liquid-Adenovirus Suspensions Enhance Gene Delivery to the Distal Lung

    Directory of Open Access Journals (Sweden)

    Jeffrey A. Kazzaz

    2011-01-01

    Full Text Available We compared lung delivery methods of recombinant adenovirus (rAd: (1 rAd suspended in saline, (2 rAd suspended in saline followed by a pulse-chase of a perfluorochemical (PFC liquid mixture, and (3 a PFC-rAd suspension. Cell uptake, distribution, and temporal expression of rAd were examined using A549 cells, a murine model using luciferase bioluminescence, and histological analyses. Relative to saline, a 4X increase in transduction efficiency was observed in A549 cells exposed to PFC-rAd for 2–4 h. rAd transgene expression was improved in alveolar epithelial cells, and the level and distribution of luciferase expression when delivered in PFC-rAd suspensions consistently peaked at 24 h. These results demonstrate that PFC-rAd suspensions improve distribution and enhance rAd-mediated gene expression which has important implications in improving lung function by gene therapy.

  8. Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery.

    Science.gov (United States)

    Lin, Steven; Staahl, Brett T; Alla, Ravi K; Doudna, Jennifer A

    2014-12-15

    The CRISPR/Cas9 system is a robust genome editing technology that works in human cells, animals and plants based on the RNA-programmed DNA cleaving activity of the Cas9 enzyme. Building on previous work (Jinek et al., 2013), we show here that new genetic information can be introduced site-specifically and with high efficiency by homology-directed repair (HDR) of Cas9-induced site-specific double-strand DNA breaks using timed delivery of Cas9-guide RNA ribonucleoprotein (RNP) complexes. Cas9 RNP-mediated HDR in HEK293T, human primary neonatal fibroblast and human embryonic stem cells was increased dramatically relative to experiments in unsynchronized cells, with rates of HDR up to 38% observed in HEK293T cells. Sequencing of on- and potential off-target sites showed that editing occurred with high fidelity, while cell mortality was minimized. This approach provides a simple and highly effective strategy for enhancing site-specific genome engineering in both transformed and primary human cells.

  9. Percutaneous delivery of methotrexate in the absence and presence of natural permeation enhancers / Mariska H. Pretorius

    OpenAIRE

    Pretorius, Mariska Heleen

    2003-01-01

    The transdermal delivery of drugs has a lot of advantages above other routes of delivery, such as the avoidance of first-pass hepatic and intestinal metabolism, the non-invasive infusion of drugs, etc. However, the transdermal delivery of drugs, especially hydrophilic drugs, is limited due to the lipophilic nature of the stratum corneum. Methotrexate is a folic acid antagonist with antineoplastic activity and is used for the treatment of psoriasis and Kaposi's sarcoma. The perm...

  10. Enhanced transbuccal salmon calcitonin (sCT) delivery: effect of chemical enhancers and electrical assistance on in vitro sCT buccal permeation.

    Science.gov (United States)

    Oh, Dong-Ho; Chun, Kyeung-Hwa; Jeon, Sang-Ok; Kang, Jeong-Won; Lee, Sangkil

    2011-10-01

    This study investigates the combined effect of absorption enhancers and electrical assistance on transbuccal salmon calcitonin (sCT) delivery, using fresh swine buccal tissue. We placed 200 IU (40 μg/mL) of each sCT formulation--containing various concentrations of ethanol, N-acetyl-L-cysteine (NAC), and sodium deoxyglycocholate (SDGC)--onto the donor part of a Franz diffusion cell. Then, 0.5 mA/cm(2) of fixed anodal current was applied alone or combined with chemical enhancers. The amount of permeated sCT was analyzed using an ELISA kit, and biophysical changes of the buccal mucosa were investigated using FT-IR spectroscopy, and hematoxylin-eosin staining methods were used to evaluate histological alteration of the buccal tissues. The flux (J(s)) of sCT increased with the addition of absorption enhancer groups, but it was significantly enhanced by the application of anodal iontophoresis (ITP). FT-IR study revealed that all groups caused an increase in lipid fluidity but only the groups containing SDGC showed statistically significant difference. Although the histological data of SDGC groups showed a possibility for tissue damage, the present enhancing methods appear to be safe. In conclusion, the combination of absorption enhancers and electrical assistance is a potential strategy for the enhancement of transbuccal sCT delivery.

  11. Structure-Based Rational Design of Prodrugs To Enable Their Combination with Polymeric Nanoparticle Delivery Platforms for Enhanced Antitumor Efficacy**

    Science.gov (United States)

    Wang, Hangxiang; Xie, Haiyang; Wu, Jiaping; Wei, Xuyong; Zhou, Lin; Xu, Xiao; Zheng, Shusen

    2014-01-01

    Drug-loaded nanoparticles (NPs) are of particular interest for efficient cancer therapy due to their improved drug delivery and therapeutic index in various types of cancer. However, the encapsulation of many chemotherapeutics into delivery NPs is often hampered by their unfavorable physicochemical properties. Here, we employed a drug reform strategy to construct a small library of SN-38 (7-ethyl-10-hydroxycamptothecin)-derived prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties. This esterification fine-tuned the polarity of the SN-38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self-assembly into biodegradable poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-PLA) nanoparticulate structures. Our strategy combining the rational engineering of prodrugs with the pre-eminent features of conventionally used polymeric materials should open new avenues for designing more potent drug delivery systems as a therapeutic modality. PMID:25196427

  12. Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery.

    Science.gov (United States)

    Pan, Wenhui; Qin, Mengyao; Zhang, Guoguang; Long, Yueming; Ruan, Wenyi; Pan, Jingtong; Wu, Zushuai; Wan, Tao; Wu, Chuanbin; Xu, Yuehong

    Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506-NPs-NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506-NPs-NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA-Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm(2)) and penetration through the skin (13.38±2.26 μg/cm(2)). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs-NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA-Chol-NPs-NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel

  13. Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

    Science.gov (United States)

    Pan, Wenhui; Qin, Mengyao; Zhang, Guoguang; Long, Yueming; Ruan, Wenyi; Pan, Jingtong; Wu, Zushuai; Wan, Tao; Wu, Chuanbin; Xu, Yuehong

    2016-01-01

    Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm2) and penetration through the skin (13.38±2.26 μg/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is

  14. 电场强化对流传热的热力学机理%Thermodynamic Mechanism of Convective Heat Transfer Enhanced by Electric Field

    Institute of Scientific and Technical Information of China (English)

    韩光泽; 陈佳佳

    2013-01-01

    Transfer processes can be effectively enhanced by external fields,and the heat transfer process enhanced by electric field is a research hotspot in nowadays.In order to reveal the thermodynamic mechanism of convective heat transfer enhanced by electric field,fundamental thermodynamic equations including the influence of electric field are put forward based on the energy postulate,enthalpy and Gibbs function are redefined with the effect of electric field,and the expressions of the partial derivatives of enthalpy and temperature with respect to electric fields are derived.The results indicate that,for most liquids in a valid temperature range,the enthalpy decreases in isothermal process and the temperature increases in adiabatic process with the increase of external electric field. When an external electric field is applied on the heat release stage,the decreased enthalpy of the liquid medium means that more heat can be released,while the increased temperature of it means that the heat release to lower reservoir tends to be more effective.Thus,it is concluded that the electric field effectively enhances the convective heat transfer.Based on the proposed thermodynamic mechanism,a principle diagram is finally presented to de-scribe the convective heat transfer enhanced by electric field.%外场作用能够有效地强化传递过程,电场强化传热便是其中的一个研究热点。为揭示电场强化对流传热过程的热力学机理,文中利用能量公理建立了电场作用下的基本热力学关系,定义了电场作用下的焓和吉布斯函数,导出了等温条件下焓随电场的变化以及绝热条件下温度随电场的变化关系。结果表明:对于常用的液体物质,在有效的工作温度范围内,焓在等温过程中随电场增加而减小,温度在绝热过程中随电场增加而上升;如果在系统放热过程中施加电场作用,焓减小意味着系统能够放出更多的热量,温度上升意味

  15. Association with amino acids does not enhance efficacy of polymerized liposomes as a system for lung gene delivery

    Directory of Open Access Journals (Sweden)

    Elga eBernardo Bandeira De Melo

    2016-04-01

    Full Text Available Development of improved drug and gene delivery systems directly into the lungs is highly desirable given the important burden of respiratory diseases. We aimed to evaluate the safety and efficacy of liposomes composed of photopolymerized lipids (1,2-bis-(tricosa-10,12-diynoyl-sn-glycero-3-phosphocholine associated with amino acids as vectors for gene delivery into the lungs of healthy animals. Lipopolymer vesicles, in particular, are more stable than other types of liposomes. In this study, lipopolymers were associated with L-arginine, L-tryptophan, or L-cysteine. We hypothesized that the addition of these amino acids would enhance the efficacy of gene delivery to the lungs by the lipopolymers. L-Arginine showed the highest association efficiency due to its positive charge and better surface interactions. None of the formulations caused inflammation or altered lung mechanics, suggesting that these lipopolymers can be safely administered as aerosols. All formulations were able to induce eGFP mRNA expression in lung tissue, but the addition of amino acids reduced delivery efficacy when compared with the simple lipopolymer particle. These results indicate that this system could be further explored for gene or drug delivery targeting lung diseases.

  16. Hydrogels as scaffolds and delivery systems to enhance axonal regeneration after injuries

    Directory of Open Access Journals (Sweden)

    Oscar A. Carballo-Molina

    2015-02-01

    Full Text Available Damage caused to neural tissue by disease or injury frequently produces a discontinuity in the nervous system. Such damage generates diverse alterations that are commonly permanent, due to the limited regeneration capacity of the adult nervous system, particularly the Central Nervous System (CNS. The cellular reaction to noxious stimulus leads to several events such as the formation of glial and fibrous scars, which inhibit axonal regeneration in both the CNS and the Peripheral Nervous System (PNS. Although in the PNS there is some degree of nerve regeneration, it is common that the growing axons reinnervate incorrect areas, causing mismatches. Providing a permissive substrate for axonal regeneration in combination with delivery systems for the release of molecules, which enhances axonal growth, could increase regeneration and the recovery of functions in the CNS or the PNS. Currently, there are no effective vehicles to supply growth factors or cells to the damaged/diseased nervous system. Hydrogels are polymers that are biodegradable, biocompatible and have the capacity to deliver a large range of molecules in situ. The inclusion of cultured neural cells into hydrogels forming three-dimensional structures allows the formation of synapses and neuronal survival. There is also evidence showing that hydrogels constitute an amenable substrate for axonal growth of endogenous or grafted cells, overcoming the presence of axonal regeneration inhibitory molecules, in both the central and peripheral nervous systems. Recent experiments suggest that hydrogels can carry and deliver several proteins relevant for improving neuronal survival and axonal growth. Although the use of hydrogels is appealing, its effectiveness is still a matter of discussion, and more results are needed to achieve consistent recovery using different parameters. This review also discusses areas of opportunity where hydrogels can be applied, in order to promote axonal regeneration of

  17. Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery.

    Science.gov (United States)

    Balakrishnan, Prabagar; Shanmugam, Srinivasan; Lee, Won Seok; Lee, Won Mo; Kim, Jong Oh; Oh, Dong Hoon; Kim, Dae-Duk; Kim, Jung Sun; Yoo, Bong Kyu; Choi, Han-Gon; Woo, Jong Soo; Yong, Chul Soon

    2009-07-30

    Niosomes have been reported as a possible approach to improve the low skin penetration and bioavailability characteristics shown by conventional topical vehicle for minoxidil. Niosomes formed from polyoxyethylene alkyl ethers (Brij) or sorbitan monoesters (Span) with cholesterol molar ratios of 0, 1 and 1.5 were prepared with varying drug amount 20-50mg using thin film-hydration method. The prepared systems were characterized for entrapment efficiency, particle size, zeta potential and stability. Skin permeation studies were performed using static vertical diffusion Franz cells and hairless mouse skin treated with either niosomes, control minoxidil solution (propylene glycol-water-ethanol at 20:30:50, v/v/v) or a leading topical minoxidil commercial formulation (Minoxyl). The results showed that the type of surfactant, cholesterol and incorporated amount of drug altered the entrapment efficiency of niosomes. Higher entrapment efficiency was obtained with the niosomes prepared from Span 60 and cholesterol at 1:1 molar ratio using 25mg drug. Niosomal formulations have shown a fairly high retention of minoxidil inside the vesicles (80%) at refrigerated temperature up to a period of 3 months. It was observed that both dialyzed and non-dialyzed niosomal formulations (1.03+/-0.18 to 19.41+/-4.04%) enhanced the percentage of dose accumulated in the skin compared to commercial and control formulations (0.11+/-0.03 to 0.48+/-0.17%) except dialyzed Span 60 niosomes. The greatest skin accumulation was always obtained with non-dialyzed vesicular formulations. Our results suggest that these niosomal formulations could constitute a promising approach for the topical delivery of minoxidil in hair loss treatment.

  18. Evaluation of a continuous improvement programme of enhanced recovery after caesarean delivery under neuraxial anaesthesia.

    Science.gov (United States)

    Deniau, Benjamin; Bouhadjari, Nacima; Faitot, Valentina; Mortazavi, Antoine; Kayem, Gilles; Mandelbrot, Laurent; Keita, Hawa

    2016-12-01

    To assess the performance of a multidisciplinary programme for enhanced recovery after caesarean delivery under neuraxial anaesthesia. Prospective single-centre study. Programme in 6 steps including 3 professional practice audits based on clinical records and questioning patients: audit T0, first "existing state", creation of a working group, drafting and implementation of a multidisciplinary rehabilitation procedure, second audit (T0+4 months), information about and implementation of corrective measures and a third audit (T0+8 months). Assessment of the performance of the continuous improvement programmes based on six measures comprising the post-caesarean rehabilitation score: duration infusion, early oral analgesia, time to removal of the urinary catheter, time to return to drinking, eating recovery time, use of carbetocin. Two hundred and thirty-one patients were included, with 45, 64 and 122 patients at T0, T0+4 months and T0+8 months, respectively. There was a significant increase in patients who received the recovery measures (P<0.0001 for all items) between T0 and T0+8 months: removal of the infusion before 24h (49% versus 93.5%), drinking before 6h (31% versus 55%), eating before 6h (2% versus 38.5%), early oral analgesia before 24h (38% versus 95%), withdrawal of the urinary catheter before 24h (80% versus 95%), use of carbetocin (0% versus 99%). Improved practices in rehabilitation after caesarean can be obtained by setting up a multidisciplinary programme as part of a quality approach. Copyright © 2016 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

  19. Natural convection in nano-fluids: Are the thermophoresis and Brownian motion effects significant in nano-fluid heat transfer enhancement?

    Energy Technology Data Exchange (ETDEWEB)

    Haddad, Zoubida [Department of Mechanical Engineering, Technology Faculty, Firat University, TR-23119, Elazig (Turkey); Department of Fluid Mechanics, Faculty of Physics, University of Sciences and Technology-Houari Boumediene, Algiers (Algeria); Abu-Nada, Eiyad [Department of Mechanical Engineering, King Faisal University, Al-Ahsa 31982 (Saudi Arabia); Oztop, Hakan F. [Department of Mechanical Engineering, Technology Faculty, Firat University, TR-23119, Elazig (Turkey); Mataoui, Amina [Department of Fluid Mechanics, Faculty of Physics, University of Sciences and Technology-Houari Boumediene, Algiers (Algeria)

    2012-07-15

    Natural convection heat transfer and fluid flow of CuO-Water nano-fluids is studied using the Rayleigh-Benard problem. A two component non-homogenous equilibrium model is used for the nano-fluid that incorporates the effects of Brownian motion and thermophoresis. Variable thermal conductivity and variable viscosity are taken into account in this work. Finite volume method is used to solve governing equations. Results are presented by streamlines, isotherms, nano-particle distribution, local and mean Nusselt numbers and nano-particle profiles at top and bottom side. Comparison of two cases as absence of Brownian and thermophoresis effects and presence of Brownian and thermophoresis effects showed that higher heat transfer is formed with the presence of Brownian and thermophoresis effect. In general, by considering the role of thermophoresis and Brownian motion, an enhancement in heat transfer is observed at any volume fraction of nano-particles. However, the enhancement is more pronounced at low volume fraction of nano-particles and the heat transfer decreases by increasing nano-particle volume fraction. On the other hand, by neglecting the role of thermophoresis and Brownian motion, deterioration in heat transfer is observed and this deterioration elevates by increasing the volume fraction of nano-particles. (authors)

  20. Application of pulsed-magnetic field enhances non-viral gene delivery in primary cells from different origins

    Energy Technology Data Exchange (ETDEWEB)

    Kamau Chapman, Sarah W. [Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstr. 190, 8057 Zurich (Switzerland); Hassa, Paul O. [Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstr. 190, 8057 Zurich (Switzerland); European Molecular Biology Laboratory (EMBL) Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg (Germany); Koch-Schneidemann, Sabine; Rechenberg, Brigitte von [Musculoskeletal Research Unit, Equine Hospital, Vetsuisse Faculty Zurich, University of Zurich, Winterthurerstr. 260, 8057 Zurich (Switzerland); Hofmann-Amtenbrink, Margarethe [MatSearch, Chemin Jean Pavillard 14, 1009 Pully (Switzerland); Steitz, Benedikt; Petri-Fink, Alke; Hofmann, Heinrich [Laboratory of Powder Technology, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne (Switzerland); Hottiger, Michael O. [Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstr. 190, 8057 Zurich (Switzerland)], E-mail: hottiger@vetbio.uzh.ch

    2008-04-15

    Primary cell lines are more difficult to transfect when compared to immortalized/transformed cell lines, and hence new techniques are required to enhance the transfection efficiency in these cells. We isolated and established primary cultures of synoviocytes, chondrocytes, osteoblasts, melanocytes, macrophages, lung fibroblasts, and embryonic fibroblasts. These cells differed in several properties, and hence were a good representative sample of cells that would be targeted for expression and delivery of therapeutic genes in vivo. The efficiency of gene delivery in all these cells was enhanced using polyethylenimine-coated polyMAG magnetic nanoparticles, and the rates (17-84.2%) surpassed those previously achieved using other methods, especially in cells that are difficult to transfect. The application of permanent and pulsating magnetic fields significantly enhanced the transfection efficiencies in synoviocytes, chondrocytes, osteoblasts, melanocytes and lung fibroblasts, within 5 min of exposure to these magnetic fields. This is an added advantage for future in vivo applications, where rapid gene delivery is required before systemic clearance or filtration of the gene vectors occurs.

  1. Convection in Type 2 supernovae

    Energy Technology Data Exchange (ETDEWEB)

    Miller, D.S.

    1993-10-15

    Results are presented here from several two dimensional numerical calculations of events in Type II supernovae. A new 2-D hydrodynamics and neutrino transport code has been used to compute the effect on the supernova explosion mechanism of convection between the neutrinosphere and the shock. This convection is referred to as exterior convection to distinguish it from convection beneath the neutrinosphere. The model equations and initial and boundary conditions are presented along with the simulation results. The 2-D code was used to compute an exterior convective velocity to compare with the convective model of the Mayle and Wilson 1-D code. Results are presented from several runs with varying sizes of initial perturbation, as well as a case with no initial perturbation but including the effects of rotation. The M&W code does not produce an explosion using the 2-D convective velocity. Exterior convection enhances the outward propagation of the shock, but not enough to ensure a successful explosion. Analytic estimates of the growth rate of the neutron finger instability axe presented. It is shown that this instability can occur beneath the neutrinosphere of the proto-neutron star in a supernova explosion with a growth time of {approximately} 3 microseconds. The behavior of the high entropy bubble that forms between the shock and the neutrinosphere in one dimensional calculations of supernova is investigated. It has been speculated that this bubble is a site for {gamma}-process generation of heavy elements. Two dimensional calculations are presented of the time evolution of the hot bubble and the surrounding stellar material. Unlike one dimensional calculations, the 2D code fails to achieve high entropies in the bubble. When run in a spherically symmetric mode the 2-D code reaches entropies of {approximately} 200. When convection is allowed, the bubble reaches {approximately} 60 then the bubble begins to move upward into the cooler, denser material above it.

  2. Convection in Type 2 supernovae

    Energy Technology Data Exchange (ETDEWEB)

    Miller, Douglas Scott [Univ. of California, Davis, CA (United States)

    1993-10-15

    Results are presented here from several two dimensional numerical calculations of events in Type II supernovae. A new 2-D hydrodynamics and neutrino transport code has been used to compute the effect on the supernova explosion mechanism of convection between the neutrinosphere and the shock. This convection is referred to as exterior convection to distinguish it from convection beneath the neutrinosphere. The model equations and initial and boundary conditions are presented along with the simulation results. The 2-D code was used to compute an exterior convective velocity to compare with the convective model of the Mayle and Wilson 1-D code. Results are presented from several runs with varying sizes of initial perturbation, as well as a case with no initial perturbation but including the effects of rotation. The M&W code does not produce an explosion using the 2-D convective velocity. Exterior convection enhances the outward propagation of the shock, but not enough to ensure a successful explosion. Analytic estimates of the growth rate of the neutron finger instability axe presented. It is shown that this instability can occur beneath the neutrinosphere of the proto-neutron star in a supernova explosion with a growth time of ~ 3 microseconds. The behavior of the high entropy bubble that forms between the shock and the neutrinosphere in one dimensional calculations of supernova is investigated. It has been speculated that this bubble is a site for γ-process generation of heavy elements. Two dimensional calculations are presented of the time evolution of the hot bubble and the surrounding stellar material. Unlike one dimensional calculations, the 2D code fails to achieve high entropies in the bubble. When run in a spherically symmetric mode the 2-D code reaches entropies of ~ 200. When convection is allowed, the bubble reaches ~60 then the bubble begins to move upward into the cooler, denser material above it.

  3. Spray-dried powders enhance vaginal siRNA delivery by potentially modulating the mucus molecular sieve structure

    Directory of Open Access Journals (Sweden)

    Wu N

    2015-08-01

    Full Text Available Na Wu,1,2,* Xinxin Zhang,2,* Feifei Li,2 Tao Zhang,2 Yong Gan,2 Juan Li1 1School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Vaginal small interfering RNA (siRNA delivery provides a promising strategy for the prevention and treatment of vaginal diseases. However, the densely cross-linked mucus layer on the vaginal wall severely restricts nanoparticle-mediated siRNA delivery to the vaginal epithelium. In order to overcome this barrier and enhance vaginal mucus penetration, we prepared spray-dried powders containing siRNA-loaded nanoparticles. Powders with Pluronic F127 (F127, hydroxypropyl methyl cellulose (HPMC, and mannitol as carriers were obtained using an ultrasound-assisted spray-drying technique. Highly dispersed dry powders with diameters of 5–15 µm were produced. These powders showed effective siRNA protection and sustained release. The mucus-penetrating properties of the powders differed depending on their compositions. They exhibited different potential of opening mesh size of molecular sieve in simulated vaginal mucus system. A powder formulation with 0.6% F127 and 0.1% HPMC produced the maximum increase in the pore size of the model gel used to simulate vaginal mucus by rapidly extracting water from the gel and interacting with the gel; the resulting modulation of the molecular sieve effect achieved a 17.8-fold improvement of siRNA delivery in vaginal tract and effective siRNA delivery to the epithelium. This study suggests that powder formulations with optimized compositions have the potential to alter the steric barrier posed by mucus and hold promise for effective vaginal siRNA delivery. Keywords: siRNA delivery, vaginal administration, spray-dried powders, mucus penetration, molecular sieve effect

  4. Novel central nervous system drug delivery systems.

    Science.gov (United States)

    Stockwell, Jocelyn; Abdi, Nabiha; Lu, Xiaofan; Maheshwari, Oshin; Taghibiglou, Changiz

    2014-05-01

    For decades, biomedical and pharmaceutical researchers have worked to devise new and more effective therapeutics to treat diseases affecting the central nervous system. The blood-brain barrier effectively protects the brain, but poses a profound challenge to drug delivery across this barrier. Many traditional drugs cannot cross the blood-brain barrier in appreciable concentrations, with less than 1% of most drugs reaching the central nervous system, leading to a lack of available treatments for many central nervous system diseases, such as stroke, neurodegenerative disorders, and brain tumors. Due to the ineffective nature of most treatments for central nervous system disorders, the development of novel drug delivery systems is an area of great interest and active research. Multiple novel strategies show promise for effective central nervous system drug delivery, giving potential for more effective and safer therapies in the future. This review outlines several novel drug delivery techniques, including intranasal drug delivery, nanoparticles, drug modifications, convection-enhanced infusion, and ultrasound-mediated drug delivery. It also assesses possible clinical applications, limitations, and examples of current clinical and preclinical research for each of these drug delivery approaches. Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous system diseases, causing improved therapies for those who are affected by central nervous system diseases.

  5. National Convective Weather Diagnostic

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Current convective hazards identified by the National Convective Weather Detection algorithm. The National Convective Weather Diagnostic (NCWD) is an automatically...

  6. Effect of formulation pH on transport of naltrexone species and pore closure in microneedle-enhanced transdermal drug delivery

    OpenAIRE

    Ghosh, Priyanka; Brogden, Nicole K.; Stinchcomb, Audra L.

    2013-01-01

    Microneedle-enhanced transdermal drug delivery greatly improves the subset of pharmacologically active molecules that can be transported across the skin. Formulation pH plays an important role in all drug delivery systems; however, for transdermal delivery it becomes specifically significant since a wide range of pH values can be exploited for patch formulation as long as it does not lead to skin irritation or sensitization issues. Wound healing literature has shown significant pH effects on ...

  7. Colon-targeted quercetin delivery using natural polymer to enhance its bioavailability

    OpenAIRE

    2011-01-01

    The aim of the present study is to develop a polymer (Guar Gum)-based matrix tablet (using quercetin as a model drug) with sufficient mechanical strength, and promising in vitro mouth-to-colon release profile. By definition, an oral colonic delivery system should retard drug release in the stomach and small intestine, and allow complete release in the colon. By drug delivery to the colon would therefore ensure direct treatment at the disease site, lower dosing, and fewer systemic side effects...

  8. Enhanced Forced Convection Heat Transfer using Small Scale Vorticity Concentrations Effected by Flow Driven, Aeroelastically Vibrating Reeds

    Science.gov (United States)

    2016-08-03

    the structural inertial force and ∗ can be thought of as the ratio between the time scale related to the reed’s natural oscillation in vacuum and...tip. Such contact clearly affects the evolution of the flow along the surface and may produce some suction force that leads to progressive...Heat Transfer Enhancement in High-Power Heat Sinks using Active Reed Technology,” THERMINIC, Barcelona, Spain, October, 2010. 29. Huang, W., Shin

  9. Novel aptamer-nanoparticle bioconjugates enhances delivery of anticancer drug to MUC1-positive cancer cells in vitro.

    Directory of Open Access Journals (Sweden)

    Chenchen Yu

    Full Text Available MUC1 protein is an attractive target for anticancer drug delivery owing to its overexpression in most adenocarcinomas. In this study, a reported MUC1 protein aptamer is exploited as the targeting agent of a nanoparticle-based drug delivery system. Paclitaxel (PTX loaded poly (lactic-co-glycolic-acid (PLGA nanoparticles were formulated by an emulsion/evaporation method, and MUC1 aptamers (Apt were conjugated to the particle surface through a DNA spacer. The aptamer conjugated nanoparticles (Apt-NPs are about 225.3 nm in size with a stable in vitro drug release profile. Using MCF-7 breast cancer cell as a MUC1-overexpressing model, the MUC1 aptamer increased the uptake of nanoparticles into the target cells as measured by flow cytometry. Moreover, the PTX loaded Apt-NPs enhanced in vitro drug delivery and cytotoxicity to MUC1(+ cancer cells, as compared with non-targeted nanoparticles that lack the MUC1 aptamer (P<0.01. The behavior of this novel aptamer-nanoparticle bioconjugates suggests that MUC1 aptamers may have application potential in targeted drug delivery towards MUC1-overexpressing tumors.

  10. Enhanced stability and antibacterial efficacy of a traditional Chinese medicine-mediated silver nanoparticle delivery system

    Directory of Open Access Journals (Sweden)

    Sun WJ

    2014-11-01

    Full Text Available Wenjie Sun,1,2,* Ding Qu,1,* Yihua Ma,1 Yan Chen,1,2 Congyan Liu,1 Jing Zhou11Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, 2Department of Pharmaceutics, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workAbstract: Silver nanoparticles (AgNPs are widely used as antibacterial products in various fields. Recent studies have suggested that AgNPs need an appropriate stabilizer to improve their stability. Some antibacterial traditional Chinese medicines (TCMs contain various reductive components, which can not only stabilize AgNPs but also enhance their antimicrobial activity. In this study, we developed a series of novel AgNPs using a TCM extract as a stabilizer, reducing agent, and antimicrobial agent (TCM-AgNPs. A storage stability investigation of the TCM-AgNPs suggested a significant improvement when compared with bare AgNPs. Further, conjugation of TCMs onto the AgNP surface resulted in stronger antimicrobial potency on antibacterial evaluation using Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus with minimum inhibitory concentration 50% (MIC50 ratios (and minimum bactericidal concentration 90% [MBC90] ratios of AgNPs to respective TCM-AgNPs as assessment indices. Among these, P. cuspidatum Sieb. et-conjugated AgNPs (P.C.-AgNPs had the advantage of a combination of TCMs and AgNPs and was studied in detail with regard to its synthesis and characterization. The extraction time, reaction temperature, and concentrations of AgNO3 and Polygonum cuspidatum Sieb. et extract were critical factors in the preparation of P.C.-AgNPs. Further, the results of X-ray diffraction and Fourier transform infrared spectroscopy indicated successful preparation of P.C.-AgNPs. In representative studies, P.C.-AgNPs showed a well-defined spherical shape, a homogeneous

  11. Lyophilized phytosomal nanocarriers as platforms for enhanced diosmin delivery: optimization and ex vivo permeation

    Directory of Open Access Journals (Sweden)

    Freag MS

    2013-07-01

    Full Text Available May S Freag, Yosra SR Elnaggar, Ossama Y AbdallahDepartment of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptAbstract: Diosmin (DSN is an outstanding phlebotonic flavonoid with a tolerable potential for the treatment of colon and hepatocellular carcinoma. Being highly insoluble, DSN bioavailability suffers from high inter-subject variation due to variable degrees of permeation. This work endeavored to develop novel DSN loaded phytosomes in order to improve drug dissolution and intestinal permeability. Three preparation methods (solvent evaporation, salting out, and lyophilization were compared. Nanocarrier optimization encompassed different soybean phospholipid (SPC types, different solvents, and different DSN:SPC molar ratios (1:1, 1:2, and 1:4. In vitro appraisal encompassed differential scanning calorimetry, infrared spectroscopy, particle size, zeta potential, polydispersity index, transmission electron microscopy, drug content, and in vitro stability. Comparative dissolution studies were performed under sink versus non-sink conditions. Ex vivo intestinal permeation studies were performed on rats utilizing noneverted sac technique and high-performance liquid chromatography analysis. The results revealed lyophilization as the optimum preparation technique using SPC and solvent mixture (Dimethyl sulphoxide:t-butylalchol in a 1:2 ratio. Complex formation was contended by differential scanning calorimetry and infrared data. Optimal lyophilized phytosomal nanocarriers (LPNs exhibited the lowest particle size (316 nm, adequate zeta-potential (−27 mV, and good in vitro stability. Well formed, discrete vesicles were revealed by transmission electron microscopy, drug content, and in vitro stability. Comparative dissolution studies were performed. LPNs demonstrated significant enhancement in DSN dissolution compared to crude drug, physical mixture, and generic and brand DSN products. Permeation studies revealed 80% DSN

  12. Effect of Penetration Enhancer Containing Vesicles on the Percutaneous Delivery of Quercetin through New Born Pig Skin

    Directory of Open Access Journals (Sweden)

    Maria Manconi

    2011-08-01

    Full Text Available Quercetin (3,3′,4′,5,7-pentahydroxyflavone exerts multiple pharmacological effects: anti-oxidant activity, induction of apoptosis, modulation of cell cycle, anti-mutagenesis, and anti-inflammatory effect. In topical formulations quercetin inhibits oxidative skin damage and the inflammatory processes induced by solar UV radiation. In this work, quercetin (2 mg/mL was loaded in vesicular Penetration Enhancer containing Vesicles (PEVs, prepared using a mixture of lipids (Phospholipon® 50, P50 and one of four selected hydrophilic penetration enhancers: Transcutol® P, propylene glycol, polyethylene glycol 400, and Labrasol® at the same concentration (40% of water phase. Photon Correlation Spectroscopy results showed a mean diameter of drug loaded vesicles in the range 80–220 nm. All formulations showed a negative surface charge and incorporation efficiency in the range 48–75%. Transmission Electron Microscopy confirmed that size and morphology varied as a function of the used penetration enhancer. The influence of PEVs on ex vivo quercetin (transdermal delivery was evaluated using Franz-type diffusion cells, new born pig skin and Confocal Laser Scanning Microscopy. Results showed that drug delivery is affected by the penetration enhancer used in the PEVs' formulation.

  13. Phospholipid microemulsion-based hydrogel for enhanced topical delivery of lidocaine and prilocaine: QbD-based development and evaluation.

