Comparison of Linear and Hyperbranched Polyether Lipids for Liposome Shielding by 18F-Radiolabeling and Positron Emission Tomography.

Science.gov (United States)

Wagener, Karolin; Worm, Matthias; Pektor, Stefanie; Schinnerer, Meike; Thiermann, Raphael; Miederer, Matthias; Frey, Holger; Rösch, Frank

2018-04-27

Multifunctional and highly biocompatible polyether structures play a key role in shielding liposomes from degradation in the bloodstream, providing also multiple functional groups for further attachment of targeting moieties. In this work hyperbranched polyglycerol ( hbPG) bearing lipids with long alkyl chain anchor are evaluated with respect to steric stabilization of liposomes. The branched polyether lipids possess a hydrophobic bis(hexadecyl)glycerol membrane anchor for the liposomal membrane. hbPG was chosen as a multifunctional alternative to PEG, enabling the eventual linkage of multiple targeting vectors. Different hbPG lipids ( M n = 2900 and 5200 g mol -1 ) were examined. A linear bis(hexadecyl)glycerol-PEG lipid ( M n = 3000 g mol -1 ) was investigated as well, comparing hbPG and PEG with respect to shielding properties. Radiolabeling of the polymers was carried out using 1-azido-2-(2-(2-[ 18 F]fluoroethoxy)ethoxy)ethane ([ 18 F]F-TEG-N) 3 via copper-catalyzed alkyne-azide cycloaddition with excellent radiochemical yields exceeding 95%. Liposomes were prepared by the thin-film hydration method followed by repeated extrusion. Use of a custom automatic extrusion device gave access to reproducible sizes of the liposomes (hydrodynamic radius of 60-94 nm). The in vivo fate of the bis(hexadecyl)glycerol polyethers and their corresponding assembled liposome structures were evaluated via noninvasive small animal positron emission tomography (PET) imaging and biodistribution studies (1 h after injection and 4 h after injection) in mice. Whereas the main uptake of the nonliposomal polyether lipids was observed in the kidneys and in the bladder after 1 h due to rapid renal clearance, in contrast, the corresponding liposomes showed uptake in the blood pool as well as in organs with good blood supply, that is, heart and lung over the whole observation period of 4 h. The in vivo behavior of all three liposomal formulations was comparable, albeit with remarkable

Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial.

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Brain, Etienne G C; Mertens, Cécile; Girre, Véronique; Rousseau, Frédérique; Blot, Emmanuel; Abadie, Sophie; Uwer, Lionel; Bourbouloux, Emmanuelle; Van Praagh-Doreau, Isabelle; Mourey, Loic; Kirscher, Sylvie; Laguerre, Brigitte; Fourme, Emmanuelle; Luneau, Sylvia; Genève, Jean; Debled, Marc

2011-10-01

Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy. In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. This study demonstrates the feasibility of an adjuvant chemotherapy

A phase II study of combination chemotherapy in early relapsed epithelial ovarian cancer using gemcitabine and pegylated liposomal doxorubicin

DEFF Research Database (Denmark)

Mirza, Mansoor Raza; Lund, Bente; Lindegaard, Jacob Christian

2010-01-01

Treatment of epithelial ovarian cancer patients relapsing with a short treatment-free interval (TFI) after prior chemotherapy is unsatisfactory. This phase II trial evaluated the activity and feasibility of pegylated liposomal doxorubicin (PLD) plus gemcitabine in this setting....

FDA Approves Irinotecan Liposome to Treat Pancreatic Cancer

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Patients with metastatic pancreatic cancer that has progressed after receiving gemcitabine-based chemotherapy now have a new treatment option: irinotecan liposome in combination with fluorouracil and leucovorin.

6-mercaptopurine (6-MP) entrapped stealth liposomes for improvement of leukemic treatment without hepatotoxicity and nephrotoxicity.

Science.gov (United States)

Umrethia, Manish; Ghosh, Pradip Kumar; Majithya, Rita; Murthy, R S R

2007-03-01

6-mercaptopurine (6-MP) is a purine analogue used in childhood leukemia. Because of the oral bioavailability of 6-MP is low and highly variable, the aim of this study was to develop a new parenteral formulation that can prolong the biological half-life of the drug, improve its therapeutic efficacy, and its associated reduce side effects. Conventional and stealth 6-MP liposomes were prepared by a thin film hydration technique followed by a high-pressure homogenization process and characterized for percent entrapment efficiency (%EE), particle size, and stability in human plasma. Pharmacokinetic, tissue distribution, and biochemical analysis were performed after intravenous (IV) administration of all formulations of 6-MP on rats. The conventional liposomes were found less stable than stealth liposomes in human plasma at 37 degrees C. Stealth liposomes exhibited high peak plasma concentration (C(max)), and long circulating capacity in blood and biological half-life. The uptake of stealth liposomes by the liver and spleen and accumulation in the kidney were significantly less than that of conventional liposomes and the free drug. Serum urea, creatinine, GOT (Glutamic Oxaloacetic Transaminase), and GPT (Glutamic Pyruvic Transaminase) increased significantly in rats given an IV injection of conventional liposomes and the free drug, but not in those administered with the same dose of stealth liposomes. Stealth liposomes may help to increase therapeutic efficacy of 6-MP and to reduce total amount of dose as well as frequency of the dose. It also may reduce the possibility of the risk of toxicity to the liver and kidney generally associated with free 6-MP.