    Science.gov (United States)

    Negi, Poonam; Singh, Bhupinder; Sharma, Gajanand; Beg, Sarwar; Raza, Kaisar; Katare, Om Prakash

    2016-01-01

    Topical delivery of local anesthetics has been an area of interest for researchers considering the barrier properties of skin and unfavorable physicochemical properties of drugs. In the present study, efforts have been made to modify the in vivo efficacy of eutectic mixture of lidocaine and prilocaine by exploiting the phospholipid modified microemulsion based delivery systems. The strategic QbD (D-optimal mixture design) enabled systematic optimization approach, after having obtained the isotropic area of interest by ternary phase diagram, has resulted into the system with most desirable attributes. Latter include nano-scale, globular structures with an average size of 40.6 nm, as characterized by TEM and DLS. The optimized microemulsion systems in gel dosage forms revealed the better permeability over commercial cream (CC) through abdominal rat skin. Enhancement in the flux from MOPT-NMP gel was 3.22-folds for prilocaine and 4.94-folds for lidocaine, in comparison to that of CC. This enhanced skin permeability is very well reflected in the in vivo studies, wherein intensity and duration of action was augmented significantly. The skin compliance of the optimized formulation was revealed in histopathological studies. The overall benefit relating to efficacy and safety-compliance could be correlated to the uniqueness of the carriers, composed of phospholipids and other components. Hence, the developed phospholipid-microemulsion based gel formulation has been proposed as more useful alternative for the topical delivery of lidocaine and prilocaine.

  14. Modeling localized delivery of Doxorubicin to the brain following focused ultrasound enhanced blood-brain barrier permeability

    Science.gov (United States)

    Nhan, Tam; Burgess, Alison; Lilge, Lothar; Hynynen, Kullervo

    2014-10-01

    Doxorubicin (Dox) is a well-established chemotherapeutic agent, however it has limited efficacy in treating brain malignancies due to the presence of the blood-brain barrier (BBB). Recent preclinical studies have demonstrated that focused ultrasound induced BBB disruption (BBBD) enables efficient delivery of Dox to the brain. For future treatment planning of BBBD-based drug delivery, it is crucial to establish a mathematical framework to predict the effect of transient BBB permeability enhancement on the spatiotemporal distribution of Dox at the targeted area. The constructed model considers Dox concentrations within three compartments (plasma, extracellular, intracellular) that are governed by various transport processes (e.g. diffusion in interstitial space, exchange across vessel wall, clearance by cerebral spinal fluid, uptake by brain cells). By examining several clinical treatment aspects (e.g. sonication scheme, permeability enhancement, injection mode), our simulation results support the experimental findings of optimal interval delay between two consecutive sonications and therapeutically-sufficient intracellular concentration with respect to transfer constant Ktrans range of 0.01-0.03 min-1. Finally, the model suggests that infusion over a short duration (20-60 min) should be employed along with single-sonication or multiple-sonication at 10 min interval to ensure maximum delivery to the intracellular compartment while attaining minimal cardiotoxicity via suppressing peak plasma concentration.

  15. Convective mass transfer enhancement in a membrane channel by delta winglets and their comparison with rectangular winglets☆

    Institute of Scientific and Technical Information of China (English)

    Jingchun Min; Bingqiang Zhang

    2015-01-01

    Numerical calculations were conducted to simulate the flow and mass transfer in narrow membrane channels equipped with delta winglets, which are often used as longitudinal vortex generators to enhance heat transfer in heat exchanger applications. The channel consists of an impermeable solid wall and a membrane. The delta winglets are attached to the solid wal surface to enhance the mass transfer near the membrane surface and sup-press the concentration polarization. The winglet performance was evaluated in terms of concentration polariza-tion factor versus consumed pumping power. Calculations were implemented for NaCl solution flow in a membrane channel having a height of 2.0 mm for Reynolds numbers ranging from 400 to 1000. The delta wing-lets were optimized under equal pumping power condition, and the results of optimization suggest winglet height of 5/6 of the channel height, aspect ratio of 2.0, attack angle of 30°, and a winglet interval equal to the chan-nel height. The optimal delta winglets were compared with the optimal rectangular winglets we found previous-ly, and it is shown that the rectangular winglets yield a somewhat better performance than the delta winglets. © 2015 The Chemical Industry and Engineering Society of China, and Chemical Industry Press. Al rights reserved.

  16. Spurious multiple equilibria introduced by convective adjustment

    NARCIS (Netherlands)

    den Toom, M.; Dijkstra, H.A.; Wubs, F.W.

    2011-01-01

    The application of bifurcation analysis to ocean climate models is substantially hampered by difficulties associated with the use of convective adjustment, i.e. a parameterisation of convection in which the vertical diffusion of heat and salt is greatly enhanced whenever the water column becomes sta

  17. Capsaicin-loaded vesicular systems designed for enhancing localized delivery for psoriasis therapy.

    Science.gov (United States)

    Gupta, Ruchi; Gupta, Madhu; Mangal, Sharad; Agrawal, Udita; Vyas, Suresh Prasad

    2016-05-01

    The aim of the current investigation is to evaluate the potential of capsaicin (CAP)-containing liposomes, niosomes and emulsomes in providing localized and controlled delivery, to improve the topical delivery of drug. CAP-bearing systems were prepared by the film hydration method and compared through various in vitro and in vivo parameters. The TEM photographs suggested that the carrier systems were spherical in shape and nanometric in size range. Skin retention studies of CAP from in vitro and in vivo experiments revealed significantly higher accumulation of drug in the case of the emul-gel formulation. Based on the results, we concluded that the emul-gel may be a potential approach for the topical delivery of CAP, for an effective therapy for psoriasis.

  18. Experimental investigation of convective heat transfer enhancement using alumina/water and copper oxide/water nanofluids

    Directory of Open Access Journals (Sweden)

    Mangrulkar Chidanand K.

    2016-01-01

    Full Text Available The nanofluids are widely used for heat transfer applications in the various engineering applications. The nanoparticles dispersed uniformly in the base fluid on proper mixing. In the present study, Al2O3 and CuO nanoparticles were selected and the changes in the heat transfer coefficient were investigated in the complete laminar and discrete points of transition fluid flow through a copper tube with constant heat flux. The heat transfer coefficient was investigated at different loading of Al2O3 and CuO nanopowders ranging from 0.1% to 0.5% of volume concentration in each case for the laminar and transition fluid flow zones, which is then compared with the distilled water as a plain base fluid. It is found that the optimum enhancement in heat transfer is observed at relatively lower volume fraction of nanoparticles ranging between 0.2 to 0.3%.

  19. Pulsed ultrasound enhances the delivery of nitric oxide from bubble liposomes to ex vivo porcine carotid tissue

    Directory of Open Access Journals (Sweden)

    Sutton JT

    2014-10-01

    Full Text Available JT Sutton,1 JL Raymond,1 MC Verleye,2 GJ Pyne-Geithman,3 CK Holland4 1University of Cincinnati, Biomedical Engineering Program, Cincinnati, OH, 2University of Notre Dame Department of Chemical Engineering, Notre Dame, IN, 3University of Cincinnati, College of Medicine, Department of Neurosurgery and the University of Cincinnati Neuroscience Institute, and Mayfield Clinic, Cincinnati, OH, 4University of Cincinnati, College of Medicine, Internal Medicine, Division of Cardiovascular Diseases, Cincinnati, OH, USA Abstract: Ultrasound-mediated drug delivery is a novel technique for enhancing the penetration of drugs into diseased tissue beds noninvasively. By encapsulating drugs into microsized and nanosized liposomes, the therapeutic can be shielded from degradation within the vasculature until delivery to a target site by ultrasound exposure. Traditional in vitro or ex vivo techniques to quantify this delivery profile include optical approaches, cell culture, and electrophysiology. Here, we demonstrate an approach to characterize the degree of nitric oxide (NO delivery to porcine carotid tissue by direct measurement of ex vivo vascular tone. An ex vivo perfusion model was adapted to assess ultrasound-mediated delivery of NO. This potent vasodilator was coencapsulated with inert octafluoropropane gas to produce acoustically active bubble liposomes. Porcine carotid arteries were excised post mortem and mounted in a physiologic buffer solution. Vascular tone was assessed in real time by coupling the artery to an isometric force transducer. NO-loaded bubble liposomes were infused into the lumen of the artery, which was exposed to 1 MHz pulsed ultrasound at a peak-to-peak acoustic pressure amplitude of 0.34 MPa. Acoustic cavitation emissions were monitored passively. Changes in vascular tone were measured and compared with control and sham NO bubble liposome exposures. Our results demonstrate that ultrasound-triggered NO release from bubble liposomes

  20. Assessment of the Ehlanzeni District health transport and logistics function: Enhancing rural healthcare delivery systems

    CSIR Research Space (South Africa)

    Mashiri, MAM

    2009-07-01

    Full Text Available This paper seeks to establish a baseline against which to assess the impacts of the ‘Ehlanzeni District Health Transport Function’ for the district’s healthcare service delivery output, and by extension, health and welfare outcomes. The main...

  1. Interpersonal Psychotherapy with a Parenting Enhancement Adapted for In-Home Delivery in Early Head Start

    Science.gov (United States)

    Beeber, Linda S.; Schwartz, Todd A.; Holditch-Davis, Diane; Canuso, Regina; Lewis, Virginia; Matsuda, Yui

    2014-01-01

    Formidable barriers prevent low-income mothers from accessing evidence-based treatment for depressive symptoms that compromise their ability to provide sensitive, responsive parenting for their infant or toddler. interpersonal psychotherapy (IPT), an evidence-based psychotherapy for depression, was tailored for in-home delivery to mothers…

  2. 77 FR 26674 - Enhancement of Electricity Market Surveillance and Analysis Through Ongoing Electronic Delivery...

    Science.gov (United States)

    2012-05-07

    ... relating to physical and virtual offers and bids, market awards, resource outputs, marginal cost estimates... pricing. Such data will facilitate the Commission's development and evaluation of its policies and.... Web-Based Delivery 45 F. Data Requested 49 G. Implementation Timeline and Phasing 64 H. Ongoing...

  3. A Collaborative Naturalistic Service Delivery Program for Enhancing Pragmatic Language and Participation in Preschoolers

    Science.gov (United States)

    Demchick, Barbara B.; Day, Karen H.

    2016-01-01

    We describe a speech-language pathology and occupational therapy service delivery program for preschoolers with developmental delays and communication and related impairments. Key features included interprofessional collaboration; parent professional partnerships; naturalistic environment; opportunities for choice and control; use of a…

  4. Ultrasound and electric pulses for transdermal drug delivery enhancement: Ex vivo assessment of methods with in vivo oriented experimental protocols.

    Science.gov (United States)

    Zorec, Barbara; Jelenc, Jure; Miklavčič, Damijan; Pavšelj, Nataša

    2015-07-25

    In our present study we focus on two physical enhancement methods for transdermal drug delivery: ultrasound and electric pulses either alone or in combination. Great emphasis has been given on the design of the experimental system and protocols, so the results and the conclusions drawn from them would have greater relevance for in vivo use and later translation into clinical practice. Our results show a statistically significant enhancement of calcein delivery (after one hour of passive diffusion following treatment) already after 5 minutes of ultrasound application, or only 6 × 100 short high voltage electrical pulses. We also experimented with combinations of the two enhancement methods hoping for synergistic effects, however, the results showed no evident drastic improvement over single method. Looking closer at physics of both methods, this absence of synergy in our in vivo oriented experimental setting is not surprising. The mechanism of action of both methods is the creation of aqueous pathways in the stratum corneum leading to increased skin permeability. However, when used in combination (regardless of the order of methods), the second method was unsuccessful in adding many new aqueous pathways in the stratum corneum, as it acted preferentially near the sites of the existing ones.

  5. Late-responding normal tissue cells benefit from high-precision radiotherapy with prolonged fraction delivery times via enhanced autophagy

    Science.gov (United States)

    Yao, Qiwei; Zheng, Rong; Xie, Guozhu; Liao, Guixiang; Du, Shasha; Ren, Chen; Li, Rong; Lin, Xiaoshan; Hu, Daokun; Yuan, Yawei

    2015-01-01

    High-precision radiotherapy (HPR) has established its important role in the treatment of tumors due to its precise dose distribution. Given its more complicated delivery process, HPR commonly requires more fraction delivery time (FDT). However, it is unknown whether it has an identical response of prolonged FDT on different normal tissues. Our results showed that fractionated irradiation with prolonged FDTs (15, 36, and 50 minutes) enhanced cell surviving fractions for normal tissue cells compared with irradiation with an FDT of 2 minutes. However, the late-responding normal cell line HEI-OC1 was more responsive to prolonged FDTs and demonstrated higher surviving fractions and significantly decreased apoptosis and DNA damage compared to the acute-responding normal cell line HaCaT. Increased autophagy mediated via the ATM-AMPK pathway was observed in HEI-OC1 cells compared with HaCaT cells when irradiated with prolonged FDTs. Furthermore, treatment with the autophagy inhibitor 3-MA or ATM inhibitor KU55933 resulted in enhanced ROS accumulation and attenuation of the effect of prolonged FDT-mediated protection on irradiated HEI-OC1 cells. Our results indicated that late-responding normal tissue cells benefitted more from prolonged FDTs compared with acute-responding tissue cells, which was mainly attributed to enhanced cytoprotective autophagy mediated via the ATM/AMPK signaling pathway. PMID:25766900

  6. Enhancing nerve regeneration in the peripheral nervous system using polymeric scaffolds, stem cell engineering and nanoparticle delivery system

    Science.gov (United States)

    Sharma, Anup Dutt

    Peripheral nerve regeneration is a complex biological process responsible for regrowth of neural tissue following a nerve injury. The main objective of this project was to enhance peripheral nerve regeneration using interdisciplinary approaches involving polymeric scaffolds, stem cell therapy, drug delivery and high content screening. Biocompatible and biodegradable polymeric materials such as poly (lactic acid) were used for engineering conduits with micropatterns capable of providing mechanical support and orientation to the regenerating axons and polyanhydrides for fabricating nano/microparticles for localized delivery of neurotrophic growth factors and cytokines at the site of injury. Transdifferentiated bone marrow stromal cells or mesenchymal stem cells (MSCs) were used as cellular replacements for lost native Schwann cells (SCs) at the injured nerve tissue. MSCs that have been transdifferentiated into an SC-like phenotype were tested as a substitute for the myelinating SCs. Also, genetically modified MSCs were engineered to hypersecrete brain- derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) to secrete therapeutic factors which Schwann cell secrete. To further enhance the regeneration, nerve growth factor (NGF) and interleukin-4 (IL4) releasing polyanhydrides nano/microparticles were fabricated and characterized in vitro for their efficacy. Synergistic use of these proposed techniques was used for fabricating a multifunctional nerve regeneration conduit which can be used as an efficient tool for enhancing peripheral nerve regeneration.

  7. A novel bile salts-lipase polymeric film-infused minitablet system for enhanced oral delivery of cholecalciferol.

    Science.gov (United States)

    Braithwaite, Miles C; Choonara, Yahya E; Kumar, Pradeep; Tomar, Lomas K; Du Toit, Lisa C; Pillay, Viness

    2016-11-01

    Few researchers have investigated the use of multiple physiological enhancers combined with synthetic carriers to augment delivery of nutraceuticals. The current work describes the development of an oral delivery system termed a bioactive association platform (BAP) capable of delivering nutraceutical actives from a formulation framework specifically for enhancing the in vitro and in vivo performance of model vitamin, cholecalciferol (Vitamin D3). Synthesis of a novel triple vitamin minitablet and an optimized bile salt/lipase alginate-glycerin film provided unique oral components for inclusion in a BAP capsule. Component validation and physicochemical characterizations included comparative ex vivo permeability, chemical structure mapping, thermodynamic analysis and magnetic resonance imaging. In vitro dissolution studies of the BAP produced an area under the dissolution curve (AUC) for cholecalciferol release that was 28% greater than a conventional comparator product. A total of 84.01% of cholecalciferol was released from the BAP within 3 h versus only 59% from a comparator. Ex vivo permeation studies revealed superior cholecalciferol membrane diffusion from the triple vitamin minitablet BAP component. In vivo performance showed a greater mean change from baseline cholecalciferol to peak plasma levels (Cmax) from the BAP compared to the comparator (55.66 versus 46.05 ng/mL). Cholecalciferol bioavailability was improved in vivo with an AUC0-inf from the BAP that was 3.2× greater than the conventional product. The BAP was also superior at improving and maintaining serum levels of the main metabolite, 25-hydroxyvitamin D3, compared to the conventional system. In vitro and in vivo results thus confirmed improvements in cholecalciferol dissolution, membrane permeability and plasma drug levels. The study results position the BAP as an ideal oral vehicle for enhanced delivery of cholecalciferol.

  8. Measurement of the Time-Resolved Reflection Matrix for Enhancing Light Energy Delivery into a Scattering Medium

    Science.gov (United States)

    Choi, Youngwoon; Hillman, Timothy R.; Choi, Wonjun; Lue, Niyom; Dasari, Ramachandra R.; So, Peter T. C.; Choi, Wonshik; Yaqoob, Zahid

    2014-01-01

    Multiple scatterings occurring in a turbid medium attenuate the intensity of propagating waves. Here, we propose a method to efficiently deliver light energy to the desired target depth in a scattering medium. We measure the time-resolved reflection matrix of a scattering medium using coherent time-gated detection. From this matrix, we derive and experimentally implement an incident wave pattern that optimizes the detected signal corresponding to a specific arrival time. This leads to enhanced light delivery at the target depth. The proposed method will lay a foundation for efficient phototherapy and deep-tissue in vivo imaging in the near future. PMID:24483661

  9. Natural oils as skin permeation enhancers for transdermal delivery of olanzapine: in vitro and in vivo evaluation.

    Science.gov (United States)

    Aggarwal, Geeta; Dhawan, Sanju; HariKumar, S L

    2012-03-01

    The feasibility of development of transdermal delivery system of olanzapine utilizing natural oils as permeation enhancers was investigated. Penetration enhancing potential of corn (maize) oil, groundnut oil and jojoba oil on in vitro permeation of olanzapine across rat skin was studied. The magnitude of flux enhancement factor with corn oil, groundnut oil and jojoba oil was 7.06, 5.31 and 1.9 respectively at 5mg/ml concentration in solvent system. On the basis of in vitro permeation studies, eudragit based matrix type transdermal patches of olanzapine were fabricated using optimized concentrations of natural oils as permeation enhancers. All transdermal patches were found to be uniform with respect to physical characteristics. The interaction studies carried out by comparing the results of ultraviolet, HPLC and FTIR analyses for the pure drug, polymers and mixture of drug and polymers indicated no chemical interaction between the drug and excipients. Corn oil containing unsaturated fatty acids was found to be promising natural permeation enhancer for transdermal delivery of olanzapine with greatest cumulative amount of drug permeated (1010.68 μg/cm²/h) up to 24 h and caused no skin irritation. The fabricated transdermal patches were found to be stable. The pharmacokinetic characteristics of the final optimized matrix patch (T2) were determined after transdermal application to rabbits. The calculated relative bioavailability of TDDS was 113.6 % as compared to oral administration of olanzapine. The therapeutic effectiveness of optimized transdermal system was confirmed by tranquillizing activity in rotarod and grip mice model.

  10. Convection in Oblate Solar-Type Stars

    CERN Document Server

    Wang, Junfeng; Liang, Chunlei

    2016-01-01

    We present the first global 3D simulations of thermal convection in the oblate envelopes of rapidly-rotating solar-type stars. This has been achieved by exploiting the capabilities of the new Compressible High-ORder Unstructured Spectral difference (CHORUS) code. We consider rotation rates up to 85\\% of the critical (breakup) rotation rate, which yields an equatorial radius that is up to 17\\% larger than the polar radius. This substantial oblateness enhances the disparity between polar and equatorial modes of convection. We find that the convection redistributes the heat flux emitted from the outer surface, leading to an enhancement of the heat flux in the polar and equatorial regions. This finding implies that lower-mass stars with convective envelopes may not have darker equators as predicted by classical gravity darkening arguments. The vigorous high-latitude convection also establishes elongated axisymmetric circulation cells and zonal jets in the polar regions. Though the overall amplitude of the surface...

  11. Targeted delivery of the hydroxylase inhibitor DMOG provides enhanced efficacy with reduced systemic exposure in a murine model of colitis.

    Science.gov (United States)

    Tambuwala, Murtaza M; Manresa, Mario C; Cummins, Eoin P; Aversa, Vincenzo; Coulter, Ivan S; Taylor, Cormac T

    2015-11-10

    Targeting hypoxia-sensitive pathways has recently been proposed as a new therapeutic approach to the treatment of intestinal inflammation. HIF-hydroxylases are enzymes which confer hypoxic-sensitivity upon the hypoxia-inducible factor (HIF), a major regulator of the adaptive response to hypoxia. Previous studies have shown that systemic (intraperitoneal) administration of hydroxylase inhibitors such as dimethyloxalylglycine (DMOG) is profoundly protective in multiple models of colitis, however the therapeutic potential of this approach is limited due to potential side-effects associated with systemic drug exposure and the fact that orally delivered DMOG is ineffective (likely due to drug inactivation by gastric acid). In order to overcome these issues, we formulated DMOG in a liquid emulsion drug delivery system which, when coated with specific polymer coatings, permits oral delivery of a reduced dose which is released locally throughout the colon. This colon-targeted DMOG formulation demonstrated increased relative colonic bioactivity with reduced systemic exposure and provided a similar degree of protection to systemic (intraperitoneal) administration at a 40-fold lower dose in DSS-induced colitis. In summary, targeted delivery of DMOG to the colon provides local protection resulting in enhanced efficacy with reduced systemic exposure in the treatment of colitis. This novel approach to targeting hydroxylase inhibitors to specific diseased regions of the GI tract may improve it's potential as a new therapeutic in inflammatory bowel diseases such as ulcerative colitis.

  12. Sustained delivery of BMP-2 enhanced osteoblastic differentiation of BMSCs based on surface hydroxyapatite nanostructure in chitosan-HAp scaffold.

    Science.gov (United States)

    Wang, Guancong; Qiu, Jichuan; Zheng, Lin; Ren, Na; Li, Jianhua; Liu, Hong; Miao, Junying

    2014-01-01

    The surface characteristics of biomaterials, especially regarding the sustained delivery of bone morphogenetic protein-2 (BMP-2), can possibly provide a novel and effective drug delivery system that can enhance osteogenesis. In this study, we evaluated the BMP-2 adsorption and release ability of the surface biomimetic hydroxyapatite (HAp) nanostructure on a new HAp-coated genipin-chitosan conjugation scaffold (HGCCS), and the resulting osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) in vitro. HGCCS exhibited a loading efficiency of 65% (1.30 μg), which is significantly higher than 28% (0.56 μg, p nanostructure of HGCCS used as a delivery system for BMP-2 is capable of promoting osteogenic differentiation in vitro. These findings demonstrated that HAp nanostructure assembled on organic porous scaffold could work as both calcium source and absorption/release platform, which opened a new research avenue for cell growth factor release, and provided a promising strategy for design and preparation of bioactive scaffold for bone tissue engineering.

  13. Colloidal nanocarriers for the enhanced cutaneous delivery of naftifine: characterization studies and in vitro and in vivo evaluations.

    Science.gov (United States)

    Erdal, M Sedef; Özhan, Gül; Mat, M Cem; Özsoy, Yıldız; Güngör, Sevgi

    2016-01-01

    In topical administration of antifungals, the drugs should pass the stratum corneum to reach lower layers of the skin in effective concentrations. Thus, the formulation of antifungal agents into a suitable delivery system is important for the topical treatment of fungal infections. Nanosized colloidal carriers have gained great interest during the recent years to serve as efficient promoters of drug penetration into the skin. Microemulsions are soft colloidal nanosized drug carriers, which are thermodynamically stable and isotropic systems. They have been extensively explored for the enhancement of skin delivery of drugs. This study was carried out to exploit the feasibility of colloidal carriers as to improve skin transport of naftifine, which is an allylamine antifungal drug. The microemulsions were formulated by construction of pseudoternary phase diagrams and composed of oleic acid (oil phase), Kolliphor(®) EL or Kolliphor(®) RH40 (surfactant), Transcutol(®) (cosurfactant), and water (aqueous phase). The plain and drug-loaded microemulsions were characterized in terms of isotropy, particle size and size distribution, pH value, refractive index, viscosity, and conductivity. The in vitro skin uptake of naftifine from microemulsions was studied using tape stripping technique in pig skin. The drug penetrated significantly into stratum corneum from microemulsions compared to its marketed cream (P2,5-diphenyltetrazolium bromide viability test. This study indicated that the nanosized colloidal carriers developed could be considered as an effective and safe topical delivery system for naftifine.

  14. Organised convection embedded in a large-scale flow

    Science.gov (United States)

    Naumann, Ann Kristin; Stevens, Bjorn; Hohenegger, Cathy

    2017-04-01

    In idealised simulations of radiative convective equilibrium, convection aggregates spontaneously from randomly distributed convective cells into organized mesoscale convection despite homogeneous boundary conditions. Although these simulations apply very idealised setups, the process of self-aggregation is thought to be relevant for the development of tropical convective systems. One feature that idealised simulations usually neglect is the occurrence of a large-scale background flow. In the tropics, organised convection is embedded in a large-scale circulation system, which advects convection in along-wind direction and alters near surface convergence in the convective areas. A large-scale flow also modifies the surface fluxes, which are expected to be enhanced upwind of the convective area if a large-scale flow is applied. Convective clusters that are embedded in a large-scale flow therefore experience an asymmetric component of the surface fluxes, which influences the development and the pathway of a convective cluster. In this study, we use numerical simulations with explicit convection and add a large-scale flow to the established setup of radiative convective equilibrium. We then analyse how aggregated convection evolves when being exposed to wind forcing. The simulations suggest that convective line structures are more prevalent if a large-scale flow is present and that convective clusters move considerably slower than advection by the large-scale flow would suggest. We also study the asymmetric component of convective aggregation due to enhanced surface fluxes, and discuss the pathway and speed of convective clusters as a function of the large-scale wind speed.

  15. Aptamer-nanoparticle bioconjugates enhance intracellular delivery of vinorelbine to breast cancer cells.

    Science.gov (United States)

    Zhou, Wenhu; Zhou, Yanbin; Wu, Jianping; Liu, Zhenbao; Zhao, Huanzhe; Liu, Juewen; Ding, Jinsong

    2014-01-01

    Targeted uptake of therapeutic nanoparticles in cell- or tissue-specific manner is an attractive technology since they can offer greater efficacy and reduce cytotoxicity on peripheral healthy tissues. In this study, AS1411 (AP), a DNA aptamer specifically binding to nucleolin that is overexpressed on the plasma membrane of breast cancer (BC) cells, was exploited as the targeting ligand of a nanoparticle-based drug delivery system. Vinorelbine (VRL) loaded PLGA-PEG nanoparticles (NP) were formulated by an emulsion/solvent evaporation method, and AP was conjugated to the particle surface using the EDC/NHS technique. The drug-loading efficiency and in vitro drug release studies were measured using HPLC. The resulting AP-NP/VRL formed spherical nanoparticles (AS1411-functionalized nanoparticles are potential carrier candidates for targeted drug delivery towards BC.

  16. Carrier-based delivery mechanism for enhanced services on passive optical networks

    Science.gov (United States)

    Compton, Mark K.; Rosher, Paul A.

    1992-02-01

    Passive optical networking is being considered for the provision of digital services in the local loop. In the UK, TPON is under investigation for the delivery of telephony and other narrowband services. This paper describes a carrier based system which is being considered as a short term overlay to TPON. Both broadband and narrowband services may be supported, representing an evolutionary path to the provision of integrated services for the information intensive customer.

  17. Formulation and optimization of nano-sized ethosomes for enhanced transdermal delivery of cromolyn sodium

    OpenAIRE

    Rakesh, R.; Anoop, K. R.

    2012-01-01

    Aim: The current study was aimed to investigate the feasibility of transdermal delivery of cromolyn sodium using a novel lipid vesicular carrier, ethosomes. Materials And Methods: Ethosomes of cromolyn sodium was prepared, optimized, and characterized for vesicle shape, vesicle size and size distribution, zeta potential, entrapment efficiency, in vitro drug release, in vitro skin permeation, in vitro skin deposition and vesicle stability. Histological examination of porcine ear skin treated w...

  18. Magnetic targeting to enhance microbubble delivery in an occluded microarterial bifurcation

    Science.gov (United States)

    de Saint Victor, M.; Carugo, D.; Barnsley, L. C.; Owen, J.; Coussios, C.-C.; Stride, E.

    2017-09-01

    Ultrasound and microbubbles have been shown to accelerate the breakdown of blood clots both in vitro and in vivo. Clinical translation of this technology is still limited, however, in part by inefficient microbubble delivery to the thrombus. This study examines the obstacles to delivery posed by fluid dynamic conditions in occluded vasculature and investigates whether magnetic targeting can improve microbubble delivery. A 2D computational fluid dynamic model of a fully occluded Y-shaped microarterial bifurcation was developed to determine: (i) the fluid dynamic field in the vessel with inlet velocities from 1–100 mm s‑1 (corresponding to Reynolds numbers 0.25–25) (ii) the transport dynamics of fibrinolytic drugs; and (iii) the flow behavior of microbubbles with diameters in the clinically-relevant range (0.6–5 µm). In vitro experiments were carried out in a custom-built microfluidic device. The flow field was characterized using tracer particles, and fibrinolytic drug transport was assessed using fluorescence microscopy. Lipid-shelled magnetic microbubbles were fluorescently labelled to determine their spatial distribution within the microvascular model. In both the simulations and experiments, the formation of laminar vortices and an abrupt reduction of fluid velocity were observed in the occluded branch of the bifurcation, severely limiting drug transport towards the occlusion. In the absence of a magnetic field, no microbubbles reached the occlusion, remaining trapped in the first vortex, within 350 µm from the bifurcation center. The number of microbubbles trapped within the vortex decreased as the inlet velocity increased, but was independent of microbubble size. Application of a magnetic field (magnetic flux density of 76 mT, magnetic flux density gradient of 10.90 T m‑1 at the centre of the bifurcation) enabled delivery of microbubbles to the occlusion and the number of microbubbles delivered increased with bubble size and with decreasing inlet

  19. Stabilization of influenza vaccine enhances protection by microneedle delivery in the mouse skin.

    Directory of Open Access Journals (Sweden)

    Fu-Shi Quan

    Full Text Available BACKGROUND: Simple and effective vaccine administration is particularly important for annually recommended influenza vaccination. We hypothesized that vaccine delivery to the skin using a patch containing vaccine-coated microneedles could be an attractive approach to improve influenza vaccination compliance and efficacy. METHODOLOGY/PRINCIPAL FINDINGS: Solid microneedle arrays coated with inactivated influenza vaccine were prepared for simple vaccine delivery to the skin. However, the stability of the influenza vaccine, as measured by hemagglutination activity, was found to be significantly damaged during microneedle coating. The addition of trehalose to the microneedle coating formulation retained hemagglutination activity, indicating stabilization of the coated influenza vaccine. For both intramuscular and microneedle skin immunization, delivery of un-stabilized vaccine yielded weaker protective immune responses including viral neutralizing antibodies, protective efficacies, and recall immune responses to influenza virus. Immunization using un-stabilized vaccine also shifted the pattern of antibody isotypes compared to the stabilized vaccine. Importantly, a single microneedle-based vaccination using stabilized influenza vaccine was found to be superior to intramuscular immunization in controlling virus replication as well as in inducing rapid recall immune responses post challenge. CONCLUSIONS/SIGNIFICANCE: The functional integrity of hemagglutinin is associated with inducing improved protective immunity against influenza. Simple microneedle influenza vaccination in the skin produced superior protection compared to conventional intramuscular immunization. This approach is likely to be applicable to other vaccines too.

  20. Local delivery of thyroid hormone enhances oligodendrogenesis and myelination after spinal cord injury

    Science.gov (United States)

    Shultz, Robert B.; Wang, Zhicheng; Nong, Jia; Zhang, Zhiling; Zhong, Yinghui

    2017-06-01

    Objective. Traumatic spinal cord injury (SCI) causes apoptosis of myelin-forming oligodendrocytes (OLs) and demyelination of surviving axons, resulting in conduction failure. Remyelination of surviving denuded axons provides a promising therapeutic target for spinal cord repair. While cell transplantation has demonstrated efficacy in promoting remyelination and functional recovery, the lack of ideal cell sources presents a major obstacle to clinical application. The adult spinal cord contains oligodendrocyte precursor cells and multipotent neural stem/progenitor cells that have the capacity to differentiate into mature, myelinating OLs. However, endogenous oligodendrogenesis and remyelination processes are limited by the upregulation of remyelination-inhibitory molecules in the post-injury microenvironment. Multiple growth factors/molecules have been shown to promote OL differentiation and myelination. Approach. In this study we screened these therapeutics and found that 3, 3‧, 5-triiodothyronine (T3) is the most effective in promoting oligodendrogenesis and OL maturation in vitro. However, systemic administration of T3 to achieve therapeutic doses in the injured spinal cord is likely to induce hyperthyroidism, resulting in serious side effects. Main results. In this study we developed a novel hydrogel-based drug delivery system for local delivery of T3 to the injury site without eliciting systemic toxicity. Significance. Using a clinically relevant cervical contusion injury model, we demonstrate that local delivery of T3 at doses comparable to safe human doses promoted new mature OL formation and myelination after SCI.

  1. Enhanced fluorescence imaging of live cells by effective cytosolic delivery of probes.

    Directory of Open Access Journals (Sweden)

    Marzia Massignani

    Full Text Available BACKGROUND: Microscopic techniques enable real-space imaging of complex biological events and processes. They have become an essential tool to confirm and complement hypotheses made by biomedical scientists and also allow the re-examination of existing models, hence influencing future investigations. Particularly imaging live cells is crucial for an improved understanding of dynamic biological processes, however hitherto live cell imaging has been limited by the necessity to introduce probes within a cell without altering its physiological and structural integrity. We demonstrate herein that this hurdle can be overcome by effective cytosolic delivery. PRINCIPAL FINDINGS: We show the delivery within several types of mammalian cells using nanometre-sized biomimetic polymer vesicles (a.k.a. polymersomes that offer both highly efficient cellular uptake and endolysomal escape capability without any effect on the cellular metabolic activity. Such biocompatible polymersomes can encapsulate various types of probes including cell membrane probes and nucleic acid probes as well as labelled nucleic acids, antibodies and quantum dots. SIGNIFICANCE: We show the delivery of sufficient quantities of probes to the cytosol, allowing sustained functional imaging of live cells over time periods of days to weeks. Finally the combination of such effective staining with three-dimensional imaging by confocal laser scanning microscopy allows cell imaging in complex three-dimensional environments under both mono-culture and co-culture conditions. Thus cell migration and proliferation can be studied in models that are much closer to the in vivo situation.

  2. Enhanced in Vivo Delivery of 5-Fluorouracil by Ethosomal Gels in Rabbit Ear Hypertrophic Scar Model

    Directory of Open Access Journals (Sweden)

    Yan Wo

    2014-12-01

    Full Text Available Applying Ethosomal Gels (EGs in transdermal drug delivery systems has evoked considerable interest because of their good water-solubility and biocompatibility. However, there has not been an explicit description of applying EGs as a vehicle for hypertrophic scars treatment. Here, a novel transdermal EGs loaded with 5-fluorouracil (5-FU EGs was successfully prepared and characterized. The stability assay in vitro revealed that 5-FU EGs stored for a period of 30 days at 4 ± 1 °C had a better size stability than that at 25 ± 1 °C. Furthermore, using confocal laser scanning microscopy, EGs labeled with Rhodamine 6 G penetrated into the deep dermis of the hypertrophic scar within 24 h in the rabbit ear hypertrophic model suggested that the EGs were an optional delivery carrier through scar tissues. In addition, the value of the Scar Elevation Index (SEI of 5-FU EGs group in the rabbit ear scar model was lower than that of 5-FU Phosphate Buffered Saline gel and Control groups. To conclude, these results suggest that EGs delivery system loaded 5-fluorouracil is a perfect candidate drug for hypertrophic scars therapy in future.

  3. Enhanced in Vivo Delivery of 5-Fluorouracil by Ethosomal Gels in Rabbit Ear Hypertrophic Scar Model

    Science.gov (United States)

    Wo, Yan; Zhang, Zheng; Zhang, Yixin; Zhang, Zhen; Wang, Kan; Mao, Xiaohui; Su, Weijie; Li, Ke; Cui, Daxiang; Chen, Jun

    2014-01-01

    Applying Ethosomal Gels (EGs) in transdermal drug delivery systems has evoked considerable interest because of their good water-solubility and biocompatibility. However, there has not been an explicit description of applying EGs as a vehicle for hypertrophic scars treatment. Here, a novel transdermal EGs loaded with 5-fluorouracil (5-FU EGs) was successfully prepared and characterized. The stability assay in vitro revealed that 5-FU EGs stored for a period of 30 days at 4 ± 1 °C had a better size stability than that at 25 ± 1 °C. Furthermore, using confocal laser scanning microscopy, EGs labeled with Rhodamine 6 G penetrated into the deep dermis of the hypertrophic scar within 24 h in the rabbit ear hypertrophic model suggested that the EGs were an optional delivery carrier through scar tissues. In addition, the value of the Scar Elevation Index (SEI) of 5-FU EGs group in the rabbit ear scar model was lower than that of 5-FU Phosphate Buffered Saline gel and Control groups. To conclude, these results suggest that EGs delivery system loaded 5-fluorouracil is a perfect candidate drug for hypertrophic scars therapy in future. PMID:25501333

  4. Titania nanotube delivery fetal bovine serum for enhancing MC3T3-E1 activity and osteogenic gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Jing, E-mail: pengjingtd@163.com [Airport College, Civil Aviation University of China, Tianjin 300300 (China); Zhang, Xinming, E-mail: xinmingmail@163.com [Tianjin Product Quality Inspection Technology Research Institute, Tianjin 300384 (China); School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China); Li, Zhaoyang [School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China); Liu, Yunde [School of Medical Laboratory, Tianjin Medical University, Tianjin 300203 (China); Yang, Xianjin [School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China)

    2015-11-01

    Titania nanotube (TNT) delivery of fetal bovine serum (FBS) was conducted on titanium (Ti) to enhance bone tissue repair. Scanning electron microscopy (SEM) and energy dispersive spectrometer (EDS) showed FBS increased the tube wall thickness and decreased the tube diameter. Attenuated total reflectance Fourier transform infrared further confirmed that FBS completely covered the TNT and changed the surface composition. Water contact angle tests showed TNT/FBS possessed hydrophilic properties. Compared to original Ti, the TNT/FBS group had more attached osteoblasts after 2 h and enhanced filopodia growth at 0.5 h. Significantly, more osteoblasts were also observed on TNT/FBS after 7 d culturing. FBS was released steadily from TNT; about 70% of FBS had been released at 3 d and 90% at 5 d, as shown by the bicinchoninic acid method. TNT/FBS also enhanced subsequent osteoblast differentiation and gene expression; the quantum real-time polymerase chain reaction test showed that TNT/FBS up-regulated alkaline phosphatase and osteocalcin gene expression at 7 d and 14 d. Therefore, TNT/FBS delivered sustained in situ nutrition and enhanced osteoblast activity and osteogenic gene expression. - Highlights: • Fetal Bovine Serum (FBS) was filled in titania nanotube (TNT) structures. • FBS provided sustained-release in situ nutrition for surface osteoblast growth. • TNT/FBS enhanced osteoblast activity and osteogenic gene expression.

  5. Enhancing in vivo Bioavailability in Beagle Dogs of GLM-7 as a Novel Anti-Leukemia Drug through a Self-Emulsifying Drug Delivery System for Oral Delivery.

    Science.gov (United States)

    Wang, Yuli; Yu, Ning; Guo, Rui; Yang, Meiyan; Shan, Li; Huang, Wei; Gong, Wei; Shao, Shuai; Chen, Xiaoping; Gao, Chunsheng

    2016-01-01

    GLM-7 is a novel anti-leukemia drug in the pre-clinical study. The previous study shows that GLM-7 is a poorly water-soluble drug with low oral bioavailability. In this study, we employed the self-emulsifying drug delivery system (SEDDS) to improve the oral bioavailability of GLM-7. The GLM-7 SEDDS formulation was prepared using MCT as oil, ovolecithin as surfactant and Transcutol as co-surfactant, and the formulation parameters were optimized by the response surface methodology. The optimized GLM-7 SEDDS formulation showed a stable liquid state, and can automatically emulsify to form the isotropic emulsion once exposure to the water phase. The generated emulsion showed the spherical shape, and had an average size of about 399 nm and a zeta potential of about -42 mV. Compared to the GLM-7 dissolution less than 1.4% from pure GLM-7 powder (reference), the GLM-7 SEDDS formulation could remarkably enhance the in vitro dissolution to 83% in the medium of 0.1N HCL. The in vivo oral bioavailability of GLM-7 SEDDS formulation was investigated in beagle dogs. The results demonstrated that the GLM-7 SEDDS formulation significantly enhanced the plasma concentrations of GLM-7, and the Cmax reached to 878 ng/ml and was 9.2 folds as high as the Cmax 95.85 ng/ml of reference. Moreover, the area under the curve (AUC) of GLM-7 SEDDS formulation was 13.6 times higher than that of reference, which suggested that the SEDDS formulation remarkably increased the oral bioavailability of GLM-7.

  6. Permeation-enhancing effects of chitosan formulations on recombinant hirudin-2 by nasal delivery in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    Yu-jie ZHANG; Chang-hua MA; Wan-liang LU; Xuan ZHANG; Xiao-liang WANG; Jian-ning SUN; Qiang ZHANG

    2005-01-01

    Aim: To investigate the enhancing effects of chitosan with or without enhancers on nasal recombinant hirudin-2 (rHV2) delivery in vitro and in vivo, and to evaluate the ciliotoxicity of these formulations. Methods: The permeation-enhancingeffect of various chitosan formulations was estimated by using the permeation coefficient of fluorescein isothiocyanate recombinant hirudin-2 (FITC-rHV2) across the excited rabbit nasal epithelium in vitro. The effect was further evaluated by measuring the blood concentration level after nasal absorption of FITC-rHV2 in rats. The mucosal ciliotoxicity of different formulations was evaluated with an in situ toad palate model. Results: Chitosan at a concentration of 0.5% with or without various enhancers significantly increased the permeability coefficient(P) and relative bioavailability (Fr) of FITC-rHV2 compared with the blank control.The addition of 1% sodium dodecylsulfate, 5% Brij35, 5% Tween 80, 1.5% menthol,1% glycyrrhizic acid monoammonium salt (GAM) or 4% Azone into the 0.5%chitosan solution resulted in a further increase in absorption (P<0.05) compared with 0.5% chitosan alone. But co-administration of chitosan with 5% hydroxylpropyl-beta-cyclodextrin (HP-β-CD), 5% lecithin or 0.1% ethylenediamine tetraacetic acid (EDTA) was not more effective than using the 0.5% chitosan solution alone.Chitosan alone and with 5% HP-β-CD, 0.1% EDTA, 1% GAM or 5%Tween80 was relatively less ciliotoxic. Conclusion: Chitosan with or without some enhancers was able to effectively promote the nasal absorption of recombinant hirudin, while not resulting in severe mucosal ciliotoxicity. A chitosan formulation system would be a useful approach for the nasal delivery of recombinant hirudin.

  7. Development of self-nanoemulsifying drug delivery system for oral bioavailability enhancement of valsartan in beagle dogs.

    Science.gov (United States)

    Li, Zhenbao; Zhang, Wenjuan; Gao, Yan; Xiang, Rongwu; Liu, Yan; Hu, Mingming; Zhou, Mei; Liu, Xiaohong; Wang, Yongjun; He, Zhonggui; Sun, Yinghua; Sun, Jin

    2017-02-01

    Valsartan, an angiotensin II receptor antagonist, is widely used to treat high blood pressure in the clinical setting. However, its poor water solubility results in the low oral bioavailability. The aim of this study was to improve dissolution rate and oral bioavailability by developing a self-nanoemulsifying drug delivery system. Saturation solubility of valsartan in various oils, surfactants, and cosurfactants was investigated, and the optimized formulation was determined by central composite design-response surface methodology. The shape of resultant VAL-SNEDDS was spherical with an average diameter of about 27 nm. And the drug loading efficiency is approximately 14 wt%. Differential scanning calorimetry and XRD studies disclosed the molecular or amorphous state of valsartan in VAL-SNEDDS. The dissolution study indicated that the self-nanoemulsifying drug delivery systems (SNEDDS) exhibited significantly enhanced dissolution compared with market capsules (Diovan®) in various media. Furthermore, the stability of formulation revealed that valsartan SNEDDS was stable under low temperature and accelerated test condition. Furthermore, the pharmacokinetics demonstrated that C max and AUC(0-∞) of SNEDDS capsules were about three- and twofold higher than Diovan® in beagle dogs, respectively. Meanwhile, the safety evaluation implied that VAL-SNEDDS was innocuous to beagle dogs during 15 days of continuous administration. Our results suggested that VAL-SNEDDS was a potential and safe delivery system with enhanced dissolution rate and oral bioavailability, as well as offered a strategy for the engineering of poorly water-soluble drugs in the clinical setting.

  8. Delivery of bioactive lipids from composite microgel-microsphere injectable scaffolds enhances stem cell recruitment and skeletal repair.

    Directory of Open Access Journals (Sweden)

    Anusuya Das

    Full Text Available In this study, a microgel composed of chitosan and inorganic phosphates was used to deliver poly(lactic-co-glycolic acid (PLAGA microspheres loaded with sphingolipid growth factor FTY720 to critical size cranial defects in Sprague Dawley rats. We show that sustained release of FTY720 from injected microspheres used alone or in combination with recombinant human bone morphogenic protein-2 (rhBMP2 improves defect vascularization and bone formation in the presence and absence of rhBMP2 as evaluated by quantitative microCT and histological measurements. Moreover, sustained delivery of FTY720 from PLAGA and local targeting of sphingosine 1-phosphate (S1P receptors reduces CD45+ inflammatory cell infiltration, promotes endogenous recruitment of CD29+CD90+ bone progenitor cells and enhances the efficacy of rhBMP2 from chitosan microgels. Companion in vitro studies suggest that selective activation of sphingosine receptor subtype-3 (S1P3 via FTY720 treatment induces smad-1 phosphorylation in bone-marrow stromal cells. Additionally, FTY720 enhances stromal cell-derived factor-1 (SDF-1 mediated chemotaxis of CD90+CD11B-CD45- bone progenitor cells in vitro after stimulation with rhBMP2. We believe that use of such small molecule delivery formulations to recruit endogenous bone progenitors may be an attractive alternative to exogenous cell-based therapy.

  9. BDNF gene delivery within and beyond templated agarose multi-channel guidance scaffolds enhances peripheral nerve regeneration

    Science.gov (United States)

    Gao, Mingyong; Lu, Paul; Lynam, Dan; Bednark, Bridget; Campana, W. Marie; Sakamoto, Jeff; Tuszynski, Mark

    2016-12-01

    Objective. We combined implantation of multi-channel templated agarose scaffolds with growth factor gene delivery to examine whether this combinatorial treatment can enhance peripheral axonal regeneration through long sciatic nerve gaps. Approach. 15 mm long scaffolds were templated into highly organized, strictly linear channels, mimicking the linear organization of natural nerves into fascicles of related function. Scaffolds were filled with syngeneic bone marrow stromal cells (MSCs) secreting the growth factor brain derived neurotrophic factor (BDNF), and lentiviral vectors expressing BDNF were injected into the sciatic nerve segment distal to the scaffold implantation site. Main results. Twelve weeks after injury, scaffolds supported highly linear regeneration of host axons across the 15 mm lesion gap. The incorporation of BDNF-secreting cells into scaffolds significantly increased axonal regeneration, and additional injection of viral vectors expressing BDNF into the distal segment of the transected nerve significantly enhanced axonal regeneration beyond the lesion. Significance. Combinatorial treatment with multichannel bioengineered scaffolds and distal growth factor delivery significantly improves peripheral nerve repair, rivaling the gold standard of autografts.

  10. Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake.

    Science.gov (United States)

    Cho, Hyun-Jong; Park, Jin Woo; Yoon, In-Soo; Kim, Dae-Duk

    2014-01-01

    Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel.

  11. Drug delivery strategies to enhance the permeability of the blood-brain barrier for treatment of glioma.

    Science.gov (United States)

    Zhang, Fang; Xu, Chun-Lei; Liu, Chun-Mei

    2015-01-01

    Gliomas are amongst the most insidious and destructive types of brain cancer and are associated with a poor prognosis, frequent recurrences, and extremely high lethality despite combination treatment of surgery, radiotherapy, and chemotherapy. The existence of the blood-brain barrier (BBB) restricts the delivery of therapeutic molecules into the brain and offers the clinical efficacy of many pharmaceuticals that have been demonstrated to be effective for other kinds of tumors. This challenge emphasizes the need to be able to deliver drugs effectively across the BBB to reach the brain parenchyma. Enhancement of the permeability of the BBB and being able to transport drugs across it has been shown to be a promising strategy to improve drug absorption and treatment efficacy. This review highlights the innovative technologies that have been introduced to enhance the permeability of the BBB and to obtain an optimal distribution and concentration of drugs in the brain to treat gliomas, such as nanotechniques, hyperthermia techniques, receptor-mediated transport, cell-penetrating peptides, and cell-mediated delivery.

  12. Delivery of bioactive lipids from composite microgel-microsphere injectable scaffolds enhances stem cell recruitment and skeletal repair.

    Science.gov (United States)

    Das, Anusuya; Barker, Daniel A; Wang, Tiffany; Lau, Cheryl M; Lin, Yong; Botchwey, Edward A

    2014-01-01

    In this study, a microgel composed of chitosan and inorganic phosphates was used to deliver poly(lactic-co-glycolic acid) (PLAGA) microspheres loaded with sphingolipid growth factor FTY720 to critical size cranial defects in Sprague Dawley rats. We show that sustained release of FTY720 from injected microspheres used alone or in combination with recombinant human bone morphogenic protein-2 (rhBMP2) improves defect vascularization and bone formation in the presence and absence of rhBMP2 as evaluated by quantitative microCT and histological measurements. Moreover, sustained delivery of FTY720 from PLAGA and local targeting of sphingosine 1-phosphate (S1P) receptors reduces CD45+ inflammatory cell infiltration, promotes endogenous recruitment of CD29+CD90+ bone progenitor cells and enhances the efficacy of rhBMP2 from chitosan microgels. Companion in vitro studies suggest that selective activation of sphingosine receptor subtype-3 (S1P3) via FTY720 treatment induces smad-1 phosphorylation in bone-marrow stromal cells. Additionally, FTY720 enhances stromal cell-derived factor-1 (SDF-1) mediated chemotaxis of CD90+CD11B-CD45- bone progenitor cells in vitro after stimulation with rhBMP2. We believe that use of such small molecule delivery formulations to recruit endogenous bone progenitors may be an attractive alternative to exogenous cell-based therapy.

  13. Iontophoretic transdermal delivery of glycyrrhizin: effects of pH, drug concentration, co-ions, current intensity, and chemical enhancers.

    Science.gov (United States)

    Yamamoto, Rie; Takasuga, Shinri; Kominami, Katsuya; Sutoh, Chiyo; Kinoshita, Mine; Kanamura, Kiyoshi; Takayama, Kozo

    2013-01-01

    The aim of the present study was to evaluate the feasibility of transdermal delivery of glycyrrhizin, an agent used in the treatment of chronic hepatitis C, by cathodal iontophoresis using Ag/AgCl electrodes in vitro. The effects of donor pH (pH 4-7), concentration of drug (0.025-0.2% (w/v)), concentration of external chloride ions (Cl(-)) (0-133 mM), current strength (0-0.5 mA/cm(2)), and permeation enhancers (urea and Tween 80) on the skin permeability of glycyrrhizin were examined in in vitro skin permeation studies using porcine ear skin as the membrane. The cumulative amount of permeated glycyrrhizin and the steady-state skin permeation flux of glycyrrhizin across porcine skin increased in a pH-dependent manner. The skin permeability of glycyrrhizin was independent of the concentration of drug and competed only with a high external Cl(-) concentration. The skin permeation flux of glycyrrhizin increased with the current (R(2)=0.8955). The combination of iontophoresis and enhancers provided an additive or synergistic effect, and a skin permeation flux of about 60 µg/h/cm(2) was achieved. The plasma concentration of glycyrrhizin in humans, extrapolated from the in vitro steady-state permeation flux across porcine skin, was within the therapeutic level. These results suggest that cathodal iontophoresis can be used as a transdermal drug delivery system for glycyrrhizin using reasonable patch sizes and acceptable levels of current intensity.

  14. Delivery of local therapeutics to the brain: working toward advancing treatment for malignant gliomas.

    Science.gov (United States)

    Chaichana, Kaisorn L; Pinheiro, Leon; Brem, Henry

    2015-03-01

    Malignant gliomas, including glioblastoma and anaplastic astrocytomas, are characterized by their propensity to invade surrounding brain parenchyma, making curative resection difficult. These tumors typically recur within two centimeters of the resection cavity even after gross total removal. As a result, there has been an emphasis on developing therapeutics aimed at achieving local disease control. In this review, we will summarize the current developments in the delivery of local therapeutics, namely direct injection, convection-enhanced delivery and implantation of drug-loaded polymers, as well as the application of these therapeutics in future methods including microchip drug delivery and local gene therapy.

  15. Design of dendrimer-based drug delivery nanodevices with enhanced therapeutic efficacies

    Science.gov (United States)

    Kannan, Rangaramanujam

    2007-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, `peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. They have significant potential compared to liposomes and nanoparticles, because of the reduced macrophage update, increased cellular transport, and the ability to modulate the local environment through functional groups. We are developing nanodevices based on dendritic systems for drug delivery, that contain a high drug payload, ligands, and imaging agents, resulting in `smart' drug delivery devices that can target, deliver, and signal. In collaboration with the Children's Hospital of Michigan, Karmanos Cancer Institute, and College of Pharmacy, we are testing the in vitro and in vivo response of these nanodevices, by adapting the chemistry for specific clinical applications such as asthma and cancer. These materials are characterized by UV/Vis spectroscopy, flow cytometry, fluorescence/confocal microscopy, and appropriate animal models. Our results suggest that: (1) We can prepare drug-dendrimer conjugates with drug payloads of greater than 50%, for a variety of drugs; (2) The dendritic polymers are capable of transporting and delivering drugs into cells faster than free drugs, with superior therapeutic efficiency. This can be modulated by the surface functionality of the dendrimer; (3) For chemotherapy drugs, the conjugates are a factor of 6-20 times more effective even in drug-resistant cell lines; (4) For corticosteroidal drugs, the dendritic polymers provide higher drug residence times in the lung, allowing for passive targeting. The ability of the drug-dendrimer-ligand conjugates to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

  16. Current Trends in Self-Emulsifying Drug Delivery Systems (SEDDSs) to Enhance the Bioavailability of Poorly Water-Soluble Drugs.

    Science.gov (United States)

    Karwal, Rohit; Garg, Tarun; Rath, Goutam; Markandeywar, Tanmay S

    2016-01-01

    The main object of the self-emulsifying drug-delivery system (SEDDS) is oral bioavailability (BA) enhancement of a poorly water-soluble drug. Low aqueous solubility and low oral BA are major concerns for formulation scientists. As many drugs are lipophilic in nature, their lower solubility and dissolution are major drawbacks for their successful formulation into oral dosage forms. More than 60% of drugs have a lipophilic nature and exhibit poor aqueous solubility. Various strategies are reported in the literature to improve the solubility and enhance BA of lipophilic drugs, including the formation of a cyclodextrin complex, solid dispersions, and micronization. SEDDSs are ideally isotropic mixtures of drug, oil, surfactant, and/or cosurfactant. SEDDSs have gained increasing attention for enhancing oral BA and reducing drug dose. SEDDSs also provide an effective and excellent solution to the various issues related to the formulation of hydrophobic drugs that have limited solubility in gastrointestinal fluid. Our major focus of this review is to highlight the importance of SEDDSs in oral BA enhancement of poorly water-soluble drugs.

  17. Cell Penetrating Peptide Conjugated Chitosan for Enhanced Delivery of Nucleic Acid

    Directory of Open Access Journals (Sweden)

    Buddhadev Layek

    2015-12-01

    Full Text Available Gene therapy is an emerging therapeutic strategy for the cure or treatment of a spectrum of genetic disorders. Nevertheless, advances in gene therapy are immensely reliant upon design of an efficient gene carrier that can deliver genetic cargoes into the desired cell populations. Among various nonviral gene delivery systems, chitosan-based carriers have gained increasing attention because of their high cationic charge density, excellent biocompatibility, nearly nonexistent cytotoxicity, negligible immune response, and ideal ability to undergo chemical conjugation. However, a major shortcoming of chitosan-based carriers is their poor cellular uptake, leading to inadequate transfection efficiency. The intrinsic feature of cell penetrating peptides (CPPs for transporting diverse cargoes into multiple cell and tissue types in a safe manner suggests that they can be conjugated to chitosan for improving its transfection efficiency. In this review, we briefly discuss CPPs and their classification, and also the major mechanisms contributing to the cellular uptake of CPPs and cargo conjugates. We also discuss immense improvements for the delivery of nucleic acids using CPP-conjugated chitosan-based carriers with special emphasis on plasmid DNA and small interfering RNA.

  18. Field Test of Enhanced Remedial Amendment Delivery Using a Shear-Thinning Fluid

    Energy Technology Data Exchange (ETDEWEB)

    Truex, Michael J.; Vermeul, Vincent R.; Adamson, David; Oostrom, Martinus; Zhong, Lirong; Mackley, Rob D.; Fritz, Brad G.; Horner, Jacob A.; Johnson, Timothy C.; Thomle, Jonathan N.; Newcomer, Darrell R.; Johnson, Christian D.; Rysz, Michal; Wietsma, Thomas W.; Newell, Charles J.

    2015-03-01

    Heterogeneity of hydraulic properties in aquifers may lead to contaminants residing in lower-permeability zones where it is difficult to deliver remediation amendments using conventional injection processes. The focus of this effort is to examine use of a shear-thinning fluid (STF) to improve the uniformity of remedial amendment distribution within a heterogeneous aquifer. Previous studies have demonstrated the significant potential of STFs for improving remedial amendment delivery in heterogeneous aquifers, but quantitative evaluation of these improvements from field applications are lacking. A field-scale test was conducted that compares data from successive injection of a tracer in water followed by injection of a tracer in a STF to evaluate the impact of the STF on tracer distribution uniformity in the presence of permeability contrasts within the targeted injection zone. Data from tracer breakthrough at multiple depth-discrete monitoring intervals and electrical resistivity tomography showed that inclusion of STF in the injection solution slowed movement in high-permeability pathways, improved delivery of amendment to low-permeability materials, and resulted in better uniformity in injected fluid distribution within the targeted treatment zone.

  19. Formulation of niosomal gel for enhanced transdermal lopinavir delivery and its comparative evaluation with ethosomal gel.

    Science.gov (United States)

    Patel, Ketul K; Kumar, Praveen; Thakkar, Hetal P

    2012-12-01

    The aim was to develop niosomal gel as a transdermal nanocarrier for improved systemic availability of lopinavir. Niosomes were prepared using thin-film hydration method and optimized for molar quantities of Span 40 and cholesterol to impart desirable characteristics. Comparative evaluation with ethosomes was performed using ex vivo skin permeation, fluorescence microscopy, and histopathology studies. Clinical utility via transdermal route was acknowledged using in vivo bioavailability study in male Wistar rats. The niosomal formulation containing lopinavir, Span 40, and cholesterol in a molar ratio of 1:0.9:0.6 possessed optimally high percentage of drug entrapment with minimum mean vesicular diameter. Ex vivo skin permeation studies of lopinavir as well as fluorescent probe coumarin revealed a better deposition of ethosomal carriers but a better release with niosomal carriers. Histopathological studies indicated the better safety profile of niosomes over ethosomes. In vivo bioavailability study in male Wistar rats showed a significantly higher extent of absorption (AUC(0→∞), 72.87 h × μg/ml) of lopinavir via transdermally applied niosomal gel as compared with its oral suspension. Taken together, these findings suggested that niosomal gel holds a great potential of being utilized as novel, nanosized drug delivery vehicle for transdermal lopinavir delivery.

  20. [Silica-coated ethosome as a novel oral delivery system for enhanced oral bioavailability of curcumin].

    Science.gov (United States)

    Li, Chong; Deng, Li; Zhang, Yan; Su, Ting-Ting; Jiang, Yin; Chen, Zhang-Bao

    2012-11-01

    The aim of this study is to investigate the feasibility of silica-coated ethosome as a novel oral delivery system for the poorly water-soluble curcumin (as a model drug). The silica-coated ethosomes loading curcumin (CU-SE) were prepared by alcohol injection method with homogenization, followed by the precipitation of silica by sol-gel process. The physical and chemical features of CU-SEs, and curcumin release were determined in vitro. The pharmacodynamics and bioavailability measurements were sequentially performed. The mean diameter of CU-SE was (478.5 +/- 80.3) nm and the polydispersity index was 0.285 +/- 0.042, while the mean value of apparent drug entrapment efficiency was 80.77%. In vitro assays demonstrated that CU-SEs were significantly stable with improved release properties when compared with curcumin-loaded ethosomes (CU-ETs) without silica-coatings. The bioavailability of CU-SEs and CU-ETs was 11.86- and 5.25-fold higher, respectively, than that of curcumin suspensions (CU-SUs) in in vivo assays. The silica coatings significantly promoted the stability of ethosomes and CU-SEs exhibited 2.26-fold increase in bioavailablity relative to CU-ETs, indicating that the silica-coated ethosomes might be a potential approach for oral delivery of poorly water-soluble drugs especially the active ingredients of traditional Chinese medicine with improved bioavailability.

  1. Close-field electroporation gene delivery using the cochlear implant electrode array enhances the bionic ear.

    Science.gov (United States)

    Pinyon, Jeremy L; Tadros, Sherif F; Froud, Kristina E; Y Wong, Ann C; Tompson, Isabella T; Crawford, Edward N; Ko, Myungseo; Morris, Renée; Klugmann, Matthias; Housley, Gary D

    2014-04-23

    The cochlear implant is the most successful bionic prosthesis and has transformed the lives of people with profound hearing loss. However, the performance of the "bionic ear" is still largely constrained by the neural interface itself. Current spread inherent to broad monopolar stimulation of the spiral ganglion neuron somata obviates the intrinsic tonotopic mapping of the cochlear nerve. We show in the guinea pig that neurotrophin gene therapy integrated into the cochlear implant improves its performance by stimulating spiral ganglion neurite regeneration. We used the cochlear implant electrode array for novel "close-field" electroporation to transduce mesenchymal cells lining the cochlear perilymphatic canals with a naked complementary DNA gene construct driving expression of brain-derived neurotrophic factor (BDNF) and a green fluorescent protein (GFP) reporter. The focusing of electric fields by particular cochlear implant electrode configurations led to surprisingly efficient gene delivery to adjacent mesenchymal cells. The resulting BDNF expression stimulated regeneration of spiral ganglion neurites, which had atrophied 2 weeks after ototoxic treatment, in a bilateral sensorineural deafness model. In this model, delivery of a control GFP-only vector failed to restore neuron structure, with atrophied neurons indistinguishable from unimplanted cochleae. With BDNF therapy, the regenerated spiral ganglion neurites extended close to the cochlear implant electrodes, with localized ectopic branching. This neural remodeling enabled bipolar stimulation via the cochlear implant array, with low stimulus thresholds and expanded dynamic range of the cochlear nerve, determined via electrically evoked auditory brainstem responses. This development may broadly improve neural interfaces and extend molecular medicine applications.

  2. Custom fractional factorial designs to develop atorvastatin self-nanoemulsifying and nanosuspension delivery systems – enhancement of oral bioavailability

    Directory of Open Access Journals (Sweden)

    Hashem FM

    2015-06-01

    Full Text Available Fahima M Hashem,1 Majid M Al-Sawahli,2 Mohamed Nasr,1 Osama AA Ahmed3,4 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo, Egypt; 2Holding Company for Biological Products and Vaccines (VACSERA, Giza, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt Abstract: Poor water solubility of a drug is a major challenge in drug delivery research and a main cause for limited bioavailability and pharmacokinetic parameters. This work aims to utilize custom fractional factorial design to assess the development of self-nanoemulsifying drug delivery systems (SNEDDS and solid nanosuspensions (NS in order to enhance the oral delivery of atorvastatin (ATR. According to the design, 14 experimental runs of ATR SNEDDS were formulated utilizing the highly ATR solubilizing SNEDDS components: oleic acid, Tween 80, and propylene glycol. In addition, 12 runs of NS were formulated by the antisolvent precipitation–ultrasonication method. Optimized formulations of SNEDDS and solid NS, deduced from the design, were characterized. Optimized SNEDDS formula exhibited mean globule size of 73.5 nm, zeta potential magnitude of -24.1 mV, and 13.5 µs/cm of electrical conductivity. Optimized solid NS formula exhibited mean particle size of 260.3 nm, 7.4 mV of zeta potential, and 93.2% of yield percentage. Transmission electron microscopy showed SNEDDS droplets formula as discrete spheres. The solid NS morphology showed flaky nanoparticles with irregular shapes using scanning electron microscopy. The release behavior of the optimized SNEDDS formula showed 56.78% of cumulative ATR release after 10 minutes. Solid NS formula showed lower rate of release in the first 30 minutes. Bioavailability estimation in Wistar albino rats revealed an augmentation

  3. Formulation of cellulose film containing permeation enhancers for prolonged delivery of propranolol hydrocloride.

    Science.gov (United States)

    Bigucci, Federica; Abruzzo, Angela; Cerchiara, Teresa; Gallucci, Maria Caterina; Luppi, Barbara

    2015-06-01

    The aim of this study was to evaluate the capacity of cellulose films enriched with oleic acid and polysorbate 80 to enhance the transdermal permeation of propranolol hydrochloride. Polymeric films were prepared by casting and drying aqueous solutions of hydroxypropylmethylcellulose or carboxymethylcellulose and characterized in chemical-physical properties, such as drug content, thickness, morphology and water uptake capacity. In vitro transport experiments were performed in order to evaluate the permeation enhancing ability of oleic acid and polysorbate 80. All carboxymethylcellulose films showed lower cumulative amounts of drug permeated than hydroxypropylmethylcellulose. Moreover, films containing both oleic acid and polysorbate 80 provided a greater permeation in comparison to film without permeation enhancers or only with one of these. The results obtained confirm that propranolol hydrochloride permeation can be easily modulated by varying the cellulose and enhancer type used for film preparation.

  4. Sequential co-delivery of miR-21 inhibitor followed by burst release doxorubicin using NIR-responsive hollow gold nanoparticle to enhance anticancer efficacy.

    Science.gov (United States)

    Ren, Yu; Wang, Ruirui; Gao, Lizhang; Li, Ke; Zhou, Xuan; Guo, Hua; Liu, Chaoyong; Han, Donglin; Tian, Jianguo; Ye, Qing; Hu, Ye Tony; Sun, Duxin; Yuan, Xubo; Zhang, Ning

    2016-04-28

    Previous literature and our study showed the delivery sequence of microRNA inhibitor and chemotherapeutic compounds achieve distinct therapeutic anticancer efficacy. Yet, it is challenging to use nanoparticle to achieve sequential drug delivery. In the current study, we designed sequential co-delivery system using a near-infrared-radiation (NIR) responsive hollow gold nanoparticle (HGNPs) to achieve sequential release of microRNA inhibitor (miR-21i)/doxirubicin(Dox) in order to achieve synergistic efficacy. PAMAM modified HGNPs was used to encapsulate miR-21i and Dox. Upon entering tumor cells, miRNA-21i was released first to sensitize the cancer cells, the subsequent burst release of Dox was achieved by NIR triggered collapse of HGNPs. This sequential delivery of miRNA-21i and Dox produced a synergistic apoptotic response, thereby enhancing anticancer efficacy by 8-fold and increasing anti-cancer stem cell activity by 50-fold. The sequential delivery of miR-21i and Dox using HGNPs under NIR after intravenous administration showed high tumor accumulation and significantly improved efficacy, which was 4-fold compared to free Dox group. These data suggested that the sequential co-delivery of miR-21i followed by burst release Dox using NIR-responsive HGNPs sensitized cancer cells to chemotherapeutic compound, which provided a novel concept for co-delivery miRNA inhibitors and chemotherapeutic compounds to enhance their efficacy.