Bleomycin-Loaded pH-Sensitive Polymer–Lipid-Incorporated Liposomes for Cancer Chemotherapy

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Eiji Yuba

2018-01-01

Full Text Available Cancer chemotherapeutic systems with high antitumor effects and less adverse effects are eagerly desired. Here, a pH-sensitive delivery system for bleomycin (BLM was developed using egg yolk phosphatidylcholine liposomes modified with poly(ethylene glycol-lipid (PEG-PE for long circulation in the bloodstream and 2-carboxycyclohexane-1-carboxylated polyglycidol-having distearoyl phosphatidylethanolamine (CHexPG-PE for pH sensitization. The PEG-PE/CHexPG-PE-introduced liposomes showed content release responding to pH decrease and were taken up by tumor cells at a rate 2.5 times higher than that of liposomes without CHexPG-PE. BLM-loaded PEG-PE/CHexPG-PE-introduced liposomes exhibited comparable cytotoxicity with that of the free drug. Intravenous administration of these liposomes suppressed tumor growth more effectively in tumor-bearing mice than did the free drug and liposomes without CHexPG-PE. However, at a high dosage of BLM, these liposomes showed severe toxicity to the spleen, liver, and lungs, indicating the trapping of liposomes by mononuclear phagocyte systems, probably because of recognition of the carboxylates on the liposomes. An increase in PEG molecular weight on the liposome surface significantly decreased toxicity to the liver and spleen, although toxicity to the lungs remained. Further improvements such as the optimization of PEG density and lipid composition and the introduction of targeting ligands to the liposomes are required to increase therapeutic effects and to reduce adverse effects.

Liposome distribution after intravenous and selective intraarterial infusion in dogs

International Nuclear Information System (INIS)

Wright, K.C.; Kasi, L.P.; Jahns, M.S.; Hashimoto, S.; Wallace, S.

1990-01-01

In an effort to improve hepatic uptake of liposomes for drug delivery, empty vesicles were administered by means of selective arterial infusion. Negatively charged, multilamellar liposomes were labeled with technetium-99m and infused into healthy adult dogs. Each dog received 100 mg/m2 of lipid over 10 minutes at 2 mL/min. Liposomes were administered via the common hepatic artery after proximal occlusion of the gastroduodenal artery, via the cranial mesenteric artery, and via the cephalic vein. Distribution (liver, spleen, and lungs) was determined by computer-assisted external imaging techniques. On the average, after arterial infusion, 69.2% of the total activity was located in the liver, 3.6% in the spleen, 3.2% in the lungs, and 3.5% in the general circulation. Following venous injection, 50.7% of the radioactivity was found in the liver, 9.1% in the spleen, 8.6% in the lungs, and 6.7% in the peripheral blood. Once the liposomes entered the systemic circulation, they were cleared at the same rate (half-life beta = 21.5 hours) independent of their route of administration. Increased hepatic liposome uptake should translate into higher local and lower systemic liposomal drug levels

A nanomedicine based combination therapy based on QLPVM peptide functionalized liposomal tamoxifen and doxorubicin against Luminal A breast cancer.

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Wang, Xiaoyou; Chen, Xianhui; Yang, Xiucong; Gao, Wei; He, Bing; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Dai, Zhifei; Zhang, Qiang

2016-02-01

Though combination chemotherapy or antitumor nanomedicine is extensively investigated, their combining remains in infancy. Additionally, enhanced delivery of estrogen or its analogs to tumor with highly-expressed estrogen-receptor (ER) is seldom considered, despite its necessity for ER-positive breast cancer treatment. Here, nanomedicine based combination therapy using QLPVM conjugated liposomal tamoxifen (TAM) and doxorubicin (DOX) was designed and testified, where the penta-peptide was derived from Ku70 Bax-binding domain. Quantitative, semi-quantitative and qualitative approaches demonstrated the enhanced endocytosis and cytotoxicity of QLPVM conjugated sterically stabilized liposomes (QLPVM-SSLs) in vitro and in vivo. Mechanism studies of QLPVM excluded the possible electrostatic, hydrophobic or receptor-ligand interactions. However, as a weak cell-penetrating peptide, QLPVM significantly induced drug release from QLPVM-SSLs during their interaction with cells, which was favorable for drug internalization. These findings suggested that the nanomedicine based combination therapy using QLPVM-SSL-TAM and QLPVM-SSL-DOX might provide a rational strategy for Luminal A breast cancer. Breast cancer remains a leading cause of mortality in women worldwide. Although combined therapy using hormonal antagonist and chemotherapy is the norm nowadays, the use of these agents together in a single delivery system has not been tested. Here, the authors investigated this approach using QLPVM conjugated liposomes in in-vitro and in-vivo models. The positive findings may provide a novel direction for breast cancer treatment in the near future. Copyright © 2015 Elsevier Inc. All rights reserved.

From conventional to stealth liposomes: a new frontier in cancer chemotherapy.

Science.gov (United States)

Cattel, Luigi; Ceruti, Maurizio; Dosio, Franco

2003-01-01

Many attempts have been made to achieve good selectivity to targeted tumor cells by preparing specialized carrier agents that are therapeutically profitable for anticancer therapy. Among these, liposomes are the most studied colloidal particles thus far applied in medicine and in particular in antitumor therapy. Although they were first described in the 1960s, only at the beginning of 1990s did the first therapeutic liposomes appear on the market. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome (Nexstar, Boulder, CO, USA), used as an antifungal drug, and Myocet (Elan Pharma Int, Princeton, NJ, USA), a doxorubicin-containing liposome, used in clinical trials to treat metastatic breast cancer. The second-generation liposomes ("pure lipid approach") were long-circulating liposomes, such as Daunoxome, a daunorubicin-containing liposome approved in the US and Europe to treat AIDS-related Kaposi's sarcoma. The third-generation liposomes were surface-modified liposomes with gangliosides or sialic acid, which can evade the immune system responsible for removing liposomes from circulation. The fourth-generation liposomes, pegylated liposomal doxorubicin, were called "stealth liposomes" because of their ability to evade interception by the immune system, in the same way as the stealth bomber was able to evade radar. Actually, the only stealth liposome on the market is Caelyx/Doxil (Schering-Plough, Madison NJ, USA), used to cure AIDS-related Kaposi's sarcoma, resistant ovarian cancer and metastatic breast cancer. Pegylated liposomal doxorubicin is characterized by a very long-circulation half-life, favorable pharmacokinetic behavior and specific accumulation in tumor tissues. These features account for the much lower toxicity shown by Caelyx in comparison to free doxorubicin, in terms of cardiotoxicity, vesicant effects, nausea, vomiting and alopecia. Pegylated liposomal doxorubicin also appeared to be less

Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

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Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

2017-05-01

Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

Catalase-loaded cisplatin-prodrug-constructed liposomes to overcome tumor hypoxia for enhanced chemo-radiotherapy of cancer.

Science.gov (United States)

Zhang, Rui; Song, Xuejiao; Liang, Chao; Yi, Xuan; Song, Guosheng; Chao, Yu; Yang, Yu; Yang, Kai; Feng, Liangzhu; Liu, Zhuang

2017-09-01

Aiming at improved therapeutic efficacies, the combination of chemotherapy and radiotherapy (chemo-radiotherapy) has been widely studied and applied in clinic. However, the hostile characteristics of tumor microenvironment such as hypoxia often limit the efficacies in both types of cancer therapies. Herein, catalase (CAT), an antioxidant enzyme, is encapsulated inside liposomes constituted by cisplatin (IV)-prodrug-conjugated phospholipid, forming CAT@Pt (IV)-liposome for enhanced chemo-radiotherapy of cancer. After being loaded inside liposomes, CAT within CAT@Pt (IV)-liposome shows retained and well-protected enzyme activity, and is able to trigger decomposition of H 2 O 2 produced by tumor cells, so as to produce additional oxygen for hypoxia relief. As the result, treatment of CAT@Pt (IV)-liposome induces the highest level of DNA damage in cancer cells after X-ray radiation compared to the control groups. In vivo tumor treatment further demonstrates a remarkably improved therapeutic outcome in chemo-radiotherapy with such CAT@Pt (IV)-liposome nanoparticles. Hence, an exquisite type of liposome-based nanoparticles is developed in this work by integrating cisplatin-based chemotherapy and catalase-induced tumor hypoxia relief together for combined chemo-radiotherapy with great synergistic efficacy, promising for clinical translation in cancer treatment. Copyright © 2017. Published by Elsevier Ltd.

PET imaging of liposomes labeled with an [¹⁸F]-fluorocholesteryl ether probe prepared by automated radiosynthesis

DEFF Research Database (Denmark)

Jensen, Andreas Tue Ingemann; Binderup, Tina; Andresen, Thomas Lars

2012-01-01

, was observed, corresponding to expected liposomal pharmacokinetics. The tumor accumulation 8 hours postinjection accounted for 2.25 +/- 0.23 (mean +/- standard error of the mean) percent of injected dose per gram (%ID/g), and the tumor-to-muscle ratio reached 2.20 +/- 0.24 after 8 hours, which...... is satisfactorily high for visualization of pathological lesions. Moreover, the blood concentration was still at a high level (13.9 +/- 1.5 %ID/g) at the end of the 8-hour time frame. The present work demonstrates the methodology for automated preparation of radiolabeled liposomes, and shows that [F-18]-labeled...... extrusion through 100-nm filters. The [F-18]-labeled liposomes were injected into nude, tumor-bearing mice, and positron emission tomography (PET) scans were performed several times over 8 hours to investigate the in vivo biodistribution. Clear tumor accumulation, as well as hepatic and splenic uptake...

Reversing multidrug resistance in Caco-2 by silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL using liposomal antisense oligonucleotides.

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Yu-Li Lo

Full Text Available Multidrug resistance (MDR is a major impediment to chemotherapy. In the present study, we designed antisense oligonucleotides (ASOs against MDR1, MDR-associated protein (MRP1, MRP2, and/or BCL-2/BCL-xL to reverse MDR transporters and induce apoptosis, respectively. The cationic liposomes (100 nm composed of N-[1-(2,3-dioleyloxypropyl]-n,n,n-trimethylammonium chloride and dioleoyl phosphotidylethanolamine core surrounded by a polyethylene glycol (PEG shell were prepared to carry ASOs and/or epirubicin, an antineoplastic agent. We aimed to simultaneously suppress efflux pumps, provoke apoptosis, and enhance the chemosensitivity of human colon adenocarcinoma Caco-2 cells to epirubicin. We evaluated encapsulation efficiency, particle size, cytotoxicity, intracellular accumulation, mRNA levels, cell cycle distribution, and caspase activity of these formulations. We found that PEGylated liposomal ASOs significantly reduced Caco-2 cell viability and thus intensified epirubicin-mediated apoptosis. These formulations also decreased the MDR1 promoter activity levels and enhanced the intracellular retention of epirubicin in Caco-2 cells. Epirubicin and ASOs in PEGylated liposomes remarkably decreased mRNA expression levels of human MDR1, MRP1, MRP2, and BCL-2. The combined treatments all significantly increased the mRNA expressions of p53 and BAX, and activity levels of caspase-3, -8, and -9. The formulation of epirubicin and ASOs targeting both pump resistance of MDR1, MRP1, and MRP2 and nonpump resistance of BCL-2/BCL-xL demonstrated more superior effect to all the other formulations used in this study. Our results provide a novel insight into the mechanisms by which PEGylated liposomal ASOs against both resistance types act as activators to epirubicin-induced apoptosis through suppressing MDR1, MRP1, and MRP2, as well as triggering intrinsic mitochondrial and extrinsic death receptor pathways. The complicated regulation of MDR highlights the necessity

Enzyme sensitive liposomes in chemotherapy and potentiation of immunotherapy

DEFF Research Database (Denmark)

Østrem, Ragnhild Garborg

efficacy and induction of severe adverse effects. Interestingly, the pharmacokinetics and biodistribution of drugs can be substantially altered by encapsulation in liposomal drug delivery vehicles. The first chapter of this thesis gives a brief introduction to cancer followed by a discussion...... of the applicability of liposomes as drug delivery vehicles in cancer therapy. The second chapter describes the development of a liposome system with an inbuilt release mechanism triggered by secretory phospholipase A2 (sPLA2). This enzyme is expressed at elevated levels in many human cancers, and as such represents...... with an introduction to the cancer-immunity cycle and to how treatment approaches can aid this interplay. Subsequently it demonstrates that the presence of a functional immune system is important in the efficacy of liposomal oxaliplatin, and that this efficacy can be substantially enhanced by combination with...