  5. Self-assembling polymeric nanoparticles for enhanced intra-articular anti-inflammatory protein delivery

    Science.gov (United States)

    Whitmire, Rachel Elisabeth

    Osteoarthritis (OA) affects 26 million Americans, or approximately 14% of the adult population. The incidence of OA is predicted to dramatically increase in the next 20 years as the US grows older and the rate of obesity continues to increase. There are currently no clinical interventions that cure OA. Current biomaterial delivery systems exhibit several limitations. First, most drug-delivery particles are hydrophobic, which is not optimal for hydrophilic protein encapsulation. Second, hydrophobic particles, such as PLGA, could cause wear damage to the already-fragile OA cartilage structure. Additionally, these particles usually suffer from non-specific protein adsorption, which causes increased phagocytosis and can lead to increased inflammation. New therapies that increase the effectiveness of OA treatments or reverse OA disease progression will greatly decrease the economic costs and individual pain associated with this disease. The goal of this thesis was to develop a new drug-delivering material to deliver anti-inflammatory protein for treating OA. Our central hypothesis for this work is that a controlled release/presentation system will more effectively deliver anti-inflammatory protein therapies to the OA joint. The primary goal of this work was to synthesize a block copolymer that could self-assemble into injectable, sub-micron-scale particles and would allow an anti-inflammatory protein, IL-1ra, to be tethered to its surface for efficient protein delivery. The block copolymer incorporated an oligo-ethylene monomer for tissue compatibility and non-fouling behavior, a 4-nitrophenol group for efficient protein tethering, and cyclohexyl methacrylate, a hydrophobic monomer, for particle stability. We engineered the copolymer and tested it in both in vitro culture experiments and an in vivo model to evaluate protein retention in the knee joint. The rationale for this project was that the rational design and synthesis of a new drug- and protein

  6. National Convective Weather Forecast

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NCWF is an automatically generated depiction of: (1) current convection and (2) extrapolated signficant current convection. It is a supplement to, but does NOT...

  7. Nutritionally enhanced fermented sausages as a vehicle for potential probiotic lactobacilli delivery.

    Science.gov (United States)

    Rubio, Raquel; Jofré, Anna; Aymerich, Teresa; Guàrdia, Maria Dolors; Garriga, Margarita

    2014-02-01

    The suitability of three potential probiotic lactobacilli strains (Lactobacillus casei CTC1677, L. casei CTC1678 and Lactobacillus rhamnosus CTC1679), previously isolated from infants' faeces and characterized, and three commercial probiotic strains (Lactobacillus plantarum 299v, L. rhamnosus GG and L. casei Shirota) was assessed during the manufacture of low-acid fermented sausages (fuets) with reduced Na(+) and fat content. The inoculated strains were successfully monitored by RAPD-PCR during the process. L. rhamnosus CTC1679 was the only strain able to grow and dominate (levels ca. 10(8)CFU/g) the endogenous lactic acid bacteria population in two independent trials, throughout the ripening process. Thus, fuet containing L. rhamnosus CTC1679 as a starter culture could be a suitable vehicle for putative probiotic bacteria delivery. All the final products recorded a satisfactory overall sensory quality without any noticeable off-flavour, and with the characteristic sensory properties of low-acid fermented sausages.

  8. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes.

    Science.gov (United States)

    Gao, Menghua; Xu, Yuzhen; Qiu, Liyan

    2015-01-01

    A novel composite liposomal system co-encapsulating paclitaxel (PTX) with chloroquine phosphate (CQ) was designed for treating PTX-resistant carcinoma. It was confirmed that liposomal CQ can sensitize PTX by means of autophagy inhibition and competitively binding with multidrug-resistance transporters. Furthermore, according to the in vitro cytotoxicity and apoptosis assay, real-time observation of cellular uptake, and in vivo tissue distribution study, co-encapsulation of PTX and CQ in liposomes was validated as superior to the mixture of PTX liposome plus CQ liposome due to the simultaneous delivery and synergetic effect of the two drugs. Consequently, this composite liposome achieved significantly stronger anticancer efficacy in vivo than the PTX liposome plus CQ liposome mixture. This study helps to guide and enlighten ongoing and future clinical trials about the optimal administration modes for drug combination therapy.

  9. An Official American Thoracic Society/European Respiratory Society Policy Statement: Enhancing Implementation, Use, and Delivery of Pulmonary Rehabilitation.

    Science.gov (United States)

    Rochester, Carolyn L; Vogiatzis, Ioannis; Holland, Anne E; Lareau, Suzanne C; Marciniuk, Darcy D; Puhan, Milo A; Spruit, Martijn A; Masefield, Sarah; Casaburi, Richard; Clini, Enrico M; Crouch, Rebecca; Garcia-Aymerich, Judith; Garvey, Chris; Goldstein, Roger S; Hill, Kylie; Morgan, Michael; Nici, Linda; Pitta, Fabio; Ries, Andrew L; Singh, Sally J; Troosters, Thierry; Wijkstra, Peter J; Yawn, Barbara P; ZuWallack, Richard L

    2015-12-01

    Pulmonary rehabilitation (PR) has demonstrated physiological, symptom-reducing, psychosocial, and health economic benefits for patients with chronic respiratory diseases, yet it is underutilized worldwide. Insufficient funding, resources, and reimbursement; lack of healthcare professional, payer, and patient awareness and knowledge; and additional patient-related barriers all contribute to the gap between the knowledge of the science and benefits of PR and the actual delivery of PR services to suitable patients. The objectives of this document are to enhance implementation, use, and delivery of pulmonary rehabilitation to suitable individuals worldwide. Members of the American Thoracic Society (ATS) Pulmonary Rehabilitation Assembly and the European Respiratory Society (ERS) Rehabilitation and Chronic Care Group established a Task Force and writing committee to develop a policy statement on PR. The document was modified based on feedback from expert peer reviewers. After cycles of review and revisions, the statement was reviewed and formally approved by the Board of Directors of the ATS and the Science Council and Executive Committee of the ERS. This document articulates policy recommendations for advancing healthcare professional, payer, and patient awareness and knowledge of PR, increasing patient access to PR, and ensuring quality of PR programs. It also recommends areas of future research to establish evidence to support the development of an updated funding and reimbursement policy regarding PR. The ATS and ERS commit to undertake actions that will improve access to and delivery of PR services for suitable patients. They call on their members and other health professional societies, payers, patients, and patient advocacy groups to join in this commitment.

  10. pH/sugar dual responsive core-cross-linked PIC micelles for enhanced intracellular protein delivery.

    Science.gov (United States)

    Ren, Jie; Zhang, Yanxin; Zhang, Ju; Gao, Hongjun; Liu, Gan; Ma, Rujiang; An, Yingli; Kong, Deling; Shi, Linqi

    2013-10-14

    Herein, a series of biocompatible, robust, pH/sugar-sensitive, core-cross-linked, polyion complex (PIC) micelles based on phenylboronic acid-catechol interaction were developed for protein intracellular delivery. The rationally designed poly(ethylene glycol)-b-poly(glutamic acid-co-glutamicamidophenylboronic acid) (PEG-b-P(Glu-co-GluPBA)) and poly(ethylene glycol)-b-poly(l-lysine-co-ε-3,4-dihydroxyphenylcarboxyl-L-lysine) (PEG-b-P(Lys-co-LysCA)) copolymers were successfully synthesized and self-assembled under neutral aqueous condition to form uniform micelles. These micelles possessed a distinct core-cross-linked core-shell structure comprised of the PEG outer shell and the PGlu/PLys polyion complex core bearing boronate ester cross-linking bonds. The cross-linked micelles displayed superior physiological stabilities compared with their non-cross-linked counterparts while swelling and disassembling in the presence of excess fructose or at endosomal pH. Notably, either negatively or positively charged proteins can be encapsulated into the micelles efficiently under mild conditions. The in vitro release studies showed that the release of protein cargoes under physiological conditions was minimized, while a burst release occurred in response to excess fructose or endosomal pH. The cytotoxicity of micelles was determined by cck-8 assay in HepG2 cells. The cytochrome C loaded micelles could efficiently delivery proteins into HepG2 cells and exhibited enhanced apoptosis ability. Hence, this type of core-cross-linked PIC micelles has opened a new avenue to intracellular protein delivery.

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

    Science.gov (United States)

    Zhang, Xuemei; Li, Xuejuan; Hua, Hongchen; Wang, Aiping; Liu, Wanhui; Li, Youxin; Fu, Fenghua; Shi, Yanan; Sun, Kaoxiang

    2017-01-01

    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-me) VK)-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. The targeted cHP/Cur-NPs, c(RGDf(N-me)VK)-C-modified Cur-NPs, exhibited improved binding, uptake, and penetration abilities than non-targeting NPs for glioma cells, cell spheres, and glioma tissue. In conclusion, c(RGDf(N-me)VK)-C can serve as an effective targeting ligand, and cHP/Cur-NPs can be exploited as a potential drug delivery system for targeting gliomas.

  12. Anodic oxidized nanotubular titanium implants enhance bone morphogenetic protein-2 delivery.

    Science.gov (United States)

    Bae, In-Ho; Yun, Kwi-Dug; Kim, Hyun-Seung; Jeong, Byung-Chul; Lim, Hyun-Pil; Park, Sang-Won; Lee, Kwang-Min; Lim, Young-Chai; Lee, Kyung-Ku; Yang, Yunzhi; Koh, Jeong-Tae

    2010-05-01

    Implant failure has been attributed to loosening of an implant from the host bone possibly due to poor osseointegration. One promising strategy for improving osseointegration is to develop a functional implant surface that promotes osteoblast differentiation. In this study, a titanium (Ti) surface was functionalized by an anodic oxidation process and was loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2). The following four groups of Ti surfaces were prepared: machined (M), anodized machined (MA), resorbable blast medium (RBM), and anodized RBM (RBMA). The surfaces were characterized by scanning electron microscopy and contact angle measurements. The results showed that a Ti oxide layer (TiO(2)) was observed in the anodized surfaces in the form of nanotubes, approximately 100 nm in diameter and 500 nm in length. The hydrophilic properties of the anodized surfaces were significantly improved. The adsorbed rhBMP-2 loaded on the nonanodized surfaces and lyophilized showed spherical particle morphology. However, the adsorbed rhBMP-2 showed a dispersed pattern over the anodized surfaces. The velocity of the rhBMP-2 released from the surfaces was measured to determine if the anodized surface can improve in delivery efficiency. The results showed that the release velocity of the rhBMP-2 from the anodized surfaces was sustained when compared with that of the nonanodized surfaces. In addition, the rhBMP-2 released from the surface was found to be bioactive according to the alkaline phosphatase activity and the level of calcium mineral deposition. These results suggest that the TiO(2) nanotubular structure formed by anodizing is a promising configuration for sustained rhBMP-2 delivery.

  13. Dual-functionalized graphene oxide for enhanced siRNA delivery to breast cancer cells.

    Science.gov (United States)

    Imani, Rana; Shao, Wei; Taherkhani, Samira; Emami, Shahriar Hojjati; Prakash, Satya; Faghihi, Shahab

    2016-11-01

    The aim of this study is to improve hydrocolloid stability and siRNA transfection ability of a reduced graphene oxide (rGO) based nano-carrier using a phospholipid-based amphiphilic polymer (PL-PEG) and cell penetrating peptide (CPPs). The dual functionalized nano-carrier is comprehensively characterized for its chemical structure, size, surface charge and morphology as well as thermal stability. The nano-carrier cytocompatibility, siRNA condensation ability both in the presence and absence of enzyme, endosomal buffering capacity, cellular uptake and intracellular localization are also assessed. The siRNA loaded nano-carrier is used for internalization to MCF-7 cells and its gene silencing ability is compared with AllStars Hs Cell Death siRNA as a model gene. The nano-carrier remains stable in biological solution, exhibits excellent cytocompatibility, retards the siRNA migration and protects it against enzyme degradation. The buffering capacity analysis shows that incorporation of the peptide in nano-carrier structure would increase the resistance to endo/lysosomal like acidic condition (pH 6-4) The functionalized nano-carrier which is loaded with siRNA in an optimal N:P ratio presents superior internalization efficiency (82±5.1% compared to HiPerFect(®)), endosomal escape quality and capable of inducing cell death in MCF-7 cancer cells (51±3.1% compared to non-treated cells). The success of siRNA-based therapy is largely dependent on the safe and efficient delivery system, therefore; the dual functionalized rGO introduced here could have a great potential to be used as a carrier for siRNA delivery with relevancy in therapeutics and clinical applications.

  14. l-Carvyl esters as penetration enhancers for the transdermal delivery of 5-fluorouracil.

    Science.gov (United States)

    Wang, Manli; Xi, Honglei; Cun, Dongmei; Chen, Yang; Xu, Yongnan; Fang, Liang

    2013-06-01

    To develop effective and safe penetration enhancers, a series of l-carvyl esters, namely, 5-isopropenyl-2-methylcyclohex-2-en-1-yl heptanoate (C-HEP), 5-isopropenyl-2- methylcyclohex-2-en-1-yl octanoate (C-OCT), 5-isopropenyl-2-methylcyclohex-2-en-1-yl decanoate (C-DEC), 5-isopropenyl-2-methylcyclohex-2-en-1-yl dodecanoate (C-DOD), 5-isopropenyl-2-methylcyclohex-2-en-1-yl tetradecanoate (C-TET), and 5-isopropenyl-2-methylcyclohex-2-en-1-yl palmitate (C-PAL), was synthesized from l-carveol and saturated fatty acids (C7-C16). The volatility of l-carveol and l-carvyl esters was evaluated by a live weight loss experiment. The enhancing effects of l-carvyl esters on 5-fluorouracil (FU) were investigated in the in vitro permeation experiment on rat skin. The stratum corneum (SC) uptakes of the enhancers were tested in vitro by gas chromatography. Only the l-carvyl esters with a moderate SC uptake, namely, C-OCT (C8), C-DEC (C10), and C-DOD (C12), showed a potential to enhance FU skin permeation. An evident parabolic relationship was found between the permeation enhancement of FU and the SC uptake of the l-carvyl esters. The l-carvyl esters with a chain length of C8-C12 seemed to be favorable for FU.

  15. Insights into synergistic interactions in binary mixtures of chemical permeation enhancers for transdermal drug delivery.

    Science.gov (United States)

    Karande, Pankaj; Jain, Amit; Mitragotri, Samir

    2006-09-28

    Chemical permeation enhancers (CPEs) are known to increase skin permeability to therapeutic drugs. Single chemicals, however, offer limited enhancements of skin permeability. Mixtures of chemicals can overcome this limitation owing to their synergistic interactions. However, identification of potent mixtures of chemicals requires screening of a large number of formulations. Discovery of CPE mixtures can be significantly accelerated by identifying patterns that occur in the existing data on CPEs. In this study, we systematically mine through a huge database on skin permeabilizing effect of over 4000 binary formulations generated by high throughput screening and extract general principles that govern the effect of binary combinations of chemicals on skin's barrier properties. Potencies and synergies of these formulations are analyzed to identify the role played by the formulation composition and chemistry. The analysis reveals several intuitive but some largely non-intuitive trends. For example, formulations made from enhancer mixtures are most potent when participating moieties are present in nearly equal fractions. Methyl pyrrolidone, a small molecule, is particularly effective in forming potent and synergistic enhancer formulations, and zwitterionic surfactants are more likely to feature in potent enhancers. Simple but invaluable rules like these will provide guiding principles for designing libraries to further speed up the formulation discovery process.

  16. Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers.

    Science.gov (United States)

    Gwak, Hye Sun; Oh, Ik Sang; Chun, In Koo

    2004-02-01

    The effects of vehicles and penetration enhancers on the in vitro permeation of ondansetron hydrochloride (OS) across dorsal hairless mouse skins were investigated. Various types of vehicles, including ester, alcohol, and ether and their mixtures were used, and then a series of fatty acids and fatty alcohols were employed as enhancers. Among pure vehicles used, water and ethanol showed high permeation fluxes, which were 48.2+/-23.7 and 41.9+/-17.9 microg/cm2 per h, respectively. Even though propylene glycol monocaprylate (PGMC) alone did not show a high permeation rate, the skin permeability of OS was increased by the addition of diethylene glycol monoethyl ether (DGME); the highest flux was achieved at 40% of DGME. Also, the combination of PGMC and ethanol (80:20) or PGMC and propylene glycol (PG) (60:40) increased the permeation flux by six- and two-fold, respectively, compared to PGMC alone. The synergistic enhancement was also obtained by using PG-oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. The enhancement factors with the addition of oleic acid or linoleic acid to PG were about 1250 and 450, respectively. But saturated fatty acids failed to show a significant enhancing effect. When the PGMC-DGME (60:40) cosolvent system was used as a vehicle, all fatty acids, including unsaturated fatty acids, failed to show significant enhancing effects. The results indicate that the combinations of oleic acid, linoleic acid, or oleyl alcohol with PG, or PGMC-DGME (60:40) cosolvent could be used for the design of the OS transdermal system.

  17. Substrate-mediated delivery of gene complex nanoparticles via polydopamine coating for enhancing competitiveness of endothelial cells.

    Science.gov (United States)

    Li, Bo-Chao; Chang, Hao; Ren, Ke-Feng; Ji, Jian

    2016-11-01

    Substrate-mediated delivery of functional plasmid DNA (pDNA) has been proven to be a promising strategy to promote competitiveness of endothelial cells (ECs) over smooth muscle cells (SMCs), which is beneficial to inducing fast endothelialization of implanted vascular devices. Thus, it is of great importance to develop universal approaches with simplicity and easiness to immobilize DNA complex nanoparticles on substrates. In this study, the bioinspired polydopamine (PDA) coating was employed in immobilization of DNA complex nanoparticles, which were composed of protamine (PrS) and plasmid DNA encoding with hepatocyte growth factor (HGF-pDNA) gene. We demonstrated that the DNA complex nanoparticles can be successfully immobilized onto the PDA surface. Consequently, the HGF expression of both ECs and SMCs were significantly improved when they cultured on the DNA complex nanoparticles-immobilized substrates. Furthermore, EC proliferation was specifically promoted due to bioactivity of HGF, leading to an enhancement of EC competitiveness over SMCs. Our findings demonstrated the substrate-mediated functional gene nanoparticle delivery through PDA coating as a simple and efficient approach. It may hold great potential in the field of interventional cardiovascular implants.

  18. Enhancement of Transdermal Drug Delivery by ns Q-swithed Nd:YAG Laser-induced Pressure Wave

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A non-invasive laser enhancing transdermal drug delivery technique has been investigated. The second harmonic wavelength of 532 nm of a Q-Switched Nd:YAG laser with pulse duration of 15 ns was used to irradiate on a black polyethylene sheet covering on the surface of the drug solution, and hence produced pressure waves in the solution. Porcine skin and Rhodamine B were used as skin model and reagent respectively.Fluorescence microscope was employed to examine the mechanisms of drug delivery via the skin samples after laser treatment. The experiment revealed that the penetration depth of Rhodamine B under the illumination of laser increased with the energy density of the laser beam. After 20 laser shots at laser energy density of 70 mJ/cm2, the penetration depth reached 440 μm in 30 minutes, which was about three times as that without laser illumination. One possible explanation was that laser-induced pressure waves formed microchannels in the stratum corneum of the skin tissue. These microchannels provided much more effective paths for infiltration of Rhodamine B through the SC than follicular and intercellular paths. The drug solution diffused into the SC under the concentration gradient through the channels.

  19. Transdermal delivery of low molecular weight heparin loaded in flexible liposomes with bioavailability enhancement: comparison with ethosomes.

    Science.gov (United States)

    Song, Yun-Kyoung; Hyun, Seo Yeon; Kim, Hyung-Tae; Kim, Chong-Kook; Oh, Jung-Mi

    2011-01-01

    Low molecular weight heparin (LMWH)-loaded flexible liposomes (flexosomes) were formulated for transdermal delivery, and their physicochemical and pharmacokinetic parameters were compared with LMWH-loaded ethosomes. Flexosomes had similar particle size compared with ethosomes, but their deformability was higher than that of ethosomes (76.7% vs. 46.8%). In vitro, flexosomes demonstrated 2.6-fold higher permeability coefficient than ethosomes. In comparison to LMWH aqueous solution, skin deposition of flexosome increased 3.2-fold, while that of ethosome increased only 2.0-fold. In vivo, after the topical application of flexosome to hairless mouse, [anti-Xa](max) was 1.11 IU/mL, while ethosomes showed only 0.32 IU/mL. Moreover, AUC(0-24 h) of flexosomes was 2.5-fold higher than ethosomes. In conclusion, the enhanced skin permeation and bioavailability of LMWH can be achieved with flexosomes in comparison with ethosomes. The LMWH transdermal delivery via flexosomes has the potential to replace the parenteral dosage forms for the treatment of venous thromboembolism, pulmonary embolism and cardiovascular events.

  20. Iron casein succinylate-chitosan coacervate for the liquid oral delivery of iron with bioavailability and stability enhancement.

    Science.gov (United States)

    Min, Kyoung Ah; Cho, Jung-Hye; Song, Yun-Kyoung; Kim, Chong-Kook

    2016-01-01

    Iron casein succinylate (ICS) liquid oral preparation as iron supplement has uncomfortable taste after a long period of storage because of its stability, and poor bioavailability of iron compared to any other iron preparations. To improve the chemical stability of ICS and enhance the bioavailability of iron, chitosan-ICS nanoparticles (NPs) were prepared by complex coacervation method and stabilized with polyethylene glycol (PEG) 400. NPs were spherical (mean diameter of 830-1070 nm) with positive charge (+30-60 mV) depending on the composition of NPs. Addition of PEG400 (2 w/v %) increased the zeta potential (26-50 %) and physical stability of chitosan-ICS NPs suspension. Also, NPs decreased iron release compared to ICS after 7-weeks of storage at 4 °C. NPs markedly increased the permeability of iron in Caco-2 cell up to 32-38-fold compared to ICS, while physical mixture of chitosan and ICS increased the iron permeability only 2.5-fold. In summary, NPs improved the physicochemical stability and enhanced the transport of iron compared to other iron preparations in Caco-2 cell model. Thus, chitosan-ICS coacervate might be a promising candidate as a liquid oral iron delivery system for iron deficiency patients with stability and bioavailability enhancement.

  1. Chitosan-based nano-in-microparticle carriers for enhanced oral delivery and anticancer activity of propolis.

    Science.gov (United States)

    Elbaz, Nancy M; Khalil, Islam A; Abd-Rabou, Ahmed A; El-Sherbiny, Ibrahim M

    2016-11-01

    This study reports a promising approach to enhance the oral delivery of propolis, improve its aqueous solubility and bioavailability, and allow its controlled release as well as enhancing its anticancer activity. Propolis was standardized then its solubility was improved via formulation into optimized solid dispersion (SD) matrices, and its release was controlled through incorporation into nanoparticles (NPs) of optimized composition followed by further inclusion into chitosan (Cs) microparticles. The anticancer activity of the newly developed propolis-loaded nano-in-microparticles (NIMs) was evaluated against human liver cancer (HepG2) and human colorectal cancer (HCT 116) cells. The prepared SDs, NPs and NIMs were characterized using SEM, TEM, DLS, FTIR, DSC and UV-vis spectrophotometry. The therapeutic efficiency of formulated propolis was bio-assessed via cytotoxicity measurements, mitochondrial dysfunction, apoptosis-induced cell death and cell cycle arrest. The results demonstrated a considerable enhancement in propolis solubility with a controlled release profile in different GIT environments. In-vitro cytotoxicity studies showed that the propolis-loaded NIMs induce more cytotoxic effect on HepG2 cells than HCT-116 cells and mediated three-fold higher therapeutic efficiency than free propolis. The apoptosis assay indicated that the propolis-loaded NIMs induce apoptosis of HepG2 cells and significantly decrease their number in the proliferative G0/G1, S and G2/M phases. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Enhanced brain-derived neurotrophic factor delivery by ultrasound and microbubbles promotes white matter repair after stroke.

    Science.gov (United States)

    Rodríguez-Frutos, Berta; Otero-Ortega, Laura; Ramos-Cejudo, Jaime; Martínez-Sánchez, Patricia; Barahona-Sanz, Inés; Navarro-Hernanz, Teresa; Gómez-de Frutos, María Del Carmen; Díez-Tejedor, Exuperio; Gutiérrez-Fernández, María

    2016-09-01

    Ultrasound-targeted microbubble destruction (UTMD) has been shown to be a promising tool to deliver proteins to select body areas. This study aimed to analyze whether UTMD was able to deliver brain-derived neurotrophic factor (BDNF) to the brain, enhancing functional recovery and white matter repair, in an animal model of subcortical stroke induced by endothelin (ET)-1. UTMD was used to deliver BDNF to the brain 24 h after stroke. This technique was shown to be safe, given there were no cases of hemorrhagic transformation or blood brain barrier (BBB) leakage. UTMD treatment was associated with increased brain BDNF levels at 4 h after administration. Targeted ultrasound delivery of BDNF improved functional recovery associated with fiber tract connectivity restoration, increasing oligodendrocyte markers and remyelination compared to BDNF alone administration in an experimental animal model of white matter injury.

  3. CRISPR/Cas9 system as an innovative genetic engineering tool: Enhancements in sequence specificity and delivery methods.

    Science.gov (United States)

    Jo, Young-Il; Suresh, Bharathi; Kim, Hyongbum; Ramakrishna, Suresh

    2015-12-01

    While human gene therapy has gained significant attention for its therapeutic promise, CRISPR/Cas9 technology has made a breakthrough as an efficient genome editing tool by emulating prokaryotic immune defense mechanisms. Although many studies have found that CRISPR/Cas9 technology is more efficient, specific and manipulable than previous generations of gene editing tools, it can be further improved by elevating its overall efficiency in a higher frequency of genome modifications and reducing its off-target effects. Here, we review the development of CRISPR/Cas9 technology, focusing on enhancement of its sequence specificity, reduction of off-target effects and delivery systems. Moreover, we describe recent successful applications of CRISPR/Cas9 technology in laboratory and clinical studies. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Soybean Lecithin Acts as both Absorption Enhancer and Oily Phase in an Insulin-loaded Emulsion System for Transmucosal Delivery

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    An insulin- loaded emulsion system (IES) was developed as a hypoglycaemic drug for transmucosal delivery. The selected formulation was a stable oil/water emulsion system. The particles in the emulsion system were distributed evenly, and the particle size ranged from 20 to 260 nm ( average size: 67.5 nm). Soybean lecithin played an important role in the emulsion system due to its abilities of acting as both absorption enhancer for insulin uptake through sublingual mucosa and oily phase for the emulsion system. The laser confocal scanning microscopic (LCSM) study showed that FITC-labelled insulin could penetrate the sublingual mucosa of rabbits,and the phase diagrams of the emulsion system suggested that soybean lecithin could take the place of oily phase to construct a stable emulsion system even if the traditional oil was absent. The applications of soybean lecithin as pharmaceutical biomaterial were extended for the further usage by present studies.

  5. Performance-enhanced mesenchymal stem cells via intracellular delivery of steroids

    Science.gov (United States)

    Ankrum, James A.; Dastidar, Riddhi G.; Ong, Joon Faii; Levy, Oren; Karp, Jeffrey M.

    2014-04-01

    Inadequate immunomodulatory potency of mesenchymal stem cells (MSC) may limit their therapeutic efficacy. We report glucocorticoid steroids augment MSC expression and activity of indoleamine-2,3-dioxygenase (IDO), a primary mediator of MSC immunomodulatory function. This effect depends on signaling through the glucocorticoid receptor and is mediated through up-regulation of FOXO3. Treatment of MSCs with glucocorticoids, budesonide or dexamethasone, enhanced IDO expression following IFN-γ stimulation in multiple donors and was able to restore IDO expression in over-passaged MSCs. As IDO enhancement was most notable when cells were continuously exposed to budesonide, we engineered MSC with budesonide loaded PLGA microparticles. MSC efficiently internalized budesonide microparticles and exhibited 4-fold enhanced IDO activity compared to budesonide preconditioned and naïve MSC, resulting in a 2-fold improvement in suppression of stimulated peripheral blood mononuclear cells in an IDO-dependent manner. Thus, the augmentation of MSC immune modulation may abrogate challenges associated with inadequate potency and enhance their therapeutic efficacy.

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

    Science.gov (United States)

    2009-12-01

    acting drugs enhance photo- sensitizer activity. FASEB J. 2003;17:1121–3. 130. James DA, Swamy N, Paz N, Hanson RN, Ray R. Synthesis and estrogen...Shoemaker, Wai Lau, Rebecca L. Shattuck, Ann P. Kwiatkowski, Paul E. Matrisian, Luis Guerra -Santos, Emily Wilson, Thomas J. Lukas, Linda J. Van Eldik, and

  7. The Status of Technology-Enhanced Education and Service Delivery in Rehabilitation Counselor Education

    Science.gov (United States)

    Oswald, Gina R.; Huber, Mary J.; Wilson, Josephine F.; Embree, Jared

    2015-01-01

    Purpose: The purpose of this article is to discuss the upsurge of technology-enhanced rehabilitation education programs and telerehabilitation services, to provide examples of these advancements, and to discuss the implications of this technology for education and the field including the unique advantage to developing technological skills through…

  8. 76 FR 66211 - Enhancement of Electricity Market Surveillance and Analysis Through Ongoing Electronic Delivery...

    Science.gov (United States)

    2011-10-26

    ... Energy Regulatory Commission 18 CFR Part 35 Enhancement of Electricity Market Surveillance and Analysis...). I. Background 2. Wholesale electricity markets have witnessed tremendous change in recent years. In... facilities ] and sold electricity to their own wholesale and retail customers. During this time, the...

  9. Colloidal nanocarriers for the enhanced cutaneous delivery of naftifine: characterization studies and in vitro and in vivo evaluations

    Directory of Open Access Journals (Sweden)

    Erdal MS

    2016-03-01

    Full Text Available M Sedef Erdal,1 Gül Özhan,2 M Cem Mat,3 Yıldız Özsoy,1 Sevgi Güngör1 1Department of Pharmaceutical Technology, 2Department of Pharmaceutical Toxicology, Faculty of Pharmacy, 3Department of Dermatology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey Abstract: In topical administration of antifungals, the drugs should pass the stratum corneum to reach lower layers of the skin in effective concentrations. Thus, the formulation of antifungal agents into a suitable delivery system is important for the topical treatment of fungal infections. Nanosized colloidal carriers have gained great interest during the recent years to serve as efficient promoters of drug penetration into the skin. Microemulsions are soft colloidal nanosized drug carriers, which are thermodynamically stable and isotropic systems. They have been extensively explored for the enhancement of skin delivery of drugs. This study was carried out to exploit the feasibility of colloidal carriers as to improve skin transport of naftifine, which is an allylamine antifungal drug. The microemulsions were formulated by construction of pseudoternary phase diagrams and composed of oleic acid (oil phase, Kolliphor® EL or Kolliphor® RH40 (surfactant, Transcutol® (cosurfactant, and water (aqueous phase. The plain and drug-loaded microemulsions were characterized in terms of isotropy, particle size and size distribution, pH value, refractive index, viscosity, and conductivity. The in vitro skin uptake of naftifine from microemulsions was studied using tape stripping technique in pig skin. The drug penetrated significantly into stratum corneum from microemulsions compared to its marketed cream (P<0.05. Moreover, the microemulsion formulations led to highly significant amount of naftifine deposition in deeper layers of skin than that of commercial formulation (P<0.001. Microemulsion–skin interaction was confirmed by attenuated total reflectance – Fourier transformed

  10. Combined delivery of PDGF-BB and BMP-6 for enhanced osteoblastic differentiation.

    Science.gov (United States)

    Demirtaş, T Tolga; Göz, Eda; Karakeçili, Ayşe; Gümüşderelioğlu, Menemşe

    2016-01-01

    Natural microenvironment during bone tissue regeneration involves integration of multiple biological growth factors which regulate mitogenic activities and differentiation to induce bone repair. Among them platelet derived growth factor (PDGF-BB) and bone morphogenic protein-6 (BMP-6) are known to play a prominent role. The aim of this study was to investigate the benefits of combined delivery of PDGF-BB and BMP-6 on proliferation and osteoblastic differentiation of MC3T3-E1 preosteoblastic cells. PDGF-BB and BMP-6 were loaded in gelatin and poly (3-hydroxybutyric acid-co-3-hydroxyvaleric acid) particles, respectively. The carrier particles were then loaded into 3D chitosan matrix fabricated by freeze drying. The fast release of PDGF-BB during 7 days was accompanied by slower and prolonged release of BMP-6. The premising release of mitogenic factor PDGF-BB resulted in an increased MC3T3-E1 cell population seeded on chitosan scaffolds. Osteogenic markers of RunX2, Col 1, OPN were higher on chitosan scaffolds loaded with growth factors either individually or in combination. However, OCN expression and bone mineral formation were prominent on chitosan scaffolds incorporating PDGF-BB and BMP-6 as a combination.

  11. Magnetothermally responsive star-block copolymeric micelles for controlled drug delivery and enhanced thermo-chemotherapy.