Near-infrared light activation of quenched liposomal Ce6 for synergistic cancer phototherapy with effective skin protection.

Science.gov (United States)

Feng, Liangzhu; Tao, Danlei; Dong, Ziliang; Chen, Qian; Chao, Yu; Liu, Zhuang; Chen, Meiwan

2017-05-01

Current photodynamic therapy (PDT) is suffering from limited efficacy towards hypoxia tumors and severe post-treatment photo-toxicity such as light-induced skin damages. To make PDT more effective in cancer treatment while being patient-comfortable, herein, a hexylamine conjugated chlorin e6 (hCe6) as the photosensitizer together with a lipophilic near-infrared (NIR) dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) are co-encapsulated into polyethylene glycol (PEG) shelled liposomes. In the obtained DiR-hCe6-liposome, the photosensitizing effect of hCe6 is quenched by DiR via fluorescence resonance energy transfer (FRET). Interestingly, upon irradiation with a 785-nm NIR laser to photobleach DiR, both fluorescence and photodynamic effect of hCe6 in DiR-hCe6-liposome would be activated. Meanwhile, such NIR irradiation applied on tumors of mice with intravenous injection of DiR-hCe6-liposome could result in mild photothermal heating, which in turn would promote intra-tumor blood flow and relieve tumor hypoxia, contributing to the enhanced photodynamic tumor treatment. Importantly, compared to hCe6-loaded liposomes, DiR-hCe6-liposome without being activated by the 785-nm laser shows much lower skin photo-toxicity, demonstrating its great skin protection effect. This work demonstrates a promising yet simple strategy to prepare NIR-light-activatable photodynamic theranostics for synergistic cancer phototherapy, which is featured high specificity/efficacy in tumor treatment with minimal photo-toxicity towards the skin. Copyright © 2016. Published by Elsevier Ltd.

The antitumor activity of a doxorubicin loaded, iRGD-modified sterically-stabilized liposome on B16-F10 melanoma cells: in vitro and in vivo evaluation

Directory of Open Access Journals (Sweden)

Yu KF

2013-07-01

Full Text Available Ke-Fu Yu,1 Wei-Qiang Zhang,1 Li-Min Luo,1 Ping Song,1 Dan Li,1 Ruo Du,1 Wei Ren,1 Dan Huang,1 Wan-Liang Lu,1,2 Xuan Zhang,1 Qiang Zhang1,2 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China Abstract: Considering the fact that iRGD (tumor-homing peptide demonstrates tumor-targeting and tumor-penetrating activity, and that B16-F10 (murine melanoma cells overexpress both αv integrin receptor and neuropilin-1 (NRP-1, the purpose of this study was to prepare a novel doxorubicin (DOX-loaded, iRGD-modified, sterically-stabilized liposome (SSL (iRGD-SSL-DOX in order to evaluate its antitumor activity on B16-F10 melanoma cells in vitro and in vivo. The iRGD-SSL-DOX was prepared using a thin-film hydration method. The characteristics of iRGD-SSL-DOX were evaluated. The in vitro leakage of DOX from iRGD-SSL-DOX was tested. The in vitro tumor-targeting and tumor-penetrating characteristics of iRGD-modified liposomes on B16-F10 cells were investigated. The in vivo tumor-targeting and tumor-penetrating activities of iRGD-modified liposomes were performed in B16-F10 tumor-bearing nude mice. The antitumor effect of iRGD-SSL-DOX was evaluated in B16-F10 tumor-bearing C57BL/6 mice in vivo. The average particle size of the iRGD-SSL-DOX was found to be 91 nm with a polydispersity index (PDI of 0.16. The entrapment efficiency of iRGD-SSL-DOX was 98.36%. The leakage of DOX from iRGD-SSL-DOX at the 24-hour time point was only 7.5%. The results obtained from the in vitro flow cytometry and confocal microscopy, as well as in vivo biodistribution and confocal immunofluorescence microscopy experiments, indicate that the tumor-targeting and tumor-penetrating activity of the iRGD-modified SSL was higher than that of unmodified SSL. In vivo antitumor activity

HPLC method for determination of SN-38 content and SN-38 entrapment efficiency in a novel liposome-based formulation, LE-SN38.

Science.gov (United States)

Xuan, Tong; Zhang, J Allen; Ahmad, Imran

2006-05-03

A simple HPLC method was developed for quantification of SN-38, 7-ethyl-10-hydroxycamptothecin, in a novel liposome-based formulation (LE-SN38). The chromatographic separation was achieved on an Agilent Zorbax SB-C18 (4.6 mmx250 mm, 5 microm) analytical column using a mobile phase consisting of a mixture of NaH2PO4 (pH 3.1, 25 mM) and acetonitrile (50:50, v/v). SN-38 was detected at UV wavelength of 265 nm and quantitatively determined using an external calibration method. The limit of detection (LOD) and limit of quantitation (LOQ) were found to be 0.05 and 0.25 microg/mL, respectively. The individual spike recovery of SN-38 ranged from 100 to 101%. The percent of relative standard deviation (%R.S.D.) of intra-day and inter-day analyses were less than 1.6%. The method validation results confirmed that the method is specific, linear, accurate, precise, robust and sensitive for its intended use. The current method was successfully applied to the determination of SN-38 content and drug entrapment efficiency in liposome-based formulation, LE-SN38 during early stage formulation development.