    Science.gov (United States)

    Deng, Li; Ren, Jie; Li, Jianbo; Leng, Junzhao; Qu, Yang; Lin, Chao; Shi, Donglu

    2015-06-07

    Magnetothermally responsive drug-loaded micelles were designed and prepared for cancer therapy. These specially designed micelles are composed of the thermo-responsive star-block copolymer poly(ε-caprolactone)-block-poly(2-(2-methoxyethoxy)ethyl methacrylate-co-oligo(ethylene glycol)methacrylate) and Mn, Zn doped ferrite magnetic nanoparticles (MZF-MNPs). The thermo-responses of 6sPCL-b-P(MEO2MA-co-OEGMA) copolymers were shown to be dependent on the MEO2MA to OEGMA ratio. The lower critical solution temperature (LCST) of the star-block copolymers was controlled at 43 °C by adjusting the feed molar ratios of MEO2MA/OEGMA at 92 : 8. With the anti-tumor drug doxorubicin (DOX) self-assembling into the carrier system, the thermo-responsive micelles exhibited excellent temperature-triggered drug release behavior. In vitro cytotoxicity results showed high biocompatibility of the polymer micelles. Efficient cellular proliferation inhibition by the drug-loaded micelles was found on the HepG2 cells under different treatments. The thermo-responsive polymer micelles are promising for controlled drug delivery in tumor therapy under an alternating magnetic field.

  12. A steerable/distance enhanced penetrometer delivery system: Phase I. Topical report, August 1994--August 1995

    Energy Technology Data Exchange (ETDEWEB)

    Amini, A.; Shenhar, J.

    1995-08-01

    The characterization, monitoring, and remediation of many of the nation`s highly contaminated sites are among the highest priorities of the Department of Energy (DOE). In underground contaminated sites, detection and mapping of the plume of contamination and in-situ remediation are the first steps towards clean up. The needs for these steps include a depth capability ranging from tens of feet to between 100 to 200 feet, ability to go around underground obstacles with curvatures that do not damage downhole components, and downhole access for delivery of environmental sensors. In addition, in some instances it is necessary to use light weight equipment over underground storage tanks in order to avoid collapse of the tank. Baseline technologies of {open_quotes}aim and shoot{close_quotes} well drilling do not satisfy all of these needs, are not as efficient, and can further contaminate the site by bringing underground contaminants to the surface. As a result new technologies are needed to carry out underground site clean up more efficiently. This report describes phase I of the development of a device for the control and penetration of penetrometers termed the Position Location Device (POLO). Work consisted of the design of steering components and vibratory penetration components.

  13. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

    Directory of Open Access Journals (Sweden)

    Gao MH

    2015-10-01

    Full Text Available Menghua Gao,1 Yuzhen Xu,1 Liyan Qiu2,3 1College of Pharmaceutical Sciences, 2Ministry of Education (MOE Key Laboratory of Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 3Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: A novel composite liposomal system co-encapsulating paclitaxel (PTX with chloroquine phosphate (CQ was designed for treating PTX-resistant carcinoma. It was confirmed that liposomal CQ can sensitize PTX by means of autophagy inhibition and competitively binding with multidrug-resistance transporters. Furthermore, according to the in vitro cytotoxicity and apoptosis assay, real-time observation of cellular uptake, and in vivo tissue distribution study, co-encapsulation of PTX and CQ in liposomes was validated as superior to the mixture of PTX liposome plus CQ liposome due to the simultaneous delivery and synergetic effect of the two drugs. Consequently, this composite liposome achieved significantly stronger anticancer efficacy in vivo than the PTX liposome plus CQ liposome mixture. This study helps to guide and enlighten ongoing and future clinical trials about the optimal administration modes for drug combination therapy. Keywords: paclitaxel, chloroquine, liposome, drug resistance, combination therapy

  14. Polyethylene glycol-grafted polyethylenimine used to enhance adenovirus gene delivery.

    Science.gov (United States)

    Singarapu, Kumar; Pal, Ivy; Ramsey, Joshua D

    2013-07-01

    An improved adenoviral-based gene delivery vector was developed by complexing adenovirus (Ad) with a biocompatible, grafted copolymer PEG-g-PEI composed of polyethylene glycol (PEG) and polyethylenimine (PEI). Although an Ad-based gene vector is considered relatively safe, its native tropism, tendency to elicit an immune response, and susceptibility to inactivating antibodies makes the virus less than ideal. The goal of the current study was to determine whether Ad could be complexed with a PEG-g-PEI copolymer that would enable the virus to transduce cells lacking the Ad receptor, while avoiding the issues commonly associated with PEI. A copolymer library was synthesized using 2 kDa PEG and either linear or branched PEI (25 kDa) with a PEG to PEI grafting ratio of 10, 20, or 30. The results of the study indicate that PEG-g-PEI/Ad complexes are indeed able to transduce CAR-negative NIH 3T3 cells. The results also demonstrate that the PEG-g-PEI/Ad complexes are less toxic, less hemolytic, and more appropriately sized than PEI/Ad complexes.

  15. Enhanced gene delivery to the lung using biodegradable polyunsaturated cationic phosphatidylcholine-detergent conjugates.

    Science.gov (United States)

    Pierrat, Philippe; Kereselidze, Dimitri; Lux, Marie; Lebeau, Luc; Pons, Françoise

    2016-09-10

    Lung diseases are among the more representative causes of mortality and morbidity worldwide and gene therapy is considered as a promising therapeutic approach for their treatment. However the design of efficient nucleic acid carriers for airway administration still is a challenge and there is a pressing need for new developments in this field. Herein, new synthetic DNA carriers based on the conjugation of a phospholipid and C12E4, a nonionic detergent, are developed. DNA complexes with phosphatidylcholine-detergent conjugates are administered in mouse airways, and transgene expression and inflammatory activity as an index of toxicity are investigated as a function of time, DNA dose, and presence of helper and stealth lipids. Introduction of a biodegradable linker between the phosphatidylcholine and detergent moieties significantly attenuates the severity of inflammatory response that characterizes cationic lipid-mediated gene transfer. Concurrent introduction of polyunsaturated fatty acid chains in the carrier scaffold improves transgene expression and further reduces airway inflammation. Finally, the biodegradable phosphatidylcholine-detergent conjugates favorably compare to GL67A, the gold standard for DNA delivery to the airway that is currently under clinical evaluation. Our findings indicate that the lipid formulations described herein may have great potential as nucleic acid carriers for gene therapy.

  16. Delivery of Vegetable Oil Suspensions in a Shear Thinning Fluid for Enhanced Bioremediation

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, Lirong; Truex, Michael J.; Kananizadeh, Negin; Li, Yusong; Lea, Alan S.; Yan, Xiulan

    2015-04-01

    In situ anaerobic biological processes are widely applied for dechlorination of chlorinated solvents in groundwater. A wide range of organic substrates have been tested and applied to support the dechlorination processes. Vegetable oils are a promising substrate and have been shown to induce effective dechlorination, have limited geochemical impacts, and good longevity. Distribution of vegetable oil in the subsurface, because it is a non-aqueous phase material, has typically been addressed by creating emulsified oil solutions. In this study, inexpensive waste vegetable oils were suspended in a xanthan gum solution, a shear-thinning fluid, as an alternative oil delivery mechanism. The stability, oil droplet size and distribution, and rheological behavior of the oil suspensions that are created in the xanthan solutions were studied in batch experiments. The injectability of the suspensions and oil distribution in porous medium were evaluated in column tests. Numerical modeling of the oil droplet transport and distribution in porous media was conducted to help interpret the column-test data. Batch studies showed that simple mixing of vegetable oil and xanthan solution produced stable suspensions of the oil as micron-size droplets. The mixture rheology retains shear-thinning properties that facilitate improved uniformity of substrate distribution in heterogeneous aquifers. Column tests demonstrated successful injection of the vegetable oil suspension into porous medium. This study provided evidence that vegetable oil suspensions in xanthan are a potential substrate to support in situ anaerobic bioremediation with favorable injection properties.

  17. Design and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced dissolution of gemfibrozil.

    Science.gov (United States)

    Villar, Ana Maria Sierra; Naveros, Beatriz Clares; Campmany, Ana Cristina Calpena; Trenchs, Monserrat Aróztegui; Rocabert, Coloma Barbé; Bellowa, Lyda Halbaut

    2012-07-15

    Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. Box-Behnken experimental design was employed as statistical tool to optimize the formulation variables, X(1) (Cremophor(®) EL), X(2) (Capmul(®) MCM-C8), and X(3) (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X(1), X(2), and X(3)) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in t(d) parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption.

  18. Enhanced topical delivery of tacrolimus by a carbomer hydrogel formulation with transcutol P.

    Science.gov (United States)

    Lee, Sang Gon; Kang, Jong Bu; Kim, Sung Rae; Kim, Chae Jin; Yeom, Dong Woo; Yoon, Ho Yub; Kwak, Seong Shin; Choi, Young Wook

    2016-10-01

    Tacrolimus (TAC), a non-steroidal anti-inflammatory and immunosuppressive agent, is used for the treatment of atopic dermatitis (AD) and skin immune diseases. TAC-loaded topical hydrogel formulations composed of carbomer, carnosine, transcutol P (diethylene glycol monoethyl ether) and humectant were prepared. For comparison, TAC-loaded topical cream-type formulations were also prepared and commercially available TAC ointment was used as a reference. A drug release study in vitro revealed that the total amount of TAC released from hydrogels over 24 h was approximately 30 times greater than that for the reference formulation. Compared to the reference ointment and creams, carbomer gel formulations showed higher skin permeation and retention of TAC (significantly different at p < 0.05), especially those with more than 10% of transcutol P. Therefore, carbomer gel formulations with sufficient levels of transcutol P are good candidates for skin delivery of TAC and have potential as therapeutic agents for the treatment of AD or immune skin disorders.

  19. Doxorubicin delivery enhanced by electroporation to gastrointestinal adenocarcinoma cells with P-gp overexpression.

    Science.gov (United States)

    Kulbacka, Julita; Daczewska, Małgorzata; Dubińska-Magiera, Magda; Choromańska, Anna; Rembiałkowska, Nina; Surowiak, Paweł; Kulbacki, Marek; Kotulska, Małgorzata; Saczko, Jolanta

    2014-12-01

    Electroporation (EP) can effectively support the penetration of macromolecules from the extracellular space into cells. Electropores induced by the influence of electromagnetic field generate additional paths of transport for macromolecules. The aim of this study was evaluation of the electroporation effect on doxorubicin transport efficiency to human colon (LoVo and LoVo/DX) and gastric (EPG85-257/P and EPG85-257/RDB) adenocarcinoma cells with overexpression of P-glycoprotein and murine macrophage cell line (P388/D1). In our EP experiments cells were placed into a cuvette with aluminum electrodes and pulsed with five square electric pulses of 1300 V/cm and duration of 50 μs each. Cells were also treated with low doxorubicin concentration ([DOX]=1.7 μM). The ultrastructure (TEM) and changes of P-glycoprotein expression of tumor cells subjected to electric field were monitored. The mitochondrial cell function and trypan blue staining were evaluated after 24h. Our results indicate the most pronounced effect of EP with DOX and disturbed ultrastructure in resistant gastric and colon cells with decrease of P-gp expression. Electroporation may be an attractive delivery method of cytostatic drugs in chemotherapy, enabling reduction of drug dose, exposure time and side effects.

  20. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery

    Science.gov (United States)

    Matsumoto, Yu; Nichols, Joseph W.; Toh, Kazuko; Nomoto, Takahiro; Cabral, Horacio; Miura, Yutaka; Christie, R. James; Yamada, Naoki; Ogura, Tadayoshi; Kano, Mitsunobu R.; Matsumura, Yasuhiro; Nishiyama, Nobuhiro; Yamasoba, Tatsuya; Bae, You Han; Kataoka, Kazunori

    2016-06-01

    Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions. This assertion is backed by studies using electron microscopy and polymer casts that show incomplete pericyte coverage of tumour vessels and the presence of intercellular gaps. However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy we show that the permeability of tumour blood vessels includes a dynamic phenomenon characterized by vascular bursts followed by brief vigorous outward flow of fluid (named ‘eruptions’) into the tumour interstitial space. We propose that ‘dynamic vents’ form transient openings and closings at these leaky blood vessels. These stochastic eruptions may explain the enhanced extravasation of nanoparticles from the tumour blood vessels, and offer insights into the underlying distribution patterns of an administered drug.

  1. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery.

    Science.gov (United States)

    Matsumoto, Yu; Nichols, Joseph W; Toh, Kazuko; Nomoto, Takahiro; Cabral, Horacio; Miura, Yutaka; Christie, R James; Yamada, Naoki; Ogura, Tadayoshi; Kano, Mitsunobu R; Matsumura, Yasuhiro; Nishiyama, Nobuhiro; Yamasoba, Tatsuya; Bae, You Han; Kataoka, Kazunori

    2016-06-01

    Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions. This assertion is backed by studies using electron microscopy and polymer casts that show incomplete pericyte coverage of tumour vessels and the presence of intercellular gaps. However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy we show that the permeability of tumour blood vessels includes a dynamic phenomenon characterized by vascular bursts followed by brief vigorous outward flow of fluid (named 'eruptions') into the tumour interstitial space. We propose that 'dynamic vents' form transient openings and closings at these leaky blood vessels. These stochastic eruptions may explain the enhanced extravasation of nanoparticles from the tumour blood vessels, and offer insights into the underlying distribution patterns of an administered drug.

  2. Enhancing Experiment Central Service Reliability: from delivery to security and virtualization

    CERN Document Server

    Donno, Flavia; Buzykaev, Alexey; Saiz Santos, Maria Dolores

    2011-01-01

    The four LHC experiments rely on experiment specific services running on machines mainly located at CERN. Some of these services have been rated by the experiments as very critical: any loss or degradation of performance has a major impact on the experiment's production and analysis activities. It is therefore important to provide a reliable and robust operational environment. In this work we describe the strategy based on service deployment, security and virtualization adopted to enhance the reliability of ATLAS and CMS central services.

  3. A Nanocomplex System as Targeted Contrast Agent Delivery Vehicle for MRI Dynamic Contrast Enhancement Study

    OpenAIRE

    Korotcov, Alexandru; Shan, Liang; Meng, Huan; Wang, Tongxin; Sridhar, Rajagopalan; Zhao, Yuliang; Liang, Xing-Jie; Wang, Paul C.

    2010-01-01

    We have developed and tested a liposomal nanocomplex system, which contains Gd-DTPA as a payload and transferrin on the surface, as a tumor specific targeting MRI contrast agent for studying prostate cancer tumors in mice. In vivo, the probe significantly enhanced the MRI signal. The image contrast between the peripheral region of the tumor and the non-involved muscle was nearly 50% higher two hours after administration of the nanocomplex. The liposomal nanocomplex increased the amount of Gd ...

  4. Cationic Albumin Nanoparticles for Enhanced Drug Delivery to Treat Breast Cancer: Preparation and In Vitro Assessment

    Directory of Open Access Journals (Sweden)

    Sana Abbasi

    2012-01-01

    Full Text Available Most anticancer drugs are greatly limited by the serious side effects that they cause. Doxorubicin (DOX is an antineoplastic agent, commonly used against breast cancer. However, it may lead to irreversible cardiotoxicity, which could even result in congestive heart failure. In order to avoid these harmful side effects to the patients and to improve the therapeutic efficacy of doxorubicin, we developed DOX-loaded polyethylenimine- (PEI- enhanced human serum albumin (HSA nanoparticles. The formed nanoparticles were ~137 nm in size with a surface zeta potential of ~+15 mV, prepared using 20 μg of PEI added per mg of HSA. Cytotoxicity was not observed with empty PEI-enhanced HSA nanoparticles, formed with low-molecular weight (25 kDa PEI, indicating biocompatibility and safety of the nanoparticle formulation. Under optimized transfection conditions, approximately 80% of cells were transfected with HSA nanoparticles containing tetramethylrhodamine-conjugated bovine serum albumin. Conclusively, PEI-enhanced HSA nanoparticles show potential for developing into an effective carrier for anticancer drugs.

  5. Non-viral FoxM1 gene delivery to hepatocytes enhances liver repopulation.

    Science.gov (United States)

    Xiang, D; Liu, C-C; Wang, M-J; Li, J-X; Chen, F; Yao, H; Yu, B; Lu, L; Borjigin, U; Chen, Y-X; Zhong, L; Wangensteen, K J; He, Z-Y; Wang, X; Hu, Y-P

    2014-05-22

    Hepatocyte transplantation as a substitute strategy of orthotopic liver transplantation is being studied for treating end-stage liver diseases. Several technical hurdles must be overcome in order to achieve the therapeutic liver repopulation, such as the problem of insufficient expansion of the transplanted hepatocytes in recipient livers. In this study, we analyzed the application of FoxM1, a cell-cycle regulator, to enhance the proliferation capacity of hepatocytes. The non-viral sleeping beauty (SB) transposon vector carrying FoxM1 gene was constructed for delivering FoxM1 into the hepatocytes. The proliferation capacities of hepatocytes with FoxM1 expression were examined both in vivo and in vitro. Results indicated that the hepatocytes with FoxM1 expression had a higher proliferation rate than wild-type (WT) hepatocytes in vitro. In comparison with WT hepatocytes, the hepatocytes with FoxM1 expression had an enhanced level of liver repopulation in the recipient livers at both sub-acute injury (fumaryl acetoacetate hydrolase (Fah)(-/-) mice model) and acute injury (2/3 partial hepatectomy mice model). Importantly, there was no increased risk of tumorigenicity with FoxM1 expression in recipients even after serial transplantation. In conclusion, expression of FoxM1 in hepatocytes enhanced the capacity of liver repopulation without inducing tumorigenesis. FoxM1 gene delivered by non-viral SB vector into hepatocytes may be a viable approach to promote therapeutic repopulation after hepatocyte transplantation.

  6. Enhancing effect of negative polypropylene electret on in vitro transdermal delivery of cyclosporine A solution and its synergistic effect with ethyl oleate

    Science.gov (United States)

    Cui, L. L.; Ma, L.; Liang, Y. Y.; Liu, H. Y.; Guo, X.; Jiang, J.

    2013-03-01

    In this study, the corona charged electrets at voltages of -500 V, -1000 V and -2000 V were made from polypropylene (PP) film. The cyclosporine A (CsA) and 10% ethyl oleate were chosen as the model drug and chemical enhancer, respectively. The charge storage stability of the electrets and the in vitro transdermal behaviour of the model drug in solution under different conditions were studied. The results indicate that the external electrostatic field of the negative PP electrets could penetrate through the rat skin and enhance the transdermal delivery of cyclosporine A. A synergistic effect on enhancing the transdermal delivery of cyclosporine A was observed by combining different surface potential negative PP electrets with 10% ethyl oleate, and the amount of transdermal delivery of CsA was greatly increased comparing with only application of electrets. Therefore, the combination application of electret and chemical enhancer could be a feasible strategy in enhancing transdermal delivery of small peptide drugs or some large molecular drugs.

  7. Poly(ester amine Composed of Polyethylenimine and Pluronic Enhance Delivery of Antisense Oligonucleotides In Vitro and in Dystrophic mdx Mice

    Directory of Open Access Journals (Sweden)

    Mingxing Wang

    2016-01-01

    Full Text Available A series of poly(esteramines (PEAs constructed from low molecular weight polyethyleneimine (LPEI and Pluronic were evaluated for the delivery of antisense oligonuclotides (AOs, 2′-O-methyl phosphorothioate RNA (2′-OMePS and phosphorodiamidate morpholino oligomer (PMO in cell culture and dystrophic mdx mice. Improved exon-skipping efficiency of both 2′-OMePS and PMO was observed in the C2C12E50 cell line with all PEA polymers compared with PEI 25k or LF-2k. The degree of efficiency was found in the order of PEA 01, PEA 04 > PEA 05 > others. The in vivo study in mdx mice demonstrated enhanced exon-skipping of 2′-OMePS with the order of PEA 06 > PEA 04, PEA 07 > PEA 03 > PEA 01 > others, and much higher than PEI 25k formulated 2′-OMePS. Exon-skipping efficiency of PMO in formulation with the PEAs were significantly enhanced in the order of PEA 02 > PEA 10 > PEA 01, PEA 03 > PEA 05, PEA 07, PEA 08 > others, with PEA 02 reaching fourfold of Endo-porter formulated PMO. PEAs improve PMO delivery more effectively than 2′-OMePS delivery in vivo, and the systemic delivery evaluation further highlight the efficiency of PEA for PMO delivery in all skeletal muscle. The results suggest that the flexibility of PEA polymers could be explored for delivery of different AO chemistries, especially for antisense therapy.

  8. Enhanced stability and dermal delivery of hydroquinone using solid lipid nanoparticles.

    Science.gov (United States)

    Ghanbarzadeh, Saeed; Hariri, Reza; Kouhsoltani, Maryam; Shokri, Javad; Javadzadeh, Yousef; Hamishehkar, Hamed

    2015-12-01

    Hydroquinone (HQ), a well-known anti-hyperpigmentation agent suffers from (a) instability due to rapid oxidation, (b) insufficient skin penetration because of hydrophilic structure, and (c) severe side effects as a results of systemic absorption. This study aimed to load HQ into solid lipid nanoparticles (SLNs) to overcome the mentioned drawbacks for the efficient treatment of hyperpigmentation. The optimized SLN formulation was prepared by hot melt homogenization method and fully characterized by various techniques. The ability of SLNs in dermal delivery of HQ was assessed through the excised rat skin. The optimized HQ-loaded SLNs (particle size of 86 nm, encapsulation efficiency% of 89.5% and loading capacity% of 11.2%) exhibited a good physicochemical stability during a period of five months. XRD and DSC results showed that HQ was dispersed in an amorphous state, confirming uniform drug dispersion in the SLNs structure and embedment of drug in the solid lipid matrix. In vitro penetration studies showed almost 3 times higher drug accumulation in the skin and 6.5 times lower drug entrance to receiving compartment of Franz diffusion cell from HQ-loaded SLN hydrogel compared with HQ Carbopol made hydrogel. These results indicated the better HQ localization in the skin and its lower systemic absorption. It was concluded that SLN is a promising colloidal drug carrier for topical administration of HQ in the treatment of hyperpigmentation due to suitable HQ loading value in spite of its hydrophilic structure, high stability against oxidation and appropriate skin penetration along with the low systemic absorption.

  9. Enhanced Electrical Integration of Engineered Human Myocardium via Intramyocardial versus Epicardial Delivery in Infarcted Rat Hearts.

    Directory of Open Access Journals (Sweden)

    Kaytlyn A Gerbin

    Full Text Available Cardiac tissue engineering is a promising approach to provide large-scale tissues for transplantation to regenerate the heart after ischemic injury, however, integration with the host myocardium will be required to achieve electromechanical benefits. To test the ability of engineered heart tissues to electrically integrate with the host, 10 million human embryonic stem cell (hESC-derived cardiomyocytes were used to form either scaffold-free tissue patches implanted on the epicardium or micro-tissue particles (~1000 cells/particle delivered by intramyocardial injection into the left ventricular wall of the ischemia/reperfusion injured athymic rat heart. Results were compared to intramyocardial injection of 10 million dispersed hESC-cardiomyocytes. Graft size was not significantly different between treatment groups and correlated inversely with infarct size. After implantation on the epicardial surface, hESC-cardiac tissue patches were electromechanically active, but they beat slowly and were not electrically coupled to the host at 4 weeks based on ex vivo fluorescent imaging of their graft-autonomous GCaMP3 calcium reporter. Histologically, scar tissue physically separated the patch graft and host myocardium. In contrast, following intramyocardial injection of micro-tissue particles and suspended cardiomyocytes, 100% of the grafts detected by fluorescent GCaMP3 imaging were electrically coupled to the host heart at spontaneous rate and could follow host pacing up to a maximum of 300-390 beats per minute (5-6.5 Hz. Gap junctions between intramyocardial graft and host tissue were identified histologically. The extensive coupling and rapid response rate of the human myocardial grafts after intramyocardial delivery suggest electrophysiological adaptation of hESC-derived cardiomyocytes to the rat heart's pacemaking activity. These data support the use of the rat model for studying electromechanical integration of human cardiomyocytes, and they

  10. Delivery of vegetable oil suspensions in a shear thinning fluid for enhanced bioremediation

    Science.gov (United States)

    Zhong, L.; Truex, M. J.; Kananizadeh, N.; Li, Y.; Lea, A. S.; Yan, X.

    2015-04-01

    In situ anaerobic biological processes are widely applied for dechlorination of chlorinated solvents in groundwater. A wide range of organic substrates have been tested and applied to support the dechlorination processes. Vegetable oils are a promising type of substrate and have been shown to induce effective dechlorination, have limited geochemical impacts, and maintain good longevity. Because they are non-aqueous phase liquids, distribution of vegetable oils in the subsurface has typically been approached by creating emulsified oil solutions for injection into the aquifer. In this study, inexpensive waste vegetable oils were suspended in a shear-thinning xanthan gum solution as an alternative approach for delivery of vegetable oil to the subsurface. The stability, oil droplet size distribution, and rheological behavior of the oil suspensions that are created in the xanthan solutions were studied in batch experiments. The injectability of the suspensions and the oil distribution in a porous medium were evaluated in column tests. Numerical modeling of oil droplet transport and distribution in porous media was conducted to help interpret the column-test data. Batch studies showed that simple mixing of vegetable oil with xanthan solution produced stable suspensions of the oil as micron-size droplets. The mixture rheology retains shear-thinning properties that facilitate improved uniformity of substrate distribution in heterogeneous aquifers. Column tests demonstrated successful injection of the vegetable oil suspension into a porous medium. This study provides evidence that vegetable oil suspensions in xanthan gum solutions have favorable injection properties and are a potential substrate for in situ anaerobic bioremediation.

  11. Enhanced noscapine delivery using estrogen-receptor-targeted nanoparticles for breast cancer therapy.

    Science.gov (United States)

    Madan, Jitender; Gundala, Sushma R; Kasetti, Yoganjaneyulu; Bharatam, Prasad V; Aneja, Ritu; Katyal, Anju; Jain, Upendra K

    2014-07-01

    Noscapine (Nos), an orally available plant-derived antitussive alkaloid, is in phase II clinical trials for cancer chemotherapy. It has extensively been shown to inhibit tumor growth in nude mice bearing human xenografts of hematopoietic, breast, lung, ovarian, brain, and prostate origin. However, high tumor-suppressive Nos dosages encumber the development of oral controlled-release formulations because of a short biological half-life (noscapine-loaded gelatin nanoparticles (Nos-ES-GN) for targeting estrogen-receptor-positive breast cancer MCF-7 cells. Gelatin nanoparticles (GN) were a uniformly compact size, stable at physiological pH, and showed a drug entrapment efficiency of 66.1±5.9 and 65.2±5.6% for Nos-GN and Nos-ES-GN, respectively. The secondary structure of gelatin nanocoacervates was predicted using circular dichroism and in-silico molecular modeling. Our data suggest that ethanol-fabricated GN retained the α-helical content of gelatin, whereas acetone favored the formation of random coils. The conjugation of estrone to Nos-GN did not affect the release rate of the drug, and both formulations followed first-order release kinetics with an initial burst, followed by a slow release. The IC50 value of Nos-ES-GN was 21.2 μmol/l, which was ∼50% lower than the free drug (43.3 μmol/l), suggesting targeted drug delivery. Our cell uptake study carried out in an estrogen-receptor-positive (MCF-7) and negative (MDA-MB-231) cancer cell lines showed greater accumulation of Nos-ES-GN in MCF-7 cells instead of MDA-MB-231 cells. Our data indicated that estrone-conjugated nanoparticles may potentially be used for targeting breast cancer cells.

  12. Sterically stabilized gelatin microassemblies of noscapine enhance cytotoxicity, apoptosis and drug delivery in lung cancer cells.

    Science.gov (United States)

    Madan, Jitender; Pandey, Ravi S; Jain, Upendra Kumar; Katare, Om P; Aneja, Ritu; Katyal, Anju

    2013-07-01

    Noscapine, recently identified as anticancer due to its microtubule-modulating properties. It is presently in Phase I/II clinical trials. The therapeutic efficacy of noscapine has been established in several xenograft models. Its pharmacokinetic limitations such as low bioavailability and high ED50 impede development of clinically relevant treatment regimens. Here we present design, synthesis, in vitro and in vivo characterization of sterically stabilized gelatin microassemblies of noscapine (SSGMS) for targeting human non-small cell lung cancer A549 cells. The average size of the sterically stabilized gelatin microassemblies of noscapine, SSGMS was 10.0±5.1 μm in comparison to noscapine-loaded gelatin microassemblies, GMS that was 8.3±5.5 μm. The noscapine entrapment efficiency of SSGMS and GMS was 23.99±4.5% and 24.23±2.6%, respectively. Prepared microassemblies were spherical in shape and did not show any drug and polymer interaction as examined by FTIR, DSC and PXRD. In vitro release data indicated that SSGMS and GMS follow first-order release kinetics and exhibited an initial burst followed by slow release of the drug. In vitro cytotoxicity evaluated using A549 cells showed a low IC50 value of SSGMS (15.5 μM) compared to GMS (30.1 μM) and free noscapine (47.2 μM). The SSGMS can facilitate a sustained therapeutic effect in terms of prolonged release of noscapine as evident by caspase-3 activity in A549 cells. Concomitantly, pharmacokinetic and biodistribution analysis showed that SSGMS increased the plasma half-life of noscapine by ~9.57-fold with an accumulation of ~48% drug in the lungs. Our data provides evidence for the potential usefulness of SSGMS for noscapine delivery in lung cancer.

  13. Light Delivery Over Extended Time Periods Enhances the Effectiveness of Photodynamic Therapy

    Science.gov (United States)

    Seshadri, Mukund; Bellnier, David A.; Vaughan, Lurine A.; Spernyak, Joseph A.; Mazurchuk, Richard; Foster, Thomas H.; Henderson, Barbara W.

    2009-01-01

    Purpose The rate of energy delivery is a principal factor determining the biological consequences of photodynamic therapy (PDT). In contrast to conventional high irradiance treatments, recent preclinical and clinical studies have focused on low irradiance schemes. The objective of this study was to investigate the relationship between irradiance, photosensitizer dose and PDT dose with regard to treatment outcome and tumor oxygenation in a rat tumor model. Experimental Design Using the photosensitizer HPPH (2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide), a wide range of PDT doses that included clinically relevant photosensitizer concentrations were evaluated. Magnetic resonance imaging (MRI) and oxygen tension measurements were performed along with the Evans blue exclusion assay to assess vascular response, oxygenation status and tumor necrosis. Results In contrast to high incident laser power (150 mW), low power regimens (7 mW) yielded effective tumor destruction. This was largely independent of PDT dose (drug-light product), with up to 30-fold differences in photosensitizer dose and 15-fold differences in drug-light product. For all drug-light products, the duration of light treatment positively influenced tumor response. Regimens utilizing treatment times of 120–240 mins showed marked reduction in signal intensity in T2-weighted MR images at both low (0.1 mg/kg) and high (3 mg/kg) drug doses compared to short duration (6–11 mins) regimens. Significantly greater reductions in pO2 were observed with extended exposures, which persisted after completion of treatment. Conclusions These results confirm the benefit of prolonged light exposure, identify vascular response as a major contributor and suggest that duration of light treatment (time) may be an important new treatment parameter. PMID:18451247

  14. Transdermal drug delivery

    OpenAIRE

    Prausnitz, Mark R.; Langer, Robert

    2008-01-01

    Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability ...

  15. Enhanced delivery of ketobemidone through porcine buccal mucosa in vitro via more lipophilic ester prodrugs

    DEFF Research Database (Denmark)

    Hansen, L.B.; Christrup, Lona Louring; Bundgaard, H.

    1992-01-01

    The in vitro penetration of ketobemidone and various ester prodrugs through porcine buccal mucosa in a modified Ussing chamber was investigated in order to support the selection of a prodrug derivative with optimal buccal absorption. The nine esters studied included carboxylic acid and carbonate...... esters formed at the phenolic hydroxy group of ketobemidone. The esters were all rapidly hydrolyzed to the parent drug in a porcine buccal epithelial homogenate and only free ketobemidone was detected in the receptor compartment of the Ussing chamber. All the ester prodrugs showed enhanced rates...

  16. Leadership styles of service professionals aiding women of abuse: enhancing service delivery.

    Science.gov (United States)

    Haeseler, Lisa Ann

    2013-01-01

    Leadership styles of service professionals--including social workers and teachers--in the area of family abuse were investigated. Leadership characteristics of the professionals were measured by their responses to a survey. Results indicated that the interviewed service professionals demonstrated productive leadership traits. Study findings are congruent with leadership styles described in the research. Holistic and collaborative services are required to enhance care for women of abuse, as their needs are multifaceted and complex. Specific leadership styles promote better care for women; leaders need to collaboratively initiate and deliver more interdisciplinary and unified service.

  17. Characterization of smart auto-degradative hydrogel matrix containing alginate lyase to enhance levofloxacin delivery against bacterial biofilms.

    Science.gov (United States)

    Islan, German A; Dini, Cecilia; Bartel, Laura C; Bolzán, Alejandro D; Castro, Guillermo R

    2015-12-30

    The aim of the present work is the characterization of smart auto-degradable microspheres composed of calcium alginate/high methoxylated pectin containing an alginate lyase (AL) from Sphingobacterium multivorum and levofloxacin. Microspheres were prepared by ionotropic gelation containing AL in its inactive form at pH 4.0. Incubation of microspheres in Tris-HCl and PBS buffers at pH 7.40 allowed to establish the effect of ion-chelating phosphate on matrix erodability and suggested an intrinsically activation of AL by turning the pH close to neutrality. Scanning electron and optical microscopies revealed the presence of holes and surface changes in AL containing microspheres. Furthermore, texturometric parameters, DSC profiles and swelling properties were showing strong changes in microspheres properties. Encapsulation of levofloxacin into microspheres containing AL showed 70% efficiency and 35% enhancement of antimicrobial activity against Pseudomonas aeruginosa biofilm. Levofloxacin release from microspheres was not changed at acidic pH, but was modified at neutral pH in presence of AL. Advantageously, only gel matrix debris were detectable after overnight incubation, indicating an autodegradative gel process activated by the pH. Absence of matrix cytotoxicity and a reduction of the levofloxacin toxicity after encapsulation were observed in mammalian CHO-K1 cell cultures. These properties make the system a potent and versatile tool for antibiotic oral delivery targeted to intestine, enhancing the drug bioavailability to eradicate bacterial biofilm and avoiding possible intestinal obstructions.