Liposomes derivatized with multimeric copies of KCCYSL peptide as targeting agents for HER-2-overexpressing tumor cells

Directory of Open Access Journals (Sweden)

Ringhieri P

2017-01-01

Full Text Available Paola Ringhieri,1 Silvia Mannucci,2 Giamaica Conti,2 Elena Nicolato,2 Giulio Fracasso,3 Pasquina Marzola,4 Giancarlo Morelli,1 Antonella Accardo1 1Department of Pharmacy and Interuniversity Research Centre on Bioactive Peptides (CIRPeB, University of Naples “Federico II”, Napoli, 2Department of Neurological Biomedical and Movement Sciences, 3Section of Immunology, Department of Medicine, 4Department of Informatics, University of Verona, Verona, Italy Abstract: Mixed liposomes, obtained by coaggregation of 1,2-dioleoyl-sn-glycero-3-phosphocholine and of the synthetic monomer containing a gadolinium complex ([C18]2DTPA[Gd] have been prepared. Liposomes externally decorated with KCCYSL (P6.1 peptide sequence in its monomeric, dimeric, and tetrameric forms are studied as target-selective delivery systems toward cancer cells overexpressing human epidermal growth factor receptor-2 (HER-2 receptors. Derivatization of liposomal surface with targeting peptides is achieved using the postmodification method: the alkyne-peptide derivative Pra-KCCYSL reacts, through click chemistry procedures, with a synthetic surfactant modified with 1, 2, or 4 azido moieties previously inserted in liposome formulation. Preliminary in vitro data on MDA-MB-231 and BT-474 cells indicated that liposomes functionalized with P6.1 peptide in its tetrameric form had better binding to and uptake into BT-474 cells compared to liposomes decorated with monomeric or dimeric versions of the P6.1 peptide. BT-474 cells treated with liposomes functionalized with the tetrameric form of P6.1 showed high degree of liposome uptake, which was comparable with the uptake of anti-HER-2 antibodies such as Herceptin. Moreover, magnetic MRI experiments have demonstrated the potential of liposomes to act as MRI contrast agents. Keywords: anti-HER2 liposomes, target peptide, KCCYSL peptide, breast cancer, click chemistry, branched peptides 

Therapeutic efficacy of the combination of doxorubicin-loaded liposomes with inertial cavitation generated by confocal ultrasound in AT2 Dunning rat tumour model.

Science.gov (United States)

Mestas, Jean-Louis; Fowler, R Andrew; Evjen, Tove J; Somaglino, Lucie; Moussatov, Alexei; Ngo, Jacqueline; Chesnais, Sabrina; Røgnvaldsson, Sibylla; Fossheim, Sigrid L; Nilssen, Esben A; Lafon, Cyril

2014-09-01

The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for the enhancement of drug delivery in a rat tumour model. The liposomes, based on the unsaturated phospholipid dierucoylphosphocholine, were designed to be stable during blood circulation in order to maximize accumulation in tumour tissue and to release drug content upon US stimulation. A confocal US setup was developed for delivering inertial cavitation to tumours in a well-controlled and reproducible manner. In vitro studies confirm drug release from liposomes as a function of inertial cavitation dose, while in vivo pharmacokinetic studies show long blood circulation times and peak tumour accumulation at 24-48 h post intravenous administration. Animals injected 6 mg kg(-1) liposomal DXR exposed to US treatment 48 h after administration show significant tumour growth delay compared to control groups. A liposomal DXR dose of 3 mg kg(-1), however, did not induce any significant therapeutic response. This study demonstrates that inertial cavitation can be generated in such a fashion as to disrupt drug carrying liposomes which have accumulated in the tumour, and thereby increase therapeutic effect with a minimum direct effect on the tissue. Such an approach is an important step towards a therapeutic application of cavitation-induced drug delivery and reduced chemotherapy toxicity.

Thermosensitive liposomal drug delivery systems: state of the art review

Directory of Open Access Journals (Sweden)

Kneidl B

2014-09-01

Full Text Available Barbara Kneidl,1,2 Michael Peller,3 Gerhard Winter,2 Lars H Lindner,1 Martin Hossann11Department of Internal Medicine III, University Hospital Munich, 2Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, 3Institute for Clinical Radiology, University Hospital Munich, Ludwig-Maximilians University, Munich, GermanyAbstract: Thermosensitive liposomes are a promising tool for external targeting of drugs to solid tumors when used in combination with local hyperthermia or high intensity focused ultrasound. In vivo results have demonstrated strong evidence that external targeting is superior over passive targeting achieved by highly stable long-circulating drug formulations like PEGylated liposomal doxorubicin. Up to March 2014, the Web of Science listed 371 original papers in this field, with 45 in 2013 alone. Several formulations have been developed since 1978, with lysolipid-containing, low temperature-sensitive liposomes currently under clinical investigation. This review summarizes the historical development and effects of particular phospholipids and surfactants on the biophysical properties and in vivo efficacy of thermosensitive liposome formulations. Further, treatment strategies for solid tumors are discussed. Here we focus on temperature-triggered intravascular and interstitial drug release. Drug delivery guided by magnetic resonance imaging further adds the possibility of performing online monitoring of a heating focus to calculate locally released drug concentrations and to externally control drug release by steering the heating volume and power. The combination of external targeting with thermosensitive liposomes and magnetic resonance-guided drug delivery will be the unique characteristic of this nanotechnology approach in medicine.Keywords: thermosensitive liposomes, phosphatidyloligoglycerol, hyperthermia, high intensity focused ultrasound, drug delivery, drug targeting

Application of multifunctional targeting epirubicin liposomes in the treatment of non-small-cell lung cancer

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Song X

2017-10-01

Full Text Available Xiao-li Song,1 Rui-jun Ju,2 Yao Xiao,1 Xin Wang,1 Shuang Liu,1 Min Fu,1 Jing-jing Liu,1 Li-yan Gu,1 Xue-tao Li,1 Lan Cheng1 1School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 2Department of Pharmaceutical Engineering, Beijing Institute of Petrochemical Technology, Beijing, China Abstract: Chemotherapy for aggressive non-small-cell lung cancer (NSCLC usually results in a poor prognosis due to tumor metastasis, vasculogenic mimicry (VM channels, limited killing of tumor cells, and severe systemic toxicity. Herein, we developed a kind of multifunctional targeting epirubicin liposomes to enhance antitumor efficacy for NSCLC. In the liposomes, octreotide was modified on liposomal surface for obtaining a receptor-mediated targeting effect, and honokiol was incorporated into the lipid bilayer for inhibiting tumor metastasis and eliminating VM channels. In vitro cellular assays showed that multifunctional targeting epirubicin liposomes not only exhibited the strongest cytotoxic effect on Lewis lung tumor cells but also showed the most efficient inhibition on VM channels. Action mechanism studies showed that multifunctional targeting epirubicin liposomes could downregulate PI3K, MMP-2, MMP-9, VE-Cadherin, and FAK and activate apoptotic enzyme caspase 3. In vivo results exhibited that multifunctional targeting epirubicin liposomes could accumulate selectively in tumor site and display an obvious antitumor efficacy. In addition, no significant toxicity of blood system and major organs was observed at a test dose. Therefore, multifunctional targeting epirubicin liposomes may provide a safe and efficient therapy strategy for NSCLC. Keywords: octreotide, honokiol, chemotherapy, vasculogenic mimicry, tumor metastasis, targeting drug delivery

Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer

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Bai F

2018-03-01

Full Text Available Fang Bai,1–3,* You Yin,4,* Ting Chen,1,* Jihui Chen,1 Meixin Ge,2 Yunshu Lu,2 Fangyuan Xie,5 Jian Zhang,1 Kejin Wu,3 Yan Liu1,6 1Department of Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 2Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 3Department of Breast Surgery, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 4Department of Neurology, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 6Department of Pharmacy, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: Breast cancer is the most common cancer among women. Pemetrexed, a new generation antifolate drug, is one of the primary treatments for breast cancer. However, multidrug resistance (MDR in breast cancer greatly hampers the therapeutic efficacy of chemotherapies such as pemetrexed. Nanomedicine is emerging as a promising alternative technique to overcome cancer MDR. Thus, pemetrexed-loaded d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS liposomes (liposomal pemetrexed were developed as a strategy to overcome MDR to pemetrexed in breast cancer. Materials and methods: Liposomal pemetrexed was developed using the calcium acetate gradient method. The cytotoxic effects, apoptosis-inducing activity, in vivo distribution, and antitumor activity of liposomal pemetrexed were investigated. Results: Liposomal pemetrexed was small in size (160.77 nm, with a small polydispersity of <0.1. The encapsulation efficacy of liposomal pemetrexed was 63.5%, which is rather high for water-soluble drugs in liposomes. The IC50 of liposomal pemetrexed following treatment with MDR breast cancer cells (MCF-7 cells overexpressing ABCC5

Concurrent Liposomal Cisplatin (Lipoplatin), 5-Fluorouracil and Radiotherapy for the Treatment of Locally Advanced Gastric Cancer: A Phase I/II Study

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Koukourakis, Michael I.; Giatromanolaki, Alexandra; Pitiakoudis, Michael; Kouklakis, George; Tsoutsou, Pelagia; Abatzoglou, Ioannis; Panteliadou, Marianthi; Sismanidou, Kyriaki M.Sc.; Sivridis, Efthimios; Boulikas, Teni

2010-01-01

Purpose: Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. We investigated the feasibility of the combination of 5-fluorouracil/lecovorin-based radio-chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin TM ). Methods and Materials: Lipoplatin was given at a dose of 120mg/m 2 /week, 5-fluorouracil at 400mg/m 2 /week (Day 1), whereas radiotherapy was given through 3.5-Gy fractions on Days 2, 3, and 4. Two groups of 6 patients received four and five consecutive cycles, respectively. Results: Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3) was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or intestinal severe acute or late sequellae were documented, although the median follow-up of 9 months is certainly too low to allow safe conclusions. A net improvement in the performance status (from a median of 1 to 0) was recorded 2 months after the end of therapy. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles. Conclusions: Lipoplatin radio-chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio-chemotherapy setting for the treatment of gastric cancer.

Concurrent liposomal cisplatin (Lipoplatin), 5-fluorouracil and radiotherapy for the treatment of locally advanced gastric cancer: a phase I/II study.

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Koukourakis, Michael I; Giatromanolaki, Alexandra; Pitiakoudis, Michael; Kouklakis, George; Tsoutsou, Pelagia; Abatzoglou, Ioannis; Panteliadou, Marianthi; Sismanidou, Kyriaki; Sivridis, Efthimios; Boulikas, Teni

2010-09-01

Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. We investigated the feasibility of the combination of 5-fluorouracil/lecovorin-based radio-chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin). Lipoplatin was given at a dose of 120 mg/m(2)/week, 5-fluorouracil at 400mg/m(2)/week (Day 1), whereas radiotherapy was given through 3.5-Gy fractions on Days 2, 3, and 4. Two groups of 6 patients received four and five consecutive cycles, respectively. Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3) was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or intestinal severe acute or late sequellae were documented, although the median follow-up of 9 months is certainly too low to allow safe conclusions. A net improvement in the performance status (from a median of 1 to 0) was recorded 2 months after the end of therapy. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles. Lipoplatin radio-chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio-chemotherapy setting for the treatment of gastric cancer. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Copper-64 labeled liposomes for imaging bone marrow