  18. Surface-mediated functional gene delivery: an effective strategy for enhancing competitiveness of endothelial cells over smooth muscle cells.

    Science.gov (United States)

    Chang, Hao; Ren, Ke-feng; Wang, Jin-Lei; Zhang, He; Wang, Bai-liang; Zheng, Shan-mei; Zhou, Yuan-yuan; Ji, Jian

    2013-04-01

    The non-biorecognition of general biomaterials and inherent biospecificity of biological systems pose key challenges to the optimal functions of medical devices. In this study, we constructed the surface-mediated functional gene delivery through layer-by-layer self-assembly of protamine sulfate (PrS) and plasmid DNA encoding hepatocyte growth factor (HGF), aiming at specific enhancing endothelial cells (EC) compeititiveness over smooth muscle cells (SMC). Characterizations of the (PrS/HGF-pDNA) multilayered films present the linear buildup with homogeneous and flat topographical feature. The amount of DNA can be easily controlled. By using these multilayered films, both human umbilical vein endothelial cells (HUVEC) and human umbilical artery smooth muscle cells (HUASMC) can be directly transfected when they contact with the multilayered films. On transfection, increasing secretion of HGF has been detected in both HUVEC and HUASMC culture, which leads to selective promotion of HUVEC proliferation. In the co-culture experiment, we also exhibit the promoted and hindered growth of HUVEC and HUASMC, respectively, which could be attributed to the inverse influence of HUVEC on HUASMC. These results collectively demonstrate that our system can be served as a powerful tool for enhancing competitiveness of EC over SMC, which opens perspectives for the regulation of intercellular competitiveness in the field of interventional therapy.

  19. Protein Modification with Amphiphilic Block Copoly(2-oxazoline)s as a New Platform for Enhanced Cellular Delivery

    KAUST Repository

    Tong, Jing

    2010-08-02

    Several homopolymers, random copolymers and block copolymers based on poly(2-oxazoline)s (POx) were synthesized and conjugated to horseradish peroxidase (HRP) using biodegradable and nonbiodegradable linkers. These conjugates were characterized by amino group titration, polyacrylamide gel electrophoresis (PAGE), isoelectric focusing, enzymatic activity assay and conformation analysis. The conjugates contained on average from about one to two polymer chains per enzyme. From 70% to 90% of enzymatic activity was retained in most cases. Circular dichroism (CD) analysis revealed that HRP modification affected the secondary structure of the apoprotein but did not affect the tertiary structure and heme environment. Enhanced cellular uptake was found in the conjugates of two block copolymers using both MDCK cells and Caco-2 cells, but not in the conjugates of random copolymer and homopolymer. Conjugation with a block copolymer of 2-methyl-2-oxazoline and 2-butyl-2-oxazoline led to the highest cellular uptake as compared to other conjugates. Our data indicates that modification with amphiphilic POx has the potential to modulate and enhance cellular delivery of proteins.

  20. Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity.

    Science.gov (United States)

    Valicherla, Guru R; Dave, Kandarp M; Syed, Anees A; Riyazuddin, Mohammed; Gupta, Anand P; Singh, Akhilesh; Wahajuddin; Mitra, Kalyan; Datta, Dipak; Gayen, Jiaur R

    2016-05-31

    Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 ± 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 ± 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy.

  1. Robust aptamer–polydopamine-functionalized M-PLGA–TPGS nanoparticles for targeted delivery of docetaxel and enhanced cervical cancer therapy

    Science.gov (United States)

    Xu, Guojun; Yu, Xinghua; Zhang, Jinxie; Sheng, Yingchao; Liu, Gan; Tao, Wei; Mei, Lin

    2016-01-01

    One limitation of current biodegradable polymeric nanoparticles (NPs) is the contradiction between functional modification and maintaining formerly excellent bioproperties with simple procedures. Here, we reported a robust aptamer–polydopamine-functionalized mannitol-functionalized poly(lactide-co-glycolide) (M-PLGA)–D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoformulation (Apt-pD-NPs) for the delivery of docetaxel (DTX) with enhanced cervical cancer therapy effects. The novel DTX-loaded Apt-pD-NPs possess satisfactory advantages: 1) increased drug loading content and encapsulation efficiency induced by star-shaped copolymer M-PLGA–TPGS; 2) significant active targeting effect caused by conjugated AS1411 aptamers; and 3) excellent long-term compatibility by incorporation of TPGS. Therefore, with simple preparation procedures and excellent bioproperties, the new functionalized Apt-pD-NPs could maximally increase the local effective drug concentration on tumor sites, achieving enhanced treatment effectiveness and minimizing side effects. In a word, the robust DTX-loaded Apt-pD-NPs could be used as potential nanotherapeutics for cervical cancer treatment, and the aptamer–polydopamine modification strategy could be a promising method for active targeting of cancer therapy with simple procedures. PMID:27382282

  2. Robust aptamer-polydopamine-functionalized M-PLGA-TPGS nanoparticles for targeted delivery of docetaxel and enhanced cervical cancer therapy.

    Science.gov (United States)

    Xu, Guojun; Yu, Xinghua; Zhang, Jinxie; Sheng, Yingchao; Liu, Gan; Tao, Wei; Mei, Lin

    2016-01-01

    One limitation of current biodegradable polymeric nanoparticles (NPs) is the contradiction between functional modification and maintaining formerly excellent bioproperties with simple procedures. Here, we reported a robust aptamer-polydopamine-functionalized mannitol-functionalized poly(lactide-co-glycolide) (M-PLGA)-D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoformulation (Apt-pD-NPs) for the delivery of docetaxel (DTX) with enhanced cervical cancer therapy effects. The novel DTX-loaded Apt-pD-NPs possess satisfactory advantages: 1) increased drug loading content and encapsulation efficiency induced by star-shaped copolymer M-PLGA-TPGS; 2) significant active targeting effect caused by conjugated AS1411 aptamers; and 3) excellent long-term compatibility by incorporation of TPGS. Therefore, with simple preparation procedures and excellent bioproperties, the new functionalized Apt-pD-NPs could maximally increase the local effective drug concentration on tumor sites, achieving enhanced treatment effectiveness and minimizing side effects. In a word, the robust DTX-loaded Apt-pD-NPs could be used as potential nanotherapeutics for cervical cancer treatment, and the aptamer-polydopamine modification strategy could be a promising method for active targeting of cancer therapy with simple procedures.

  3. Molecular insight into the enhancement of benzene-carbon nanotube interactions by surface modification for drug delivery systems (DDS)

    Science.gov (United States)

    Zhao, Jianghao; Liu, Xiaoshan; Zhu, Zhu; Wang, Ning; Sun, Wenjing; Chen, Congmei; He, Zhiwei

    2017-09-01

    Anthracyclines are effective anticancer drugs but have drawbacks including systemic toxicity and drug resistance. Delivering them directly to the tumor may improve therapeutic efficacy and reduce adverse effects. Carbon nanotubes (CNTs) can act as excellent drug delivery systems (DDS), but pristine CNTs have inert surfaces, which contributes poor drug loading capacity and limits dispersion. In this study, we designed a series of functionalized CNTs (f-CNTs) with anchored hydrophilic groups (OH, COOH, and NH2) by substitutional doping of the CNT lattice (DNT) using N or B atoms or the combination of both. The aromatic compound benzene (Ben) was selected as a model for anthracycline drugs. The effect of CNT curvature, chemical groups (CGs), and doping on the Ben-CNTs interactions was studied using quantum chemistry calculations. Our results show that π-π interactions between Ben and CNTs are influenced by CNT curvature. When the CNTs were functionalized only with CGs and not doped, the system was unstable, resulting in weak Ben-CNT interactions. However, anchoring CGs on DNTs greatly enhanced the Ben-CNT interactions. CNTs with good affinity for drug molecules, improved solubility, and lower tendency to aggregate have potential as DDS for enhancing the efficacy of medicines. We believe that these studies have general applicability and anticipate that our findings will motivate additional theoretical and experimental studies on the biology and chemistry of CNTs as DDS.

  4. Bioadhesive Drug Delivery System for Enhancing the Permeability of a BCS Class III Drug via Hot-Melt Extrusion Technology.

    Science.gov (United States)

    Mendonsa, Nicole S; Thipsay, Priyanka; Kim, Dong Wuk; Martin, Scott T; Repka, Michael A

    2017-02-28

    As the buccal route of administration has the ability to avoid the GI tract and first-pass effect by directing the absorption toward the cheek area, the bioavailability of BCS class III drugs can be increased through this route. Only a handful of studies have been conducted using oleic acid as a permeation enhancer in any transbuccal drug delivery system. Therefore, the objectives of this novel study were to develop a buccal tablet using two concentrations of oleic acid for a model BCS class III drug via hot-melt extrusion technology and to investigate the effects of oleic acid on the physicochemical properties of the tablet. The model drug selected was ondansetron hydrochloride. Formulations consisting of polymers (hydroxypropyl methylcellulose and polyethylene oxide) and two concentrations of oleic acid were prepared by hot-melt extrusion techniques. A melting point depression of the drug was obtained in the extruded granules as seen by the DSC thermograms. The ex vivo permeation studies showed a greater permeation of the drug in the formulation containing 10% oleic acid (F2) as compared to the formulation containing 20% oleic acid (F1), although not statistically significant. The in vitro bioadhesion studies, swelling studies, and surface pH measurements of the tablets were also conducted. In conclusion, permeation studies exhibited the potential of oleic acid as a buccal permeation enhancer as a significant permeation of the drug was obtained in the formulations. Hot-melt extrusion technology was successfully employed to formulate buccal tablets of ondansetron hydrochloride.

  5. Enhanced intra-cutaneous delivery of a Mn-containing antioxidant drug by high-frequency ultrasounds.

    Science.gov (United States)

    Bani, Daniele; Bencini, Andrea; Bergonzi, Maria Camilla; Bilia, Anna Rita; Guccione, Clizia; Severi, Mirko; Udisti, Roberto; Valtancoli, Barbara

    2015-03-15

    This study was carried out to evaluate whether high-frequency ultrasounds, a commonly used aesthetic medicine treatment for skin rejuvenation, may enhance the penetration of the Mn-containing compound Mn(II)(Me2DO2A) (manganese(II) 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) biologically active as a superoxide anion scavenger, in the cutaneous layers of ex vivo human skin explants. Although its antioxidant properties are well known and the compound is basically not toxic in animal models, its trans-cutaneous permeation and its toxicological profile at a systemic level have not yet fully analyzed. Therefore, its possible penetration in the deep cutaneous layers was also evaluated. To this purpose, Mn(II)(Me2DO2A) was formulated as emulsion-gel, lipogel and hydrogel. These different formulations were also tested in combination with high-frequency ultrasounds (10-3500 Hz frequency modulation on a 5 MHz main frequency) used as physical permeation enhancers, delivered by a MedVisage™ device (General Project, Montespertoli, Italy) currently used for aesthetic medicine purposes. The permeation of the Mn-containing compound from the formulations was evaluated by inductively coupled plasma atomic emission spectrometry (ICP-AES) measurements of Mn in horizontal cryosections of the skin samples cut at different depths to separate the epidermis, papillary and reticular dermis, as well as by vertical Franz diffusion cells. The results show that the hydrogel formulation yielded the highest transepidermal delivery of Mn(II)(Me2DO2A) and that the application of ultrasounds (3 W, FM 100 Hz, 2×10 s) significantly enhanced its penetration into the epidermis and upper dermal layers. Of note, nearly undetectable amounts of Mn(II)(Me2DO2A) were detected in the reticular dermis and the Franz cell fluid. Although an in vivo confirmation of these results will be necessary, this method may allow to minimize undesired drug passage to the bloodstream and undesired delivery

  6. Efficiency of drug delivery enhanced by acoustic pressure during blood–brain barrier disruption induced by focused ultrasound

    Directory of Open Access Journals (Sweden)

    Yang FY

    2012-05-01

    Full Text Available Feng-Yi Yang, Pei-Yi LeeDepartment of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, TaiwanPurpose: We evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood–brain barrier (BBB-D, induced by focused ultrasound (FUS using various acoustic parameters.Materials and methods: Male Sprague-Dawley rats were injected intravenously with Evans blue (EB before or after BBB-D induction by pulsed FUS. We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA at four different doses to induce BBB-D resulting from cavitation. The permeability of the BBB was assessed quantitatively based on the extravasation of EB. Contrast enhanced magnetic resonance imaging (MRI was used to monitor the gadolinium deposition associated with FUS. Histological analysis was performed to examine tissue damage.Results: The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D. Administration of EB followed by sonication resulted in greater EB extravasation than that for rats subjected to sonication prior to EB injection. To reduce tissue damage, EB extravasation was enhanced by first administering EB by intravenous injection, followed by sonication at reduced acoustic power or UCA dosage. The normalized signal intensity change in rat brains that received the same dose of UCA and sonicated after gadolinium injection was significantly greater than in rats undergoing sonication followed by gadolinium administration. Moreover, contrast enhanced MRI showed a more precise distribution of gadolinium in the brain when gadolinium was administered before sonication.Conclusion: We demonstrated that a compound administered prior to sonication treatment promotes extravasation of the sonicated region. Thus, it is possible to

  7. Enhanced acute anti-inflammatory effects of CORM-2-loaded nanoparticles via sustained carbon monoxide delivery.

    Science.gov (United States)

    Qureshi, Omer Salman; Zeb, Alam; Akram, Muhammad; Kim, Myung-Sic; Kang, Jong-Ho; Kim, Hoo-Seong; Majid, Arshad; Han, Inbo; Chang, Sun-Young; Bae, Ok-Nam; Kim, Jin-Ki

    2016-11-01

    The aim of this study was to enhance the anti-inflammatory effects of carbon monoxide (CO) via sustained release of CO from carbon monoxide-releasing molecule-2-loaded lipid nanoparticles (CORM-2-NPs). CORM-2-NPs were prepared by hot high pressure homogenization method using trilaurin as a solid lipid core and Tween 20/Span 20/Myrj S40 as surfactant mixture. The physicochemical properties of CORM-2-NPs were characterized and CO release from CORM-2-NPs was assessed by myoglobin assay. In vitro anti-inflammatory effects were evaluated by nitric oxide assay in lipopolysaccharide-stimulated RAW 264.7 macrophages. In vivo anti-inflammatory activity was investigated by measuring paw volumes and histological examination in carrageenan-induced rat paw edema. Spherical CORM-2-NPs were around 100nm with narrow particle size distribution. The sustained CO release from CORM-2-NPs was observed and the half-life of CO release increased up to 10 times compared with CORM-2 solution. CORM-2-NPs showed enhanced in vitro anti-inflammatory effects by inhibition of nitric oxide production. Edema volume in rat paw was significantly reduced after treatment with CORM-2-NPs. Taken together, CORM-2-NPs have a great potential for CO therapeutics against inflammation via sustained release of CO. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Magnetofection Enhances Adenoviral Vector-based Gene Delivery in Skeletal Muscle Cells

    Science.gov (United States)

    Pereyra, Andrea Soledad; Mykhaylyk, Olga; Lockhart, Eugenia Falomir; Taylor, Jackson Richard; Delbono, Osvaldo; Goya, Rodolfo Gustavo; Plank, Christian; Hereñu, Claudia Beatriz

    2016-01-01

    The goal of magnetic field-assisted gene transfer is to enhance internalization of exogenous nucleic acids by association with magnetic nanoparticles (MNPs). This technique named magnetofection is particularly useful in difficult-to-transfect cells. It is well known that human, mouse, and rat skeletal muscle cells suffer a maturation-dependent loss of susceptibility to Recombinant Adenoviral vector (RAd) uptake. In postnatal, fully differentiated myofibers, the expression of the primary Coxsackie and Adenoviral membrane receptor (CAR) is severely downregulated representing a main hurdle for the use of these vectors in gene transfer/therapy. Here we demonstrate that assembling of Recombinant Adenoviral vectors with suitable iron oxide MNPs into magneto-adenovectors (RAd-MNP) and further exposure to a gradient magnetic field enables to efficiently overcome transduction resistance in skeletal muscle cells. Expression of Green Fluorescent Protein and Insulin-like Growth Factor 1 was significantly enhanced after magnetofection with RAd-MNPs complexes in C2C12 myotubes in vitro and mouse skeletal muscle in vivo when compared to transduction with naked virus. These results provide evidence that magnetofection, mainly due to its membrane-receptor independent mechanism, constitutes a simple and effective alternative to current methods for gene transfer into traditionally hard-to-transfect biological models. PMID:27274908

  9. Enhanced efficacy of clindamycin hydrochloride encapsulated in PLA/PLGA based nanoparticle system for oral delivery.

    Science.gov (United States)

    Rauta, Pradipta Ranjan; Das, Niladri Mohan; Nayak, Debasis; Ashe, Sarbani; Nayak, Bismita

    2016-08-01

    Clindamycin hydrochloride (CLH) is a clinically important oral antibiotic with wide spectrum of antimicrobial activity that includes gram-positive aerobes (staphylococci, streptococci etc.), most anaerobic bacteria, Chlamydia and certain protozoa. The current study was focused to develop a stabilised clindamycin encapsulated poly lactic acid (PLA)/poly (D,L-lactide-co-glycolide) (PLGA) nano-formulation with better drug bioavailability at molecular level. Various nanoparticle (NPs) formulations of PLA and PLGA loaded with CLH were prepared by solvent evaporation method varying drug: polymer concentration (1:20, 1:10 and 1:5) and characterised (size, encapsulation efficiency, drug loading, scanning electron microscope, differential scanning calorimetry [DSC] and Fourier transform infrared [FTIR] studies). The ratio 1:10 was found to be optimal for a monodispersed and stable nano formulation for both the polymers. NP formulations demonstrated a significant controlled release profile extended up to 144 h (both CLH-PLA and CLH-PLGA). The thermal behaviour (DSC) studies confirmed the molecular dispersion of the drug within the system. The FTIR studies revealed the intactness as well as unaltered structure of drug. The CLH-PLA NPs showed enhanced antimicrobial activity against two pathogenic bacteria Streptococcus faecalis and Bacillus cereus. The results notably suggest that encapsulation of CLH into PLA/PLGA significantly increases the bioavailability of the drug and due to this enhanced drug activity; it can be widely applied for number of therapies.

  10. A simple and powerful co-delivery system based on pH-responsive metal-organic frameworks for enhanced cancer immunotherapy.

    Science.gov (United States)

    Duan, Fei; Feng, Xiaochen; Yang, Xinjian; Sun, Wentong; Jin, Yi; Liu, Huifang; Ge, Kun; Li, Zhenhua; Zhang, Jinchao

    2017-04-01

    Tumor-associated antigens (TAAs)-loaded nanoparticles are able to be actively internalized by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy. However, current TAAs delivery strategy exhibits limitations of complicated synthesis process, low loading efficiency and inefficient CD8(+) cytotoxic T lymphocyte activation leading to unsatisfactory therapeutic effect. Thus, the construction of novel TAAs-delivery systems for enhanced cancer therapy is highly desirable. In this work, we fabricated a very simple yet powerful antigens-delivery system for cancer immunotherapy based-on pH-responsive metal-organic frameworks (MOFs) with size about 30 nm. TAAs can be loaded into MOFs in the one-pot synthesis process and released with the degradation of MOFs in the acidic environment of endo/lysosome as the result of relatively labile metal-ligand bonds. The endosomolytic nanoparticles would facilitate protein antigens escape from endo/lysosome and optimal for enhancing antigen cross-presentation. Furthermore, the introduction of immunostimulatory unmethylated cytosine-phosphate-guanine oligonucleotide (CpG) through Watson-Crick base pairing would further enhance CD8(+) cytotoxic T lymphocyte responses. We demonstrated that the method to co-delivery antigens and immunostimulatory molecules was very simple, convenient and effective and showed no obvious toxicity both in vitro and in vivo. This method gave a high antigens-loading capacity and the maximal antigen encapsulating efficiency was about 55% (w/w). Additionally, the pH-responsive co-delivery system exerted enhanced antitumor outcome (about 100% survival) in B16-OVA melanoma cancers in vivo. Furthermore, we confirmed that this high rating of therapeutic effect was attributed to the recruitment of tumor-killing immunocyte. This work demonstrates the ability of pH-responsive, endosomolytic MOFs to induce strong cellular immune responses for cancer therapy by co-delivery of CpG ODN

  11. Sources and delivery of carbon dioxide for enhanced oil recovery. Final report, October 1977--December 1978

    Energy Technology Data Exchange (ETDEWEB)

    Hare, M.; Perlich, H.; Robinson, R.; Shah, M.; Zimmerman, F.

    1978-12-01

    Results are presented from a comprehensive study by Pullman Kellogg, with assistance from Gulf Universities Research Consortium (GURC) and National Cryo-Chemics Incorporated (NCI), of the carbon dioxide supply situation for miscible flooding operations to enhance oil recovery. A survey of carbon dioxide sources within the geographic areas of potential EOR are shown on four regional maps with the tabular data for each region to describe the sources in terms of quantity and quality. Evaluation of all the costs, such as purchase, production, processing, and transportation, associated with delivering the carbon dioxide from its source to its destination are presented. Specific cases to illustrate the use of the maps and cost charts generated in this study have been examined.

  12. Fractional laser-assisted topical delivery leads to enhanced, accelerated and deeper cutaneous 5-fluorouracil uptake

    DEFF Research Database (Denmark)

    Wenande, Emily; Olesen, Uffe H; Nielsen, Mette M B

    2017-01-01

    BACKGROUND: Topical 5-Fluorouracil (5-FU) exhibits suboptimal efficacy for non-melanoma skin cancer, attributed to insufficient intracutaneous penetration. This study investigates the impact of ablative fractional laser (AFXL) at different laser-channel depths on cutaneous 5-FU pharmacokinetics...... uniform 5-FU distribution after AFXL versus controls. CONCLUSIONS: AFXL offers laser-channel depth-dependent, enhanced and accelerated 5-FU uptake, with increased deposition in deep skin layers....... and biodistribution. METHODS: In vitro porcine skin underwent AFXL-exposure using a fractional 10,600nm CO2-laser, generating microscopic ablation zones (MAZ) reaching the dermoepidermal junction (MAZ-ED), superficial-(MAZ-DS), or mid-dermis(MAZ-DM). 5-FU in AFXL-exposed and control skin was measured in Franz...

  13. N-succinyl chitosan as buccal penetration enhancer for delivery of herbal agents in treatment of oral mucositis.

    Science.gov (United States)

    Dhawan, Neha; Kumar, Krishan; Kalia, A N; Arora, Saahil

    2014-01-01

    Oral mucositis is one of the major side effects of cancer chemotherapy (30-76%) and radiotherapy (over 50%). Current palliative treatments of oral mucositis include specialized agents like pelifermin, platelet derived factors etc. or oral hygienic agents which suffered from various drawbacks like systemic side effect, least effect owing to fast wash out of buccal mucosa, patient unfriendly delivery systems, and mere symptomatic relief. In this research work, N-succinyl chitosan gel delivery system of microemulsified eugenol, honey and sodium hyaluronate was prepared to explore their multiple and synergistic effects on various pathological factors of oral mucositis. N-succinyl chitosan was synthesized in our laboratory and loaded with microemulsified eugenol (10% v/v), honey (10% v/v) and sodium hyaluronate (0.2% w/v) to prepare orogel with optimum pH, spreadability, mucoadhesion strength, and viscosity. In vitro eugenol release from N-succinyl chitosan gel after 8 hours in PBS (pH-6.4) was found to be 87.45±0.14%, which was better in comparison to that released from chitosan gel. Ex vivo penetration studies using rat buccal mucosal tissue also suggested better J-efflux of eugenol through N-succinyl chitosan in comparison to chitosan gel with enhancement ratio (ER) of 1.71. The antimicrobial effect of N-succinyl chitosan based orogel against S. aureus and C. albicans efficacy was found to be statistically high in comparison to chitosan based orogel as well as marketed formulation of chlorhexidine (pgel formulation within 15 days. The formulation was successful in elevating the survival and reducing the inflammation in the oral mucosa of animals compared to disease control (p<0.05) and hence suggesting the potential of N-succinyl chitosan orogel in the treatment of oral mucositis.

  14. Novel mucus-penetrating liposomes as a potential oral drug delivery system: preparation, in vitro characterization, and enhanced cellular uptake

    Directory of Open Access Journals (Sweden)

    Li X

    2011-12-01

    Full Text Available Xiuying Li1, Dan Chen1, Chaoyi Le2, Chunliu Zhu1, Yong Gan1, Lars Hovgaard3, Mingshi Yang41Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; 2University of Toronto Mississauga Campus, Ontario, Canada; 3Oral Formulation Development, Novo Nordisk A/S, Maalov; 4Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Copenhagen, DenmarkBackground: The aim of this study was to investigate the intestinal mucus-penetrating properties and intestinal cellular uptake of two types of liposomes modified by Pluronic F127 (PF127.Methods: The two types of liposomes, ie, PF127-inlaid liposomes and PF127-adsorbed liposomes, were prepared by a thin-film hydration method followed by extrusion, in which coumarin 6 was loaded as a fluorescence marker. A modified Franz diffusion cell mounted with the intestinal mucus of rats was used to study the diffusion characteristics of the two types of PF127 liposomes. Cell uptake studies were conducted in Caco-2 cells and analyzed using confocal laser scanning microcopy as well as flow cytometry.Results: The diffusion efficiency of the two types of PF127-modified liposomes through intestinal rat mucus was 5–7-fold higher than that of unmodified liposomes. Compared with unmodified liposomes, PF127-inlaid liposomes showed significantly higher cellular uptake of courmarin 6. PF127-adsorbed liposomes showed a lower cellular uptake. Moreover, and interestingly, the two types of PF127-modified liposomes showed different cellular uptake mechanisms in Caco-2 cells.Conclusion: PF127-inlaid liposomes with improved intestinal mucus-penetrating ability and enhanced cellular uptake might be a potential carrier candidate for oral drug delivery.Keywords: Pluronic F127, mucus-penetrating, particles, liposomes, oral drug delivery

  15. Ultra-flexible nanocarriers for enhanced topical delivery of a highly lipophilic antioxidative molecule for skin cancer chemoprevention.

    Science.gov (United States)

    Boakye, Cedar H A; Patel, Ketan; Doddapaneni, Ravi; Bagde, Arvind; Behl, Gautam; Chowdhury, Nusrat; Safe, Stephen; Singh, Mandip

    2016-07-01

    In this study, we developed cationic ultra-flexible nanocarriers (UltraFLEX-Nano) to surmount the skin barrier structure and to potentiate the topical delivery of a highly lipophilic antioxidative diindolylmethane derivative (DIM-D) for the inhibition of UV-induced DNA damage and skin carcinogenesis. UltraFLEX-Nano was prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-3-trimethylammonium-propane, cholesterol and tween-80 by ethanolic injection method; was characterized by Differential Scanning Calorimetric (DSC), Fourier Transform Infrared (FT-IR) and Atomic Force Microscopic (phase-imaging) analyses and permeation studies were performed in dermatomed human skin. The efficacy of DIM-D-UltraFLEX-Nano for skin cancer chemoprevention was evaluated in UVB-induced skin cancer model in vivo. DIM-D-UltraFLEX-Nano formed a stable mono-dispersion (110.50±0.71nm) with >90% encapsulation of DIM-D that was supported by HPLC, DSC, FT-IR and AFM phase imaging. The blank formulation was non-toxic to human embryonic kidney cells. UltraFLEX-Nano was vastly deformable and highly permeable across the stratum corneum; there was significant (pskin deposition of DIM-D for UltraFLEX-Nano that was superior to PEG solution (13.83-fold). DIM-D-UltraFLEX-Nano pretreatment delayed the onset of UVB-induced tumorigenesis (2 weeks) and reduced (pskin inflammation (PCNA), epidermal hyperplasia (c-myc, CyclinD1), immunosuppression (IL10), cell survival (AKT), metastasis (Vimentin, MMP-9, TIMP1) but increase in apoptosis (p53 and p21). UltraFLEX-Nano was efficient in enhancing the topical delivery of DIM-D. DIM-D-UltraFLEX-Nano was efficacious in delaying skin tumor incidence and multiplicity in SKH mice comparable to sunscreen (SPF30). Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Enhanced endosomal/lysosomal escape by distearoyl phosphoethanolamine-polycarboxybetaine lipid for systemic delivery of siRNA.

    Science.gov (United States)

    Li, Yan; Cheng, Qiang; Jiang, Qian; Huang, Yuanyu; Liu, Hongmei; Zhao, Yuliang; Cao, Weipeng; Ma, Guanghui; Dai, Fengying; Liang, Xingjie; Liang, Zicai; Zhang, Xin

    2014-02-28

    Cationic liposome based siRNA delivery system has improved the efficiencies of siRNA. However, cationic liposomes are prone to be rapidly cleared by the reticuloendothelial system (RES). Although modification of cationic liposomes with polyethylene glycol (PEG) could prolong circulation lifetime, PEG significantly inhibits siRNA entrapment efficiency, cellular uptake and endosomal/lysosomal escape process, resulting in low gene silencing efficiency of siRNA. In this study, we report the synthesis of zwitterionic polycarboxybetaine (PCB) based distearoyl phosphoethanolamine-polycarboxybetaine (DSPE-PCB) lipid for cationic liposome modification. The DSPE-PCB20 cationic liposome/siRNA complexes (lipoplexes) show an excellent stability in serum medium. The siRNA encapsulation efficiency of DSPE-PCB20 lipoplexes could reach 92% at N/P ratio of 20/1, but only 73% for DSPE-PEG lipoplexes. The zeta potential of DSPE-PCB20 lipoplexes is 8.19±0.53mV at pH 7.4, and increases to 24.6±0.87mV when the pH value is decreased to 4.5, which promotes the endosomal/lysosomal escape of siRNA. The DSPE-PCB20 modification could enhance the silencing efficiency of siRNA by approximately 20% over the DSPE-PEG 2000 lipoplexes at the same N/P ratio in vitro. Furthermore, DSPE-PCB20 lipoplexes could efficiently mediate the down-regulation of Apolipoprotein B (ApoB) mRNA in the liver and consequently decrease the total cholesterol in the serum in vivo, suggesting therapeutic potentials for siRNA delivery in hypercholesterolemia-related diseases. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Distal phenylalanine modification for enhancing cellular delivery of fluorophores, proteins and quantum dots by cell penetrating peptides.

    Science.gov (United States)

    Sayers, E J; Cleal, K; Eissa, N G; Watson, P; Jones, A T

    2014-12-10

    For cell penetrating peptides (CPPs) to fulfil their promise as effective delivery vectors we need a better understanding of their mechanisms of cell binding and uptake. This is especially the case when they are linked to different types of cargo. Here we describe new studies based on our previous findings suggesting that, for peptide-CPP chimeras, distal hydrophobic residues upstream of the CPP sequence can have profound effects on the way they interact with cells. We studied peptides bearing an N-terminal Glycine or Phenylalanine linked via a neutral and flexible bridging group, SGSGSGSG, to three well-studied CPPs: octaarginine, penetratin and TP10. Using a combination of flow cytometry, live-cell imaging and image analysis we examined the effects of this single amino acid change on binding and uptake of Alexa488-fluorophore, bovine serum albumin and quantum dot cargoes. The influence of the glycine-phenylalanine switch for fluorophore delivery was most dramatic in TP10, increasing cellular uptake by 4.4 and 9.9 fold in non-adherent and adherent cells, respectively. Only penetratin showed effective uptake of bovine serum albumin with the phenylalanine variant showing an increase of 1.6 fold over the glycine variant. The uptake of quantum dots was most efficiently demonstrated by octaarginine, with the glycine variant increasing uptake 4.8 fold and the phenylalanine variant increasing uptake 9.5 fold over quantum dots alone. Overall the data demonstrate that hydrophobicity distal to the CPP could be utilised to enhance their capacity to bind to the cell membrane and deliver a range of macromolecules to the insides of cells.

  18. Fabrication and in vitro characterization of gadolinium-based nanoclusters for simultaneous drug delivery and radiation enhancement

    Science.gov (United States)

    Yoo, Shannon S.; Guo, Linghong; Sun, Xuejun; Shaw, Andrew R.; Yuan, Zhipeng; Löbenberg, Raimar; Roa, Wilson H.

    2016-09-01

    We report the synthesis of a gadolinium hydroxide (Gd(OH)3) nanorod based doxorubicin (Dox) delivery system that can enhance both magnetic resonance imaging contrast and radiation sensitivity. A simple and cost effective wet-chemical method was utilized in the presence of manganese (Mn) ions and Dox to produce the Gd(OH)3:Mn·Dox nanocluster structure. The Gd(OH)3:Mn·Dox nanocluster was composed of Mn-doped Gd(OH)3 nanorods arranged in parallel with Dox as a linker molecule between the adjacent nanorods. No other studies have utilized Dox as both the linker and therapeutic molecule in a nanostructure to date. The Gd(OH)3 nanorod is reported to have no significant cellular or in vivo toxicity, which makes it an ideal base material for this biomedical application. The Gd(OH)3:Mn·Dox nanocluster exhibited paramagnetic behavior and was stable in a colloidal solution. The nanocluster also enabled high Dox loading capacity and specifically released Dox in a sustained and pH-dependent manner. The positively charged Gd(OH)3:Mn·Dox nanoclusters were readily internalized into MDA-MB-231 breast cancer cells via endocytosis, which resulted in intracellular release of Dox. The released Dox in cells was effective in conferring cytotoxicity and inhibiting proliferation of cancer cells. Furthermore, a synergistic anticancer effect could be observed with radiation treatment. Overall, the Gd(OH)3:Mn·Dox nanocluster drug delivery system described herein may have potential utility in clinics as a multifunctional theranostic nanoparticle with combined benefits in both diagnosis and therapy in the management of cancer.