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Lee, Sang-gyu; Gangangari, Kishore; Kalidindi, Teja Muralidhar; Punzalan, Blesida; Larson, Steven M.; Pillarsetty, Naga Vara Kishore

2016-01-01

Introduction: Bone marrow is the soft tissue compartment inside the bones made up of hematopoietic cells, adipocytes, stromal cells, phagocytic cells, stem cells, and sinusoids. While [ 18 F]-FLT has been utilized to image proliferative marrow, to date, there are no reports of particle based positron emission tomography (PET) imaging agents for imaging bone marrow. We have developed copper-64 labeled liposomal formulation that selectively targets bone marrow and therefore serves as an efficient PET probe for imaging bone marrow. Methods: Optimized liposomal formulations were prepared with succinyl PE, DSPC, cholesterol, and mPEG-DSPE (69:39:1:10:0.1) with diameters of 90 and 140 nm, and were doped with DOTA-Bn-DSPE for stable 64 Cu incorporation into liposomes. Results: PET imaging and biodistribution studies with 64 Cu-labeled liposomes indicate that accumulation in bone marrow was as high as 15.18 ± 3.69%ID/g for 90 nm liposomes and 7.01 ± 0.92%ID/g for 140 nm liposomes at 24 h post-administration. In vivo biodistribution studies in tumor-bearing mice indicate that the uptake of 90 nm particles is approximately 0.89 ± 0.48%ID/g in tumor and 14.22 ± 8.07%ID/g in bone marrow, but respective values for Doxil® like liposomes are 0.83 ± 0.49%ID/g and 2.23 ± 1.00%ID/g. Conclusion: Our results indicate that our novel PET labeled liposomes target bone marrow with very high efficiency and therefore can function as efficient bone marrow imaging agents.

Metabolic response assessment with 18F-FDG-PET/CT is superior to modified RECIST for the evaluation of response to platinum-based doublet chemotherapy in malignant pleural mesothelioma

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Kanemura, Shingo [Department of Respiratory Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Kuribayashi, Kozo, E-mail: kuririn@hyo-med.ac.jp [Department of Respiratory Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Funaguchi, Norihiko [Department of Respiratory Medicine, Murakami Memorial Hospital, Asahi University, 3-23 Hashimoto-cho, Gifu 500-8523 (Japan); Shibata, Eisuke; Mikami, Koji [Department of Respiratory Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Doi, Hiroshi [Department of Radiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Kitajima, Kazuhiro [Division of Nuclear Medicine and PET center, Department of Radiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Hasegawa, Seiki [Department of Thoracic Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Nakano, Takashi [Department of Respiratory Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan)

2017-01-15

Highlights: • 18F-FDG-PET/CT and mRESIST were used for tumour responsiveness evaluation in MPM. • 29% of mRESIST stable disease (SD) patients were metabolic non-responders. • Disease control rate was 93.9% and metabolic response rate was 71.9%. • Progressive metabolic disease patients had lower time to progression. • MRESIST stable disease (SD) patients should be further screened by 18F-FDG-PET/CT. - Abstract: Purpose: Efficient monitoring of tumor responsiveness to chemotherapy is essential to mitigate high mortality risks and cytotoxic effects of chemotherapeutics. However, there is no consensus on the most suitable diagnostic technique/parameters for assessing response to chemotherapy in malignant pleural mesothelioma (MPM). We compared the tumor responsiveness of MPM patients as assessed using modified RECIST (mRECIST) criteria and integrated 18F-FDG-PET/CT. Methods: Histologically confirmed MPM patients (N = 82) who were treated with three cycles of cisplatin and pemetrexed, or carboplatin and pemetrexed, were included. mRECIST and integrated 18F-FDG-PET/CT were used to evaluate MPM tumor response to chemotherapy. Metabolic non-responders were defined as those with a 25% or greater increase in SUVmax compared with the previous value. Time to progression (TTP) and overall survival (OS) were compared between metabolic-responders and non-responders. Results: After three cycles of chemotherapy, 62(75.6%) of the patients were classified as having SD, 15 (18%) with partial remission (PR), and 5 (6%) with progressive disease (PD), based on mRECIST criteria. The cumulative median OS was 728.0 days (95% confidence interval [CI]: 545.9–910.1) and cumulative median TTP was 365.0 days (95% CI: 296.9–433.1). For the 82 patients, the disease control rate was 93.9%, whereas the metabolic response rate was only 71.9% (p < 0.001). All PD and PR patients were found to be metabolic responders on 18F-FDG-PET/CT; however, among the 62mRECIST SD patients, 18 (29

The efficacy and safety of the targeted drug combined with adriamycin liposome solution for HER-2-positive breast cancer

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Zi-Ping Zhou

2017-05-01

Full Text Available Objective: To study the efficacy and safety of the targeted drug trastuzumab combined with adriamycin liposome solution for HER-2-positive breast cancer. Methods: A total of 112 patients with breast cancer who received chemotherapy in Department of Cardiothoracic Breast Surgery, Guangdong TongJiang Hospital between May 2014 and April 2016 were selected as the research subjects and divided into two groups by random number table, liposome group received trastuzumab + adriamycin liposome chemotherapy, and the control group received trastuzumab + adriamycin chemotherapy. Before chemotherapy as well as 4 weeks and 8 weeks after chemotherapy, serum levels of tumor markers, cytokines and myocardial injury indexes were detected, the electrocardiography was conducted and the degree of myocardial injury was determined. Results: 4 weeks and 8 weeks after chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF and MK levels of both groups were significantly lower than those before chemotherapy, serum CK-MB and cTnI levels were significantly higher than those before chemotherapy, limb leads QRS amplitudes and chest leads QRS amplitudes were significantly lower than those before chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF, MK, CK-MB and cTnI levels of liposome group were significantly lower than those of control group, and the limb leads QRS amplitudes and chest lead QRS amplitudes were significantly higher than those of control group. Conclusion: Targeted drug combined with adriamycin liposome therapy for HER-2-positive breast cancer can improve the curative effect and reduce the cardiotoxicity.