  19. Systems Change Enhances Access to Family Planning Training and Care Delivery.

    Science.gov (United States)

    Carvajal, Diana N; Khanna, Niharika; Williams, Mozella; Gold, Marji

    2016-09-01

    Long-acting reversible contraceptives (LARCs) are very effective methods of pregnancy prevention. To ensure autonomy over childbearing, women need access to contraception and abortion services. Family physicians can improve access by increasing numbers and locations of trained providers. In 2014, the University of Maryland (UMD) Reproductive Health EDucation In family medicine (RHEDI) program sought to enhance LARC and abortion training by increasing: (1) resident participation in LARC services, (2) resident participation/interest in abortion care, (3) patient access to LARCs and medication abortions (MABs). We used a pre-post framework comparing years 2013 and 2014 with respect to number of resident-provided LARC services, number of residents participating in abortion, and total number of LARCs and MABs provided practice-wide. The setting is an urban residency practice. (1) increased dedicated appointments for LARC and MABs, (2) dedicated appointment scheduler, (3) comprehensive family planning didactics and clinical workshops, (4) faculty-supported Residents for Choice group. 2014: Residents provided substantially more LARC services compared to 2013. Placement increased from 50 to 90, and removals tripled (25 to 73). 2014 site-wide LARC placement also increased (160 versus 98), removals increased (44 in 2013, 106 in 2014). Twelve residents per year are eligible to participate in abortion care. In 2013, two participated: in 2014, 10 participated. MABs provided in 2014 (18) did not change from 2013 (17). The UMD RHEDI program demonstrated that attention to care-provision systems and education enhances resident training and increases patient access to family planning services. Programs with similar goals may find our methods helpful.

  20. Enhancement of cytotoxicity of antimicrobial peptide magainin Ⅱ in tumor cells by bombesin-targeted delivery

    Institute of Scientific and Technical Information of China (English)

    Shan LIU; Hao YANG; Lin WAN; Hua-wei CAI; Sheng-fu LI; You-ping LI; Jing-qiu CHENG; Xiao-feng LU

    2011-01-01

    Aim: To investigate whether the conjugation of magainin II(MG2),an antimicrobial peptides(AMPs),to the tumor-homing peptide bombesin could enhance its cytotoxicity in tumor cells.Methods: A magainin Ⅱ-bombesin conjugate(MG2B)was constructed by attaching magainin Ⅱ(MG2)to bombesin at its N-terminus.The peptides were synthesized using Fmoc-chemistry.The in vitro cytotoxicity of the peptide in cancer cells was quantitatively determined using the CCK-8 celt counting kit.Moreover,the in vivo antitumor effect of the peptide was determined in tumor xenograft models.Results: The IC50 of MG2B for cancer cells(10-15 μmol/L)was at least 10 times lower than the IC50 of unconjugated MG2(125μmol/L).Moreover,the binding affinity of MG2B for cancer cells was higher than that of unconjugated MG2.In contrast,conjugation to a bombesin analog lacking the receptor-binding domain failed to increase the cytotoxicity of MG2,suggesting that bombesin conjugation enhances the cytotoxicity of MG2 in cancer cells through improved binding.Indeed,MG2B selectively induced cell death in cancer cells in vitro with the IC50 ranging from 10 to 15 μmol/L,which was about 6-10 times lower than the IC50 for normal cells.MG2B(20mg/kg per day,intratumorally injected for 5 d)also exhibited antitumor effects in mice bearing MCF-7 tumor grafts.The mean weights of tumor grafts in MG2B-and PBS-treated mice were 0.21±0.05 g and 0.59±0.12 g,respectively.Conclusion: The results suggest that conjugation of AMPs to bombesin might be an alternative approach for targeted cancer therapy.

  1. Enhanced noscapine delivery using uPAR-targeted optical-MR imaging trackable nanoparticles for prostate cancer therapy.

    Science.gov (United States)

    Abdalla, Mohamed O; Karna, Prasanthi; Sajja, Hari Krishna; Mao, Hui; Yates, Clayton; Turner, Timothy; Aneja, Ritu

    2011-02-10

    The tubulin-binding anticancer activity of noscapine, an orally available plant-derived anti-tussive alkaloid, has been recently identified. Noscapine inhibits tumor growth in nude mice bearing human xenografts of hematopoietic, breast, lung, ovarian, brain and prostate origin. Despite its nontoxic attributes, significant elimination of the disease has not been achieved, perhaps since the bioavailability of noscapine to tumors saturates at an oral dose of 300 mg/kg body weight. To enable the selective and specific delivery of noscapine to prostate cancer cells, we have engineered a multifunctional nanoscale delivery vehicle that takes advantage of urokinase plasminogen activator receptor (uPAR) overexpression in prostate cancer compared to normal prostate epithelia and can be tracked by magnetic resonance imaging (MRI) and near-infrared (NIR) imaging. Specifically, we employed the human-type 135 amino-acid amino-terminal fragment (hATF) of urokinase plasminogen activator (uPA), a high-affinity natural ligand for uPAR. Noscapine (Nos) was efficiently adsorbed onto the amphiphilic polymer coating of uPAR-targeted nanoparticles (NPs). Nos-loaded NPs were uniformly compact-sized, stable at physiological pH and efficiently released the drug at pH 4 to 5 within a span of 4h. Our results demonstrate that these uPAR-targeted NPs were capable of binding to the receptor and were internalized by PC-3 cells. uPAR-targeted Nos-loaded NPs enhanced intracellular noscapine accumulation as evident by the ~6-fold stronger inhibitory effect on PC-3 growth compared to free noscapine. In addition, Nos-loaded iron oxide NPs maintained their T2 MRI contrast effect upon internalization into tumor cells owing to their significant susceptibility effect in cells. Thus, our data provide compelling evidence that these optically and magnetic resonance imaging (MRI)-trackable uPAR-targeted NPs may offer a great potential for image-directed targeted delivery of noscapine for the management of

  2. Robust aptamer–polydopamine-functionalized M-PLGA–TPGS nanoparticles for targeted delivery of docetaxel and enhanced cervical cancer therapy

    Directory of Open Access Journals (Sweden)

    Xu GJ

    2016-06-01

    Full Text Available Guojun Xu,1–3,* Xinghua Yu,2,* Jinxie Zhang,1,2,* Yingchao Sheng,4 Gan Liu,2 Wei Tao,1,2 Lin Mei1,2 1School of Life Sciences, Tsinghua University, Beijing, 2Graduate School at Shenzhen, Tsinghua University, Shenzhen, 3School of Materials Science and Engineering, Tsinghua University, Beijing, 4Department of Orthopedic Surgery, Changshu Hospital of TCM, Changshu, People’s Republic of China *These authors contributed equally to this work Abstract: One limitation of current biodegradable polymeric nanoparticles (NPs is the contradiction between functional modification and maintaining formerly excellent bioproperties with simple procedures. Here, we reported a robust aptamer–polydopamine-functionalized mannitol-functionalized poly(lactide-co-glycolide (M-PLGA–D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS nanoformulation (Apt-pD-NPs for the delivery of docetaxel (DTX with enhanced cervical cancer therapy effects. The novel DTX-loaded Apt-pD-NPs possess satisfactory advantages: 1 increased drug loading content and encapsulation efficiency induced by star-shaped copolymer M-PLGA–TPGS; 2 significant active targeting effect caused by conjugated AS1411 aptamers; and 3 excellent long-term compatibility by incorporation of TPGS. Therefore, with simple preparation procedures and excellent bioproperties, the new functionalized Apt-pD-NPs could maximally increase the local effective drug concentration on tumor sites, achieving enhanced treatment effectiveness and minimizing side effects. In a word, the robust DTX-loaded Apt-pD-NPs could be used as potential nanotherapeutics for cervical cancer treatment, and the aptamer–polydopamine modification strategy could be a promising method for active targeting of cancer therapy with simple procedures. Keywords: dopamine, AS1411 aptamer, active targeting, polymeric NPs, enhanced cervical chemotherapy

  3. Recent Approaches to Platinum(IV) Prodrugs: A Variety of Strategies for Enhanced Delivery and Efficacy.

    Science.gov (United States)

    Najjar, Anas; Rajabi, Naeema; Karaman, Rafik

    2017-01-01

    Intensive efforts have been implemented to improve the efficacy of platinum complexes especially with emerging cisplatin resistance and elevated cancer deaths. Platinum(IV) agents show better pharmacokinetics and decreased side effects compared to Platinum(II) agents. This review aims to summarize and categorize the strategies being employed to improve the efficacy of Platinum-based anticancer agents in recent years. Nanoparticles and nanoplatforms offer a vast variety of strategies in targeting specific tumor types and delivering one or two lethal drugs simultaneously. Theranostic agents are being developed to achieve enhanced imaging and provide further insight into the activity of platinum containing chemotherapy. Moreover, photoactivation of Pt(IV) prodrugs specifically at the tumor site is gaining attention due to a controlled activity. A platinum agent formulated as large multi-activity complex is the most common strategy being employed. Platinum(IV) agents offer great potential in targeting, increasing efficacy, and decreasing toxicity of Platinum-based anticancer agents. The strategies being employed are aiming to increase specificity and targeting as well as provide more potent agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Fundamental mathematical model shows that applied electrical field enhances chemotherapy delivery to tumors.

    Science.gov (United States)

    Moarefian, Maryam; Pascal, Jennifer A

    2016-02-01

    Biobarriers imposed by the tumor microenvironment create a challenge to deliver chemotherapeutics effectively. Electric fields can be used to overcome these biobarriers in the form of electrochemotherapy, or by applying an electric field to tissue after chemotherapy has been delivered systemically. A fundamental understanding of the underlying physical phenomena governing tumor response to an applied electrical field is lacking. Building upon the work of Pascal et al. [1], a mathematical model that predicts the fraction of tumor killed due to a direct current (DC) applied electrical field and chemotherapy is developed here for tumor tissue surrounding a single, straight, cylindrical blood vessel. Results show the typical values of various parameters related to properties of the electrical field, tumor tissue and chemotherapy drug that have the most significant influence on the fraction of tumor killed. We show that the applied electrical field enhances tumor death due to chemotherapy and that the direction and magnitude of the applied electrical field have a significant impact on the fraction of tumor killed. Published by Elsevier Inc.

  5. Thiolated polycarbophil as an adjuvant for permeation enhancement in nasal delivery of antisense oligonucleotides.

    Science.gov (United States)

    Vetter, A; Martien, R; Bernkop-Schnürch, A

    2010-03-01

    The purpose of this study was to investigate the effect of thiolated polycarbophil as an adjuvant to enhance the permeation and improve the stability of a phosphorothioate antisense oligonucleotide (PTO-ODN) on the nasal mucosa. Polycarbophil-cysteine (PCP-Cys) was synthesized by the covalent attachment of L-cysteine to the polymeric backbone. Cytotoxicity tests were examined on human nasal epithelial cells from surgery of nasal polyps confirmed by histological studies. Deoxyribonuclease I activity in respiratory region of the porcine nasal cavity was analyzed by an enzymatic assay. The enzymatic degradation of PTO-ODNs on freshly excised porcine nasal mucosa was analyzed and protection of PCP-cysteine toward DNase I degradation was evaluated. Permeation studies were performed in Ussing-type diffusion chambers. PCP-Cys/GSH did not arise a remarkable mortal effect. Porcine respiratory mucosa was shown to possess nuclease activity corresponding to 0.69 Kunitz units/mL. PTO-ODNs were degraded by incubation with nasal mucosa. In the presence of 0.45% thiolated polycarbophil and 0.5% glutathione (GSH), this degradation process could be lowered. In the presence of thiolated polycarbophil and GSH the uptake of PTO-ODNs from the nasal mucosa was 1.7-fold improved. According to these results thiolated polycarbophil/GSH might be a promising excipient for nasal administration of PTO-ODNs.

  6. A novel thermo-mechanical system enhanced transdermal delivery of hydrophilic active agents by fractional ablation.

    Science.gov (United States)

    Sintov, Amnon C; Hofmann, Maja A

    2016-09-25

    The Tixel is a novel device based on a thermo-mechanical ablation technology that combines a sophisticated motion and a temperature control. The fractional technology is used to transfer a very precise thermal energy to the skin thereby creating an array of microchannels, accompanying by no signs of pain or inconvenience. This study aimed to evaluate the effect of the Tixel on the skin permeability of three hydrophilic molecular models: verapamil hydrochloride, diclofenac sodium, and magnesium ascorbyl phosphate. Tixel's gold-platted stainless steel tip heated to a temperature of 400°C was applied on skin for 8ms or 9ms at a protrusion of 400μm (the distance in which the tip protrudes beyond the distance gauge). The experiments were carried out partly in vivo in humans using a fluorescent dye and a confocal microscopy and partly in vitro using porcine skin and a Franz diffusion cell system. The results obtained in this study have shown that (a) no significant collateral damage to the skin tissue and no necrosis or dermal coagulation have been noted, (b) the microchannels remained open and endured for at least 6h, and (c) the skin permeability of hydrophilic molecules, which poorly penetrate the lipophilic stratum corneum barrier, was significantly enhanced by using Tixel's pretreatment.

  7. Enhanced stability and antibacterial efficacy of a traditional Chinese medicine-mediated silver nanoparticle delivery system.

    Science.gov (United States)

    Sun, Wenjie; Qu, Ding; Ma, Yihua; Chen, Yan; Liu, Congyan; Zhou, Jing

    2014-01-01

    Silver nanoparticles (AgNPs) are widely used as antibacterial products in various fields. Recent studies have suggested that AgNPs need an appropriate stabilizer to improve their stability. Some antibacterial traditional Chinese medicines (TCMs) contain various reductive components, which can not only stabilize AgNPs but also enhance their antimicrobial activity. In this study, we developed a series of novel AgNPs using a TCM extract as a stabilizer, reducing agent, and antimicrobial agent (TCM-AgNPs). A storage stability investigation of the TCM-AgNPs suggested a significant improvement when compared with bare AgNPs. Further, conjugation of TCMs onto the AgNP surface resulted in stronger antimicrobial potency on antibacterial evaluation using Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus with minimum inhibitory concentration 50% (MIC50) ratios (and minimum bactericidal concentration 90% [MBC90] ratios) of AgNPs to respective TCM-AgNPs as assessment indices. Among these, P. cuspidatum Sieb. et-conjugated AgNPs (P.C.-AgNPs) had the advantage of a combination of TCMs and AgNPs and was studied in detail with regard to its synthesis and characterization. The extraction time, reaction temperature, and concentrations of AgNO3 and Polygonum cuspidatum Sieb. et extract were critical factors in the preparation of P.C.-AgNPs. Further, the results of X-ray diffraction and Fourier transform infrared spectroscopy indicated successful preparation of P.C.-AgNPs. In representative studies, P.C.-AgNPs showed a well-defined spherical shape, a homogeneous small particle size (36.78 nm), a narrow polydispersity index (0.105), and a highly negative zeta potential (-23.6 mV) on transmission electron microscopy and dynamic light scattering. These results indicate that TCM-AgNPs have a potential role as antibacterial agents in the clinic setting.

  8. Gd-DTPA T1 relaxivity in brain tissue obtained by convection-enhanced delivery, magnetic resonance imaging and emission spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Haar, Peter J [Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA (United States); Broaddus, William C; Chen Zhijian; Gillies, George T [Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA (United States); Fatouros, Panos P; Corwin, Frank D, E-mail: wbroaddus@mcvh-vcu.ed [Department of Radiology, Virginia Commonwealth University, Richmond, VA (United States)

    2010-06-21

    A common approach to quantify gadolinium (Gd) contrast agents involves measuring the post-contrast change in T1 rate and then using the constant T1 relaxivity R to determine the contrast agent concentration. Because this method is fast and non-invasive, it could be potentially valuable in many areas of brain research. However, to accurately measure contrast agent concentrations in the brain, the T1 relaxivity R of the specific agent must be accurately known. Furthermore, the macromolecular content and compartmentalization of the brain extracellular space (ECS) are expected to significantly alter R from values measured in aqueous solutions. In this study, the T1 relaxivity R of gadolinium-diethylene-triamine penta-acetic acid (Gd-DTPA) was measured following direct interstitial infusions of three different contrast agent concentrations to the parenchyma of rat brains. Changes in magnetic resonance (MR) T1 values were compared to brain slice concentrations determined with inductively coupled plasma atomic emission spectroscopy (ICP-AES) to determine R in 15 rats. Additionally, samples of cerebrospinal fluid, blood and urine were analyzed to evaluate possible Gd-DTPA clearance from the brain. The T1 relaxivity R of Gd-DTPA in the brain ECS was measured to be 5.35 (mM s){sup -1} in a 2.4 T field. This value is considerably higher than estimations used in studies by other groups. Measurements of brain Gd-DTPA tissue concentrations using MRI and ICP-AES demonstrated a high degree of coincidence. Clearance of Gd-DTPA was minimal at the time point immediately after infusion. These results suggest that the environment of the brain does in fact significantly affect Gd T1 relaxivity, and that MRI can accurately measure contrast agent concentrations when this relaxivity is well characterized.

  9. ET-22CONVECTION-ENHANCED DELIVERY OF THE AUGER-ELECTRON-EMITTER 125I-UdR: A HIGHLY EFFICIENT THERAPY IN AN ORTHOTOPIC GLIOBLASTOMA XENOGRAFT MODEL

    OpenAIRE

    Halle, Bo; Thisgaard, Helge; Aaberg-Jessen, Charlotte; Olsen, Birgitte; Dam, Johan; Langkjær, Niels; Munthe, Sune; Någren, Kjell; Høilund-Carlsen, Poul Flemming; Kristensen, Bjarne

    2014-01-01

    BACKGROUND: Glioblastomas (GBMs), the most common and malignant primary brain tumors, always recur after standard treatment. In order to develop more efficient therapies, we tested a novel therapeutic approach using the radioactive Auger-electron-emitter (AEE) [125I]5-Iodo-2'-deoxyuridine (125I-UdR). This drug incorporates into DNA of dividing cells and upon decay emission of Auger-electrons causes clusters of double strand breaks leading to cell death. METHODS: In vitro, cells from two GBM s...

  10. Convection-enhanced delivery of an anti-miR is well-tolerated, preserves anti-miR stability and causes efficient target de-repression

    DEFF Research Database (Denmark)

    Halle, Bo; Marcusson, Eric G; Aaberg-Jessen, Charlotte;

    2016-01-01

    xenograft model and targeted a well-validated miR, let-7a, with a 2'-O-methoxyethyl anti-miR with a combined phosphodiester/phosphorothioate backbone to establish an initial proof of concept. In vitro, anti-let-7a was delivered unassisted to the patient-derived T87 glioblastoma spheroid culture. In vivo...

  11. Chitosan-coated boron nitride nanospheres enhance delivery of CpG oligodeoxynucleotides and induction of cytokines

    Directory of Open Access Journals (Sweden)

    Zhang H

    2013-05-01

    G oligodeoxynucleotides. The loading capacity of the CpG oligodeoxynucleotides depended on the molecular weight of chitosan, which affected the positive charge density on the surface of the BNNS. CpG oligodeoxynucleotides loaded onto BNNS-CS complexes significantly enhanced production of interleukin-6 and tumor necrosis factor-a by peripheral blood mononuclear cells compared with CpG oligodeoxynucleotides directly loaded onto BNNS, or when Lipofectamine™ 2000 was used as the carrier. The molecular weight of the chitosan used to coat the BNNS affected the magnitude of cytokine induction by varying the strength of condensation of the CpG oligodeoxynucleotides. Conclusion: Although the loading capacity of BNNS coated with low molecular weight chitosan preparations was the lowest of all the preparations, they induced the highest levels of cytokines. Keywords: chitosan, boron nitride nanospheres, CpG oligodeoxynucleotides, drug delivery, cytokines

  12. Destabilization of free convection by weak rotation

    CERN Document Server

    Gelfgat, Alexander

    2011-01-01

    This study offers an explanation of a recently observed effect of destabilization of free convective flows by weak rotation. After studying several models where flows are driven by a simultaneous action of convection and rotation, it is concluded that the destabilization is observed in the cases where centrifugal force acts against main convective circulation. At relatively low Prandtl numbers this counter action can split the main vortex into two counter rotating vortices, where the interaction leads to instability. At larger Prandtl numbers, the counter action of the centrifugal force steepens an unstable thermal stratification, which triggers Rayleigh-B\\'enard instability mechanism. Both cases can be enhanced by advection of azimuthal velocity disturbances towards the axis, where they grow and excite perturbations of the radial velocity. The effect was studied considering a combined convective/rotating flow in a cylinder with a rotating lid and a parabolic temperature profile at the sidewall. Next, explana...

  13. Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy.

    Science.gov (United States)

    Talekar, Meghna; Ganta, Srinivas; Amiji, Mansoor; Jamieson, Stephen; Kendall, Jackie; Denny, William A; Garg, Sanjay

    2013-06-25

    PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-α over the other PI3K class Ia isoforms p110-β and p110-δ, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity. In vitro analysis of drug uptake, cell viability and cell survival was conducted in SKOV-3 cells. Drug pharmacokinetics and pAkt expression were determined in SKOV-3 tumor bearing mice. PIK-75 nanosuspensions showed an improvement in dissolution velocity and an 11-fold increase in saturation solubility over pre-milled PIK-75. In vitro studies in SKOV-3 cells indicated a 2-fold improvement in drug uptake and 0.4-fold decrease in IC50 value of PIK-75 following treatment with targeted nanosuspension compared to non-targeted nanosuspension. The improvement in cytotoxicity was attributed to an increase in caspase 3/7 and hROS activity. In vivo studies indicated a 5-10-fold increased PIK-75 accumulation in the tumor with both the nanosuspension formulations compared to PIK-75 suspension. The targeted nanosuspension showed an enhanced downregulation of pAkt compared to non-targeted formulation system. These results illustrate the opportunity to formulate PIK-75 as a targeted nanosuspension to enhance uptake and cytotoxicity of the drug in tumor.

  14. Biomaterial-based regional chemotherapy: Local anticancer drug delivery to enhance chemotherapy and minimize its side-effects.

    Science.gov (United States)

    Krukiewicz, Katarzyna; Zak, Jerzy K

    2016-05-01

    Since the majority of anticancer pharmacological agents affect not only cancer tissue but also normal cells, chemotherapy is usually accompanied with severe side effects. Regional chemotherapy, as the alternative version of conventional treatment, leads to the enhancement of the therapeutic efficiency of anticancer drugs and, simultaneously, reduction of toxic effects to healthy tissues. This paper provides an insight into different approaches of local delivery of chemotherapeutics, such as the injection of anticancer agents directly into tumor tissue, the use of injectable in situ forming drug carriers or injectable platforms in a form of implants. The wide range of biomaterials used as reservoirs of anticancer drugs is described, i.e. poly(ethylene glycol) and its copolymers, polyurethanes, poly(lactic acid) and its copolymers, poly(ɛ-caprolactone), polyanhydrides, chitosan, cellulose, cyclodextrins, silk, conducting polymers, modified titanium surfaces, calcium phosphate based biomaterials, silicone and silica implants, as well as carbon nanotubes and graphene. To emphasize the applicability of regional chemotherapy in cancer treatment, the commercially available products approved by the relevant health agencies are presented. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Bioavailability Enhancement of Paclitaxel via a Novel Oral Drug Delivery System: Paclitaxel-Loaded Glycyrrhizic Acid Micelles

    Directory of Open Access Journals (Sweden)

    Fu-Heng Yang

    2015-03-01

    Full Text Available Paclitaxel (PTX, taxol, a classical antitumor drug against a wide range of tumors, shows poor oral bioavailability. In order to improve the oral bioavailability of PTX, glycyrrhizic acid (GA was used as the carrier in this study. This was the first report on the preparation, characterization and the pharmacokinetic study in rats of PTX-loaded GA micelles The PTX-loaded micelles, prepared with ultrasonic dispersion method, displayed small particle sizes and spherical shapes. Differential scanning calorimeter (DSC thermograms indicated that PTX was entrapped in the GA micelles and existed as an amorphous state. The encapsulation efficiency was about 90%, and the drug loading rate could reach up to 7.90%. PTX-loaded GA micelles displayed a delayed drug release compared to Taxol in the in vitro release experiment. In pharmacokinetic study via oral administration, the area under the plasma concentration-time curve (AUC0→24 h of PTX-loaded GA micelles was about six times higher than that of Taxol (p < 0.05. The significant oral absorption enhancement of PTX from PTX-loaded GA micelles could be largely due to the increased absorption in jejunum and colon intestine. All these results suggested that GA would be a promising carrier for the oral delivery of PTX.

  16. cRGD-Modified Benzimidazole-based pH-Responsive Nanoparticles for Enhanced Tumor Targeted Doxorubicin Delivery.

    Science.gov (United States)

    Liu, Jinjian; Liu, Qian; Yang, Cuihong; Sun, Yu; Zhang, Yumin; Huang, Pingsheng; Zhou, Junhui; Liu, Qiang; Chu, Liping; Huang, Fan; Deng, Liandong; Dong, Anjie; Liu, Jianfeng

    2016-05-04

    Finding a smart cancer drug delivery carrier with long blood circulation, enhanced cancer targeting, and quick drug release in tumors is critical for efficient cancer chemotherapy. Herein, we design a cRGD-polycarboxybetaine methacrylate-b-polybenzimidazole methacrylate (cRGD-PCB-b-PBBMZ) copolymer to self-assemble into smart drug-loaded nanoparticles (cRGD-PCM NPs) which can target αvβ3 integrin overexpressed cancer tissue by cRGD peptide unit and release drug quickly in cancer cells by protonation of benzimidazole groups. The outer PCB layer can resist protein adhesion, and there are only about 10% of proteins in mouse serum adhered to the surface of PCM NPs. With the pKa value of 5.08 of the benzimidazole units, DOX can be released from NPs in pH 5.0 PBS. cRGD-PCM NPs can bring more DOX into HepG2 cells than nontargeting PCM NPs, and there has high DOX release rate in HepG2 cells because of the protonation of benzimidazole groups in endosome and lysosome. MTT assay verifies that higher cellular uptake of DOX causes higher cytotoxicity. Furthermore, the results of ex vivo imaging studies confirm that cRGD-PCM/DOX NPs can successfully deliver DOX into tumor tissue from the injection site. Therefore, the multifunctional cRGD-PCM NPs show great potential as novel nanocarriers for targeting cancer chemotherapy.

  17. Enhanced adenoviral gene delivery to motor and dorsal root ganglion neurons following injection into demyelinated peripheral nerves.

    Science.gov (United States)

    Zhang, Yongjie; Zheng, Yiyan; Zhang, Yi Ping; Shields, Lisa B E; Hu, Xiaoling; Yu, Panpan; Burke, Darlene A; Wang, Heming; Jun, Cai; Byers, Jonathan; Whittemore, Scott R; Shields, Christopher B

    2010-08-15

    Injection of viral vectors into peripheral nerves may transfer specific genes into their dorsal root ganglion (DRG) neurons and motoneurons. However, myelin sheaths of peripheral axons block the entry of viral particles into nerves. We studied whether mild, transient peripheral nerve demyelination prior to intraneural viral vector injection would enhance gene transfer to target DRG neurons and motoneurons. The right sciatic nerve of C57BL/6 mice was focally demyelinated with 1% lysolecithin, and the left sciatic nerve was similarly injected with saline (control). Five days after demyelination, 0.5 microl of Ad5-GFP was injected into both sciatic nerves at the site of previous injection. The effectiveness of gene transfer was evaluated by counting GFP(+) neurons in the DRGs and ventral horns. After peripheral nerve demyelination, there was a fivefold increase in the number of infected DRG neurons and almost a 15-fold increase in the number of infected motoneurons compared with the control, nondemyelinated side. Focal demyelination reduced the myelin sheath barrier, allowing greater virus-axon contact. Increased CXADR expression on the demyelinated axons facilitated axoplasmic viral entry. No animals sustained any prolonged neurological deficits. Increased gene delivery into DRG neurons and motoneurons may provide effective treatment for amyotrophic lateral sclerosis, pain, and spinal cord injury.

  18. Stimuli-responsive protamine-based biodegradable nanocapsules for enhanced bioavailability and intracellular delivery of anticancer agents

    Energy Technology Data Exchange (ETDEWEB)

    Radhakrishnan, Krishna; Thomas, Midhun B.; Pulakkat, Sreeranjini [Indian Institute of Science, Department of Materials Engineering (India); Gnanadhas, Divya P.; Chakravortty, Dipshikha [Indian Institute of Science, Department of Microbiology and Cell Biology (India); Raichur, Ashok M., E-mail: amr@materials.iisc.ernet.in [Indian Institute of Science, Department of Materials Engineering (India)

    2015-08-15

    Enzyme- and pH-responsive polyelectrolyte nanocapsules having diameters in the range of 200 ± 20 nm were fabricated by means of Layer-by-Layer assembly of biopolymers, protamine, and heparin, and then loaded with anticancer drug doxorubicin. The incorporation of the FDA-approved peptide drug protamine as a wall component rendered the capsules responsive to enzyme stimuli. The stimuli-responsive drug release from these nanocapsules was evaluated, and further modulation of capsule permeability to avoid premature release was demonstrated by crosslinking the wall components. The interaction of the nanocapsules with cancer cells was studied using MCF-7 breast cancer cells. These capsules were readily internalized and disintegrated inside the cells, culminating in the release of the loaded doxorubicin and subsequent cell death as observed by confocal microscopy and MTT Assay. The bioavailability studies performed using BALB/c mice revealed that the encapsulated doxorubicin exhibited enhanced bioavailability compared to free doxorubicin. Our results indicate that this stimuli-responsive system fabricated from clinically used FDA-approved molecules and exhibiting minimal premature release has great potential for drug-delivery applications.

  19. Novel mucus-penetrating liposomes as a potential oral drug delivery system: preparation, in vitro characterization, and enhanced cellular uptake

    Science.gov (United States)

    Li, Xiuying; Chen, Dan; Le, Chaoyi; Zhu, Chunliu; Gan, Yong; Hovgaard, Lars; Yang, Mingshi

    2011-01-01

    Background The aim of this study was to investigate the intestinal mucus-penetrating properties and intestinal cellular uptake of two types of liposomes modified by Pluronic F127 (PF127). Methods The two types of liposomes, ie, PF127-inlaid liposomes and PF127-adsorbed liposomes, were prepared by a thin-film hydration method followed by extrusion, in which coumarin 6 was loaded as a fluorescence marker. A modified Franz diffusion cell mounted with the intestinal mucus of rats was used to study the diffusion characteristics of the two types of PF127 liposomes. Cell uptake studies were conducted in Caco-2 cells and analyzed using confocal laser scanning microcopy as well as flow cytometry. Results The diffusion efficiency of the two types of PF127-modified liposomes through intestinal rat mucus was 5–7-fold higher than that of unmodified liposomes. Compared with unmodified liposomes, PF127-inlaid liposomes showed significantly higher cellular uptake of courmarin 6. PF127-adsorbed liposomes showed a lower cellular uptake. Moreover, and interestingly, the two types of PF127-modified liposomes showed different cellular uptake mechanisms in Caco-2 cells. Conclusion PF127-inlaid liposomes with improved intestinal mucus-penetrating ability and enhanced cellular uptake might be a potential carrier candidate for oral drug delivery. PMID:22163166

  20. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.

    Directory of Open Access Journals (Sweden)

    Kuo-Chen Wei

    Full Text Available The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI-monitored focused ultrasound (FUS-induced blood-brain barrier (BBB disruption to enhance Temozolomide (TMZ delivery for improving Glioblastoma Multiforme (GBM treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI, animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.

  1. Co-delivery of docetaxel and bortezomib based on a targeting nanoplatform for enhancing cancer chemotherapy effects.

    Science.gov (United States)

    Nie, Junpeng; Cheng, Wei; Peng, Yunmei; Liu, Gan; Chen, Yuhan; Wang, Xusheng; Liang, Chaoyu; Tao, Wei; Wei, Yinping; Zeng, Xiaowei; Mei, Lin

    2017-11-01

    Using facile polydopamine (PDA)-based surface modification and a pH-sensitive catechol-boronate binding mechanism, a novel drug delivery system was designed for the treatment of breast cancer. The system was able to achieve the following goals: active targeting, pH responsiveness, in vivo blood circulation for a prolonged period of time, and dual drug loading. After coating with PDA, the docetaxel (DTX)-loaded star-shaped copolymer cholic acid-poly(lactide-co-glycolide) nanoparticles (CA-PLGA@PDA/NPs) were functionalized with amino-poly(ethylene glycol)-folic acid (NH2-PEG-FA) and bortezomib (BTZ) to form the targeting composition, DTX-loaded CA-PLGA@PDA-PEG-FA + BTZ/NPs. The novel NPs exhibited similar drug release characteristics compared to unfunctionalized CA-PLGA/NPs. Meanwhile, the incorporated NH2-PEG-FA contributed to active targeting which was illustrated by cellular uptake experiments and biodistribution studies. Moreover, the pH responsive binding between BTZ and PDA was demonstrated to be effective to release BTZ at the tumor acidic environment for synergistic action with DTX. Both in vitro cytotoxicity and in vivo antitumor studies demonstrated that the novel nanoplatform exhibited the most suitable therapeutic effects. Taken together, the versatile PDA modified DTX-loaded CA-PLGA@PDA-PEG-FA + BTZ/NPs offered a promising chemotherapeutic strategy for enhancing breast cancer treatment.

  2. Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil: in vitro evaluation of drug permeation by infrared spectroscopy.

    Science.gov (United States)

    Mura, Simona; Manconi, Maria; Fadda, Anna Maria; Sala, Maria Chiara; Perricci, Jacopo; Pini, Elena; Sinico, Chiara

    2013-01-01

    Recently, we carried out a research on new liposomal systems prepared by using in their composition a few penetration enhancers which differ for chemical structure and physicochemical properties. The penetration enhancer-containing vesicles (PEVs) were prepared by using soy lecithin and different amounts of three penetration enhancers, 2-(2-ethoxyethoxy) ethanol (Transcutol(®)), capryl-caproyl macrogol 8-glyceride (Labrasol(®)), and cineole.To study the influence of the PEVs on (trans)dermal delivery of minoxidil, in vitro diffusion experiments were performed through new born pig skin and the results were compared with that obtained applying the vesicular system without enhancer (control) after pretreatment of the skin with the various enhancers. In this study, Fourier transform infrared spectroscopy (FTIR), attenuated total reflectance FTIR (ATR-FTIR) and FTIR imaging were used to evaluate the effective penetration of minoxidil in the skin layers and to discover the influence of the enhancer on the drug topical delivery. These analytical studies allowed us to characterize the drug formulations and to evaluate the vesicle distribution into the skin. Recorded spectra confirmed that the vesicle formulations with penetration enhancers promoted drug deposition into the skin.

  3. Stochastic Convection Parameterizations

    Science.gov (United States)

    Teixeira, Joao; Reynolds, Carolyn; Suselj, Kay; Matheou, Georgios

    2012-01-01

    computational fluid dynamics, radiation, clouds, turbulence, convection, gravity waves, surface interaction, radiation interaction, cloud and aerosol microphysics, complexity (vegetation, biogeochemistry, radiation versus turbulence/convection stochastic approach, non-linearities, Monte Carlo, high resolutions, large-Eddy Simulations, cloud structure, plumes, saturation in tropics, forecasting, parameterizations, stochastic, radiation-clod interaction, hurricane forecasts

  4. Convection and oscillations

    CERN Document Server

    Houdek, G

    2010-01-01

    In this short review on stellar convection dynamics I address the following, currently very topical, issues: (1) the surface effects of the Reynolds stresses and nonadiabaticity on solar-like pulsation frequencies, and (2) oscillation mode lifetimes of stochastically excited oscillations in red giants computed with different time-dependent convection formulations.

  5. CFD simulations of enhanced condensational growth (ECG) applied to respiratory drug delivery with comparisons to in vitro data

    Science.gov (United States)

    Longest, P. Worth; Hindle, Michael

    2010-01-01

    Enhanced condensational growth (ECG) is a newly proposed concept for respiratory drug delivery in which a submicrometer aerosol is inhaled in combination with saturated or supersaturated water vapor. The initially small aerosol size provides for very low extrathoracic deposition, whereas condensation onto droplets in vivo results in size increase and improved lung retention. The objective of this study was to develop and evaluate a CFD model of ECG in a simple tubular geometry with direct comparisons to in vitro results. The length (29 cm) and diameter (2 cm) of the tubular geometry were representative of respiratory airways of an adult from the mouth to the first tracheobronchial bifurcation. At the model inlet, separate streams of humidified air (25, 30, and 39 °C) and submicrometer aerosol droplets with mass median aerodynamic diameters (MMADs) of 150, 560, and 900 nm were combined. The effects of condensation and droplet growth on water vapor concentrations and temperatures in the continuous phase (i.e., two-way coupling) were also considered. For an inlet saturated air temperature of 39 °C, the two-way coupled numerical (and in vitro) final aerosol MMADs for initial sizes of 150, 560, and 900 nm were 1.75 μm (vs. 1.23 μm), 2.58 μm (vs. 2.66 μm), and 2.65 μm (vs. 2.63 μm), respectively. By including the effects of two-way coupling in the model, agreements with the in vitro results were significantly improved compared with a one-way coupled assumption. Results indicated that both mass and thermal two-way coupling effects were important in the ECG process. Considering the initial aerosol sizes of 560 and 900 nm, the final sizes were most influenced by inlet saturated air temperature and aerosol number concentration and were not largely influenced by initial size. Considering the growth of submicrometer aerosols to above 2 μm at realistic number concentrations, ECG may be an effective respiratory drug delivery approach for minimizing mouth

  6. Estimating the gross moist stability in shallow and deep convection

    Science.gov (United States)

    Chen, C. A.; Jong, B. T.; Chou, C.

    2015-12-01

    Gross moist stability has been used to study the link between tropical deep convection and large scale circulation in a moist static energy (MSE) budget. Here we aim to calculate the gross moist stability from more realistic profiles of vertical velocity and extend it beyond deep convection, adding shallow convection. Based on a principal component analysis, we were able to decompose the vertical velocity into two leading modes, which are dominated by deep and shallow convection, respectively. According to the deep and shallow modes, we calculate the gross moist stability for these two modes and discuss the roles of deep and shallow convection in the MSE budget. The gross moist stability of deep convection tends to be positive in the tropics, while that of shallow convection is negative over most areas of the tropics. This implies that deep convection exports MSE to stabilize the atmosphere and shallow convection imports MSE to enhance deep convection and destabilize the atmosphere. Based on the spatial distribution, moisture tends to reduce the gross moist stability of deep convection, while dry static energy has little impact. Deeper deep convection tends to have greater gross moist stability. For shallow convection, on the other hand, the gross moist stability is affected not only by low-level moisture but also mid-level moisture. Both moister low-level and drier mid-level moisture reduce the gross moist stability of shallow convection. Greater low-level dry static energy, which is associated with warmer sea surface temperature, also tends to reduce gross moist stability.

  7. Effect of Marangoni Convection on Mass Transfer in Liquid Phase

    Institute of Scientific and Technical Information of China (English)

    YU Liming; ZENG Aiwu; YU Kuo Tsung

    2006-01-01

    Marangoni convection and its influence on the mass transfer in the liquid phase were investigated.Marangoni convection was visualized using laser Schlieren technique.Orderly polygonal convection patterns and random interfacial turbulence were observed.The effect of Marangoni convection on the mass transfer rate was studied by desorbing ethanol from aqueous solution in the falling film.The experimental results show that Marangoni convection can speed up the surface renewal and enhance the mass transfer rate in the liquid phase.The liquid mass transfer coefficient can be enhanced by as much as 3 folds.The corresponding empirical correlations are given in terms of the mass transfer enhancement factor.Furthermore,in considering the Marangoni effect,the conventional mass transfer correlation was modified.The differences between the values predicted by the correlation and the experimental data are within ± 8.2% and the average difference is 4.2%.

  8. Electroporation and lipid nanoparticles with cyanine IR-780 and flavonoids as efficient vectors to enhanced drug delivery in colon cancer.

    Science.gov (United States)

    Kulbacka, Julita; Pucek, Agata; Kotulska, Małgorzata; Dubińska-Magiera, Magda; Rossowska, Joanna; Rols, Marie-Pierre; Wilk, Kazimiera Anna

    2016-08-01

    Nanocarriers and electroporation (also named electropermeabilization) are convenient methods to increase drug transport. In the current study, we present an effective support of drug delivery into cancer cells, utilizing these methods. We compare the efficiency of each of them and their combination. Multifunctional solid lipid nanoparticles (SLNs) loaded with a cyanine-type IR-780 - acting as a diagnostic agent and a photosensitizer, and a flavonoid derivative - baicalein (BAI) or fisetin (FIS) as a therapeutic cargo - were fabricated via solvent-diffusion method. A therapy supplemented with flavonoids may provide a more precise method to apply desirable lower drug doses and is more likely to result in lower toxicity and a decrease in tumor growth. The SLNs were stabilized with Phospholipon 90G at various concentrations; cetyl palmitate (CP) was applied as a solid matrix. The obtained nanosystems were characterized by dynamic light scattering (size along with size distribution), UV-vis (cargos encapsulation efficiency) and atomic force microscopy (morphology and shape). The obtained SLNs were used as drug carriers alone and in combination with electropermeabilization induced by millisecond pulsed electric fields of high intensity. Two cell lines were selected for the study: LoVo and CHO-K1. The viability was assessed after electroporation alone, the use of electroporation and nanoparticles, and nanoparticles or drugs alone. The intracellular accumulation of cyanine IR-780 and the impact on intracellular structure organization of cytoskeleton was visualized with confocal microscopy method with alpha-actin and beta-tubulin. In this study, the efficacy of nanoparticles with mixed cargo, additionally enhanced by electroporation, is demonstrated to act as an anticancer modality to eliminate cancer cells.

  9. Synthesis and characterization of insulin/zirconium phosphate@TiO2 hybrid composites for enhanced oral insulin delivery applications.

    Science.gov (United States)

    Safari, Mostafa; Kamari, Younes; Ghiaci, Mehran; Sadeghi-Aliabadi, Hojjat; Mirian, Mina

    2017-05-01

    In this work, a series of composites of insulin (Ins)/zirconium phosphate (ZrP) were synthesized by intercalation method, then, these composites were coated with TiO2 by sol-gel method to prepare Ins/ZrP@TiO2 hybrid composites and the drug release of the composites was investigated by using UV-Vis spectroscopy. Ins/ZrP (10, 30, 60 wt%) composites were prepared by intercalation of insulin into the ZrP layers in water. Then Ins/ZrP composites were coated with different amounts of TiO2 (30, 50, 100 wt %) by using titanium tetra n-butoxide, as precursor. Formation of intercalated Ins/ZrP and Ins/ZrP@TiO2 hybrid composites was characterized by FT-IR, FE-SEM, BET and XRD analysis. Zeta potential of the optimized Ins/ZrP@TiO2 hybrid composite was determined -27.2 mV. Cytotoxic effects of the optimized Ins/ZrP@TiO2 hybrid composite against HeLa and Hek293T cell lines were evaluated using MTT assay and the results showed that designed drug delivery system was not toxic in biological environment. Compared to the Ins/ZrP composites, incorporation of TiO2 coating enhanced the drug entrapment considerably, and reduced the drug release. The Ins/ZrP composites without TiO2 coating released the whole drug after 30 min in pH 7.4 (phosphate buffer solution) while the TiO2-coated composites released the entrapped drug after 20 h. In addition to increasing the shelf life of hormone, this nanoencapsulation and nanocoating method can convert the insulin utilization from injection to oral and present a painless and more comfortable treatment for diabetics.

  10. Hexanoic acid and polyethylene glycol double grafted amphiphilic chitosan for enhanced gene delivery: influence of hydrophobic and hydrophilic substitution degree.

    Science.gov (United States)

    Layek, Buddhadev; Haldar, Manas K; Sharma, Gitanjali; Lipp, Lindsey; Mallik, Sanku; Singh, Jagdish

    2014-03-03

    Gene therapy holds immense potential as a future therapeutic strategy for the treatment of numerous genetic diseases which are incurable to date. Nevertheless, safe and efficient gene delivery remains the most challenging aspects of gene therapy. To overcome this difficulty a series of hexanoic acid (HA) and monomethoxy poly(ethylene glycol) (mPEG) double grafted chitosan-based (HPC) nanomicelles were developed as nonviral gene carrier. HPC polymers with various HA and mPEG substitution degrees were synthesized, and their chemical structures were confirmed by (1)H NMR spectroscopy. HPC nanomicelles exhibited excellent blood compatibility and cell viability, as demonstrated by in vitro hemolysis and MTT assay, respectively. The cationic HPC nanomicelles retained the plasmid DNA (pDNA) binding capacity of chitosan and formed stable HPC/pDNA polyplexes with diameters below 200 nm. Both hydrophobic and hydrophilic substitution resulted in suppressed nonspecific protein adsorption on HPC/pDNA polyplexes and increased pDNA dissociation. However, resistance against DNase I degradation was enhanced by HA conjugation while being inhibited by mPEG substitution. Amphiphilic modification resulted in 3-4.5-fold higher cellular uptake in human embryonic kidney 293 cells (HEK 293) mainly through clathrin-mediated pathway. The optimal HPC/pDNA polyplexes displayed 50-fold and 1.2-fold higher gene transfection compared to unmodified chitosan and Fugene, respectively, in HEK 293 cells. Moreover, both the cellular uptake and in vitro transfection study suggested a clear dependence of gene expression on the extent of HA and mPEG substitution. These findings demonstrate that amphiphilic HPC nanomicelles with the proper combination of HA and mPEG substitution could be used as a promising gene carrier for efficient gene therapy.

  11. Targeted delivery of human VEGF gene via complexes of magnetic nanoparticle-adenoviral vectors enhanced cardiac regeneration.

    Directory of Open Access Journals (Sweden)

    Yue Zhang

    Full Text Available This study assessed the concept of whether delivery of magnetic nanobeads (MNBs/adenoviral vectors (Ad-encoded hVEGF gene (Ad(hVEGF could regenerate ischaemically damaged hearts in a rat acute myocardial infarction model under the control of an external magnetic field. Adenoviral vectors were conjugated to MNBs with the Sulfo-NHS-LC-Biotin linker. In vitro transduction efficacy of MNBs/Ad-encoded luciferase gene (Ad(luc was compared with Ad(luc alone in human umbilical vein endothelial cells (HUVECs under magnetic field stimulation. In vivo, in a rat acute myocardial infarction (AMI model, MNBs/Ad(hVEGF complexes were injected intravenously and an epicardial magnet was employed to attract the circulating MNBs/Ad(hVEGF complexes. In vitro, compared with Ad(luc alone, MNBs/Ad(luc complexes had a 50-fold higher transduction efficiency under the magnetic field. In vivo, epicardial magnet effectively attracted MNBs/Ad(hVEGF complexes and resulted in strong therapeutic gene expression in the ischemic zone of the infarcted heart. When compared to other MI-treated groups, the MI-M(+/Ad(hVEGF group significantly improved left ventricular function (p<0.05 assessed by pressure-volume loops after 4 weeks. Also the MI-M(+/Ad(hVEGF group exhibited higher capillary and arteriole density and lower collagen deposition than other MI-treated groups (p<0.05. Magnetic targeting enhances transduction efficiency and improves heart function. This novel method to improve gene therapy outcomes in AMI treatment offers the potential into clinical applications.

  12. Liposomes containing cholesterol analogues of botanical origin as drug delivery systems to enhance the oral absorption of insulin.

    Science.gov (United States)

    Cui, Meng; Wu, Wei; Hovgaard, Lars; Lu, Yi; Chen, Dawei; Qi, Jianping

    2015-07-15

    In fear of animal-associated diseases, there is a trend in searching for non-animal derived substitutes for existing excipients in the pharmaceutical industries. This paper aimed to screen cholesterol analogues as membrane stabilizers of liposomes from botanical sterols, including β-sitosterol, stigmasterol, ergosterol and lanosterol. Liposomes containing four kinds of sterols were prepared and evaluated in vitro and in vivo as oral delivery system of insulin. Liposomes containing β-sitosterol (Si-Lip), stigmasterol (St-Lip) and lanosterol (La-Lip) was found not to protect insulin against degradation. Only 10% of the initial insulin in liposomes was preserved after a 30 min exposure to simulated gastric fluids. However, the protective ability of liposomes containing ergosterol (Er-Lip) was similar to that of liposomes containing sodium glycocholate (Sgc-Lip) and superior to that of liposomes containing cholesterol (Ch-Lip). In addition, the blood glucose level can decrease to about 50% of initial level after oral Er-Lip which was significantly superior to the in vivo performance of Si-Lip and Ch-Lip and similar to Sgc-Lip. Er-Lips of ergosterol/phospholipids ratios of 1:4 or 1:6 exerts more pronounced protective ability of insulin in simulated gastrointestinal fluids and hypoglycemic effects in rats than other formulations. Furthermore, Er-Lips exerted low toxicity to Caco-2 cells through a cell viability study. Meahwhile, insulin permeability was significantly increased across Caco-2 monolayers by encapsulating in Er-Lip. It was concluded that ergosterol could be used as a substitute for cholesterol and bile salt derivatives in liposomes to enhance oral bioavailability of insulin.

  13. Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery.

    Directory of Open Access Journals (Sweden)

    Ching-Hsiang Fan

    Full Text Available The use of focused ultrasound (FUS with microbubbles has been proven to induce transient blood-brain barrier opening (BBB-opening. However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1-4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

  14. Observing Convective Aggregation

    Science.gov (United States)

    Holloway, Christopher E.; Wing, Allison A.; Bony, Sandrine; Muller, Caroline; Masunaga, Hirohiko; L'Ecuyer, Tristan S.; Turner, David D.; Zuidema, Paquita

    2017-06-01

    Convective self-aggregation, the spontaneous organization of initially scattered convection into isolated convective clusters despite spatially homogeneous boundary conditions and forcing, was first recognized and studied in idealized numerical simulations. While there is a rich history of observational work on convective clustering and organization, there have been only a few studies that have analyzed observations to look specifically for processes related to self-aggregation in models. Here we review observational work in both of these categories and motivate the need for more of this work. We acknowledge that self-aggregation may appear to be far-removed from observed convective organization in terms of time scales, initial conditions, initiation processes, and mean state extremes, but we argue that these differences vary greatly across the diverse range of model simulations in the literature and that these comparisons are already offering important insights into real tropical phenomena. Some preliminary new findings are presented, including results showing that a self-aggregation simulation with square geometry has too broad distribution of humidity and is too dry in the driest regions when compared with radiosonde records from Nauru, while an elongated channel simulation has realistic representations of atmospheric humidity and its variability. We discuss recent work increasing our understanding of how organized convection and climate change may interact, and how model discrepancies related to this question are prompting interest in observational comparisons. We also propose possible future directions for observational work related to convective aggregation, including novel satellite approaches and a ground-based observational network.

  15. In situ formation of nanocrystals from a self-microemulsifying drug delivery system to enhance oral bioavailability of fenofibrate.

    Science.gov (United States)

    Lin, You-Meei; Wu, Jui-Yu; Chen, Ying-Chen; Su, Yu-Der; Ke, Wen-Tin; Ho, Hsiu-O; Sheu, Ming-Thau

    2011-01-01

    In situ formation of nanocrystals and dissolution profiles of fenofibrate (FFB) from a self-microemulsifying drug delivery system (SMEDDS) were characterized. SMEDDS formulated with Myritol and surfactant mixture (Smix) of D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) and either Tween 20 (A, C, E, G, M, S, N, T, O) or Tween 80 (B, D, F, H, P, U, Q, V, R) at various oil/Smix ratios (Group I: A and B of 0.42, C and D of 0.25, E and F of 0.11; Group II: G and H of 1.38, M and P of 1.11, S and U of 0.9, N and Q of 0.73, T and V of 0.58, and O and R of 0.46) and water contents (1: 9.5%, 2: 5.0%, 3: 0.0%, G-V: 4.5%). Their dissolutions were conducted at different rotation speeds. Two optimal SMEDDSs containing Tween 80(B2) or a higher oil/Smix ratio(Q) and B2(solution) were selected for pharmacokinetic study. FFB particles formed within the nanosize range from Group I gradually increased with time but decreased with increasing stirring rates. However, the mean size of FFB formed by B series was as low as 200 nm, which was smaller than that of A series at three stirring rates. The release rate from both groups obviously increased with increasing stirring rate. However, incomplete release was observed for S and N in Tween 20 series, whereas a faster release rate and complete release were observed for Tween 80 series with an insignificant difference among them. Results of pharmacokinetic study demonstrated that the highest-ranked area under the curve and Cmax values were for Q(SMEDDS) and B2(solution), respectively. The relative bioavailability of Q(SMEDDS) with respect to Tricor was enhanced by about 1.14-1.22-fold. SMEDDS, consisting of Myritol 318 and TPGS combined with Tween 80 at 4:1, was able to enhance the oral bioavailability of FFB.

  16. Convective Mixing in Distal Pipes Exacerbates Legionella pneumophila Growth in Hot Water Plumbing

    Directory of Open Access Journals (Sweden)

    William J. Rhoads

    2016-03-01

    Full Text Available Legionella pneumophila is known to proliferate in hot water plumbing systems, but little is known about the specific physicochemical factors that contribute to its regrowth. Here, L. pneumophila trends were examined in controlled, replicated pilot-scale hot water systems with continuous recirculation lines subject to two water heater settings (40 °C and 58 °C and three distal tap water use frequencies (high, medium, and low with two pipe configurations (oriented upward to promote convective mixing with the recirculating line and downward to prevent it. Water heater temperature setting determined where L. pneumophila regrowth occurred in each system, with an increase of up to 4.4 log gene copies/mL in the 40 °C system tank and recirculating line relative to influent water compared to only 2.5 log gene copies/mL regrowth in the 58 °C system. Distal pipes without convective mixing cooled to room temperature (23–24 °C during periods of no water use, but pipes with convective mixing equilibrated to 30.5 °C in the 40 °C system and 38.8 °C in the 58 °C system. Corresponding with known temperature effects on L. pneumophila growth and enhanced delivery of nutrients, distal pipes with convective mixing had on average 0.2 log more gene copies/mL in the 40 °C system and 0.8 log more gene copies/mL in the 58 °C system. Importantly, this work demonstrated the potential for thermal control strategies to be undermined by distal taps in general, and convective mixing in particular.

  17. Diclofenac enables unprecedented week-long microneedle-enhanced delivery of a skin impermeable medication in humans.

    Science.gov (United States)

    Brogden, Nicole K; Banks, Stan L; Crofford, Leslie J; Stinchcomb, Audra L

    2013-08-01

    Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals. The purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans. Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application. Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n = 6), vs. 72 h in Group 2 (placebo + naltrexone, n = 2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores). This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases.

  18. Field synergy theory based convective heat transfer in an enhanced tube with multiple spiral coils%基于场协同的多叶螺旋线圈强化管内对流换热研究

    Institute of Scientific and Technical Information of China (English)

    金光; 王正文; 田瑞; 于晔

    2015-01-01

    To solve the prominent problem of convective heat transfer enhancement in solar collector tubes, experimental investigation on enhancing heat transfer between tube well and medium by copper inserts with double multiple spiral coils and three multiple spiral coils was conducted,by using field synergy theory.The results show that,the convective field synergy number Fc increases sharply with the synergy angle cosine cosβin the multiple spiral coils tubes.Moreover,the velocity field and temperature field also show a good cooperativity.The working fluid with three spiral coils has the best comprehensive heat trans-fer performance,under the condition with constant heat flow (240

  19. Pulsation driving and convection

    Science.gov (United States)

    Antoci, Victoria

    2015-08-01

    Convection in stellar envelopes affects not only the stellar structure, but has a strong impact on different astrophysical processes, such as dynamo-generated magnetic fields, stellar activity and transport of angular momentum. Solar and stellar observations from ground and space have shown that the turbulent convective motion can also drive global oscillations in many type of stars, allowing to study stellar interiors at different evolutionary stages. In this talk I will concentrate on the influence of convection on the driving of stochastic and coherent pulsations across the Hertzsprung-Russell diagram and give an overview of recent studies.

  20. In Vitro and In Vivo Evaluation of a Water-in-Oil Microemulsion System for Enhanced Peptide Intestinal Delivery

    National Research Council Canada - National Science Library

    Liu, Dongyun; Kobayashi, Taku; Russo, Steven; Li, Fengling; Plevy, Scott E; Gambling, Todd M; Carson, Johnny L; Mumper, Russell J

    .... The aim of this work was to develop and evaluate a water-in-oil (w/o) microemulsion system in vitro and in vivo for local intestinal delivery of water-soluble peptides after oral administration...

  1. SELF EMULSIFYING DELIVERY SYSTEM -MOSTLY DISCUSSED BUT STILL REMAINED CHALLENGING ASPECT TO ENHANCE THE ORAL ABSORPTION OF LIPOPHILIC DRUG

    National Research Council Canada - National Science Library

    Niranjan Chivate; Kiran Wadkar; Rohit Shah; Anuradha Chivate

    2016-01-01

    ... in the gastro-intestinal lumen or other aqueous media. Therefore in order to be delivered orally and to achieve acceptable bioavailability, lipophilic drugs require a co-administered drug delivery system...

  2. A REVIEW ON SELF MICRO EMULSIFYING DRUG DELIVERY SYSTEM: AN APPROACH TO ENHANCE THE ORAL BIOAVAILABILITY OF POORLY WATER SOLUBLE DRUGS

    Directory of Open Access Journals (Sweden)

    Shukla Prachi

    2012-09-01

    Full Text Available Technology Catalysts International reported in 2002 that approximately 35-40% of all new chemical compounds suffer from poor aqueous solubility and present a major challenge to modern drug delivery system, because of their low oral bioavailability. Several strategies to improve the solubility and dissolution of poorly water soluble drugs have been developed, which were at start primarily based on modifying the drug’s physicochemical properties. Realization that the oral bioavailability of poor water soluble drugs may be enhanced when co-administered with meal rich in fat has led to increasing recent interest in the formulation of poorly water soluble drugs in lipids. Lipid-based drug delivery systems have gained considerable interest after the commercial success of Sandimmune NeoralTM (Cyclosporine A, Novartis Pvt. Ltd. and Fortovase (Saquinavir, Roche Laboratories Inc. Self micro-emulsifying drug delivery systems are a class of lipid based drug delivery systems. Self micro emulsifying drug delivery systems are isotropic mixtures of oil, surfactant, and co-surfactant and are a vital tool in solving low bioavailability issues of poorly soluble drugs. Lipophilic drugs can be dissolved in these systems, enabling them to be administered as a unit dosage form for per-oral administration. When such a system is released in the lumen of the gastrointestinal tract, it disperses to form a fine w/o microemulsion with the aid of GI fluid. This leads to in situ solubilization of drug that can subsequently be absorbed by lymphatic pathways, bypassing the hepatic first-pass effect. This article represents a complete review on self micro-emulsifying drug delivery system.

  3. Sequential Delivery of BMP-2 and IGF-1 Using a Chitosan Gel with gelatin Microspheres Enhances Early osteoblastic Differentiation

    Science.gov (United States)

    2016-06-07

    including suggestions for reducing this burden, to Washington Headquarters Services , Directorate for Information Operations and Reports, 1215 Jefferson...01 MAY 2012 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with...polymers [5,25 28]. The purpose of this study was to cre ate and characterize a sequential delivery system consisting of a chitosan gel and gelatin

  4. Association with amino acids does not enhance efficacy of polymerized liposomes as a system for lung gene delivery

    OpenAIRE

    Elga eBernardo Bandeira De Melo; Miquéias eLopes-Pacheco; Nadia eChiaramoni; Débora eFerreira; Maria Julieta eFernandez-Ruocco; Maria Jimena ePrieto; Tatiana eMaron-Gutierrez; Perrotta, Ramiro M.; Hugo C Castro-Faria-Neto; Patricia Rieken Macedo Rocco; Silvia del Valle Alonso; Marcelo Marcos Morales

    2016-01-01

    Development of improved drug and gene delivery systems directly into the lungs is highly desirable given the important burden of respiratory diseases. We aimed to evaluate the safety and efficacy of liposomes composed of photopolymerized lipids (1,2-bis-(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine) associated with amino acids as vectors for gene delivery into the lungs of healthy animals. Lipopolymer vesicles, in particular, are more stable than other types of liposomes. In this study,...

  5. Transparent electric convection heater

    OpenAIRE

    Khalid, A.; Luck, J.L.

    2001-01-01

    An optically transparent electrically heated convection heater for use as a space heater in homes, offices, shops. Typically, said convection heater consists of a transparent layer 1 upon which is deposited a layer of a transparent electrically conductive material 2 such as indium-tin-oxide, electrodes 3 and 3a are formed on opposite edges of the transparent electrically conductive layer 2 and electrical wires 4 and 4a are connected to the electrodes. The transparent electrically conductive l...

  6. Convection and convective overshooting in stars more massive than 10 $M_\\odot$

    CERN Document Server

    Jie, Jin; Lv, Guoliang

    2015-01-01

    In this paper, four sets of evolutionary models are computed with different values of the mixing length parameter $\\alpha_{\\rm p}$ and the overshooting parameter $\\delta_{\\rm ov}$. The properties of the convective cores and the convective envelopes are studied in the massive stars. We get three conclusions: First, the larger $\\alpha_{\\rm p}$ leads to enhancing the convective mixing, removing the chemical gradient, and increasing the convective heat transfer efficiency. Second, core potential $\\phi_{\\rm c} = M_{\\rm c} / R_{\\rm c}$ describes sufficiently the evolution of a star, whether it is a red or blue supergiant at central helium ignition. Third, the discontinuity of hydrogen profile above the hydrogen burning shell seriously affect the occurrence of blue loops in the Hertzsprung--Russell diagram.

  7. From convection rolls to finger convection in double-diffusive turbulence

    CERN Document Server

    Yang, Yantao; Lohse, Detlef

    2015-01-01

    Double diffusive convection (DDC), which is the buoyancy driven flow with fluid density depending on two scalar components, is ubiquitous in many natural and engineering enviroments. Of great interests are scalers transfer rate and flow structures. Here we systematically investigate DDC flow between two horizontal plates, driven by an unstable salinity gradient and stabilized by a temperature gradient. Counterintuitively, when increasing the stabilizing temperature gradient, the salinity flux first increases, even though the velocity monotonically decreases, before it finally breaks down to the purely diffusive value. The enhanced salinity transport is traced back to a transition in the overall flow pattern, namely from large scale convection rolls to well-organised vertically-oriented salt fingers. We also show and explain that the unifying theory of thermal convection originally developed by Grossmann and Lohse for Rayleigh-B\\'{e}nard convection can be directly applied to DDC flow for a wide range of contro...

  8. Enhanced delivery and bioactivity of the neurturin neurotrophic factor through focused ultrasound-mediated blood--brain barrier opening in vivo.

    Science.gov (United States)

    Samiotaki, Gesthimani; Acosta, Camilo; Wang, Shutao; Konofagou, Elisa E

    2015-03-31

    The blood-brain barrier (BBB) constitutes a major obstacle in brain drug delivery. Focused ultrasound (FUS) in conjunction with microbubbles has been shown to open the BBB noninvasively, locally, and transiently to allow large molecules diffusion. Neurturin (NTN), a member of the glial-derived neurotrophic factor (GDNF) family, has been demonstrated to have neuroprotective and regenerative effects on dopaminergic neurons in vivo using invasive drug delivery methods. The brain's ascending nigrostriatal pathway is severely damaged in Parkinson's disease (PD), and therefore the substantia nigra (SN) and striatal caudoputamen (CP) were selected as the target areas. The objective of the study was to investigate whether safe and efficient NTN delivery can be achieved through FUS-induced BBB opening via intravenous administration, and thus trigger the neuroregeneration cascade in the nigrostriatal pathway. After the optimization of FUS parameters and target locations in the murine brain, NTN bioavailability and downstream signaling were detected and characterized through immunostaining. FUS significantly enhanced the delivery of NTN compared with the direct injection technique, whereas triggering of the signaling cascade was detected downstream to the neuronal nuclei. These findings thus indicate the potential of the FUS method to mediate transport of proteins through the blood-brain barrier in a PD animal model.

  9. Efficient delivery of C/EBP beta gene into human mesenchymal stem cells via polyethylenimine-coated gold nanoparticles enhances adipogenic differentiation

    Science.gov (United States)

    Joydeep, Das; Choi, Yun-Jung; Yasuda, Hideyo; Han, Jae Woong; Park, Chankyu; Song, Hyuk; Bae, Hojae; Kim, Jin-Hoi

    2016-01-01

    The controlled differentiation of stem cells via the delivery of specific genes encoding appropriate differentiation factors may provide useful models for regenerative medicine and aid in developing therapies for human patients. However, the majority of non-viral vectors are not efficient enough to manipulate difficult-to-transfect adult human stem cells in vitro. Herein, we report the first use of 25 kDa branched polyethylenimine-entrapped gold nanoparticles (AuPEINPs) and covalently bound polyethylenimine-gold nanoparticles (AuMUAPEINPs) as carriers for efficient gene delivery into human mesenchymal stem cells (hMSCs). We determined a functional application of these nanoparticles by transfecting hMSCs with the C/EBP beta gene, fused to EGFP, to induce adipogenic differentiation. Transfection efficacy with AuPEINPs and AuMUAPEINPs was 52.3% and 40.7%, respectively, which was 2.48 and 1.93 times higher than that by using Lipofectamine 2000. Luciferase assay results also demonstrated improved gene transfection efficiency of AuPEINPs/AuMUAPEINPs over Lipofectamine 2000 and polyethylenimine. Overexpression of exogenous C/EBP beta significantly enhanced adipogenesis in hMSCs as indicated by both of Oil Red O staining and mRNA expression analyses. Nanoparticle/DNA complexes exhibited favorable cytocompatibility in hMSCs. Taken together, AuPEINPs and AuMUAPEINPs potentially represent safe and highly efficient vehicles for gene delivery to control hMSC differentiation and for therapeutic gene delivery applications. PMID:27677463

  10. PEGylated dendritic diaminocyclohexyl-platinum (II) conjugates as pH-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy.

    Science.gov (United States)

    Pan, Dayi; She, Wenchuan; Guo, Chunhua; Luo, Kui; Yi, Qiangying; Gu, Zhongwei

    2014-12-01

    Environmentally responsive peptide dendrimers loaded with drugs are suitable candidates for cancer therapy. In this study, we report the preparation and characterization of mPEGylated peptide dendrimer-linked diaminocyclohexyl platinum (II) (dendrimer-DACHPt) conjugates as pH-responsive drug delivery vehicles for tumor suppression in mice. The DACHPt has a molecular structure, is and activity closely related to oxaliplatin and was linked to dendrimer via N,O-chelate coordination. The products were pH-responsive and released drug significantly faster in acidic environments (pH 5.0) than pH 7.4. Consequently, the conjugates suppressed tumor growth better than clinical oxaliplatin(®) without inducing toxicity in an SKOV-3 human ovarian cancer xenograft. Through the systemic delivery of conjugates, 25-fold higher tumor platinum uptake at 36 h post-injection was seen observed due to the enhanced permeability and retention (EPR) effect thereby remarkably enhancing the therapeutic indexes of this small-molecule drug. Thus, the mPEGylated peptide dendrimer-linked DACH-platinum conjugates are novel potential drug delivery systems with implications in future ovarian cancer therapy.

  11. Thermal convection in a liquid metal battery