Liposome-based Formulation for Intracellular Delivery of Functional Proteins

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Benoît Chatin

2015-01-01

Full Text Available The intracellular delivery of biologically active protein represents an important emerging strategy for both fundamental and therapeutic applications. Here, we optimized in vitro delivery of two functional proteins, the β-galactosidase (β-gal enzyme and the anti-cytokeratin8 (K8 antibody, using liposome-based formulation. The guanidinium-cholesterol cationic lipid bis (guanidinium-tren-cholesterol (BGTC (bis (guanidinium-tren-cholesterol combined to the colipid dioleoyl phosphatidylethanolamine (DOPE (dioleoyl phosphatidylethanolamine was shown to efficiently deliver the β-gal intracellularly without compromising its activity. The lipid/protein molar ratio, protein amount, and culture medium were demonstrated to be key parameters affecting delivery efficiency. The protein itself is an essential factor requiring selection of the appropriate cationic lipid as illustrated by low K8 binding activity of the anti-K8 antibody using guanidinium-based liposome. Optimization of various lipids led to the identification of the aminoglycoside lipid dioleyl succinyl paromomycin (DOSP associated with the imidazole-based helper lipid MM27 as a potent delivery system for K8 antibody, achieving delivery in 67% of HeLa cells. Cryo-transmission electron microscopy showed that the structure of supramolecular assemblies BGTC:DOPE/β-gal and DOSP:MM27/K8 were different depending on liposome types and lipid/protein molar ratio. Finally, we observed that K8 treatment with DOSP:MM27/K8 rescues the cyclic adenosine monophosphate (cAMP-dependent chloride efflux in F508del-CFTR expressing cells, providing a new tool for the study of channelopathies.

Radiolabeling of liposomes and polymeric micelles with PET-isotopes

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Ingemann Jensen, A.T.

2013-06-01

This thesis is divided into three separate chapters that can be read independently. Chapter 1 is a general introduction, touching upon liposomes and polymeric micelles and radiolabeling with 18F and 64Cu. Chapter 2 and 3 address two separate research projects, each described below. A complete reference list is compiled in the end, immediately after the three chapters. This is followed by the supplementary information, divided into appropriate sections. Finally, the two first-authored manuscripts are attached as appendices. Chapter 1. The field of nanoparticulate drug delivery has been hailed as a revolution in modern therapeutics, especially in chemotherapy. A major reason is the ability of nanoparticles to accumulate in tumor tissue. Liposomes are the classic nanoparticle, consisting of a lipid membrane with an aqueous core. Polymeric micelles are made from amphiphilic detergent-like copolymers, that self-assemble in water. Therapy with nanoparticles is hampered by often poor tumor accumulation, combined with massive uptake by macrophages in the liver and spleen. For this reason, visualizing nanoparticle pharmacokinetics in-vivo is a valuable tool in the on-going research. Such visualization can be done by labeling with radio isotopes. Isotopes that emit positrons (PET-isotopes) can be detected by PET (positron emission tomography) technology, an accurate technique that has gained popularity in recent years. PET-isotopes of interest include 18F and 64Cu. In addition to being a research tool, radiolabeled nanoparticles hold promise as a radiopharmaceutical in themselves, as a means of imaging tumor tissue, aiding in diagnosis and surgery. Chapter 2. A method for labeling liposomes with 18F (97% positron decay, T = 110 min) was investigated. 18F is widely available, but is hampered by a short half-life only allowing up to 8 hours scans. 18F must be covalently attached to components of the liposome. By binding to a lipid, it can be stably lodged in the membrane. A

Radiolabeling of liposomes and polymeric micelles with PET-isotopes

International Nuclear Information System (INIS)

Ingemann Jensen, A.T.

2013-01-01

This thesis is divided into three separate chapters that can be read independently. Chapter 1 is a general introduction, touching upon liposomes and polymeric micelles and radiolabeling with 18F and 64Cu. Chapter 2 and 3 address two separate research projects, each described below. A complete reference list is compiled in the end, immediately after the three chapters. This is followed by the supplementary information, divided into appropriate sections. Finally, the two first-authored manuscripts are attached as appendices. Chapter 1. The field of nanoparticulate drug delivery has been hailed as a revolution in modern therapeutics, especially in chemotherapy. A major reason is the ability of nanoparticles to accumulate in tumor tissue. Liposomes are the classic nanoparticle, consisting of a lipid membrane with an aqueous core. Polymeric micelles are made from amphiphilic detergent-like copolymers, that self-assemble in water. Therapy with nanoparticles is hampered by often poor tumor accumulation, combined with massive uptake by macrophages in the liver and spleen. For this reason, visualizing nanoparticle pharmacokinetics in-vivo is a valuable tool in the on-going research. Such visualization can be done by labeling with radio isotopes. Isotopes that emit positrons (PET-isotopes) can be detected by PET (positron emission tomography) technology, an accurate technique that has gained popularity in recent years. PET-isotopes of interest include 18F and 64Cu. In addition to being a research tool, radiolabeled nanoparticles hold promise as a radiopharmaceutical in themselves, as a means of imaging tumor tissue, aiding in diagnosis and surgery. Chapter 2. A method for labeling liposomes with 18F (97% positron decay, T = 110 min) was investigated. 18F is widely available, but is hampered by a short half-life only allowing up to 8 hours scans. 18F must be covalently attached to components of the liposome. By binding to a lipid, it can be stably lodged in the membrane. A

Liposome-coated mesoporous silica nanoparticles loaded with L-cysteine for photoelectrochemical immunoassay of aflatoxin B1.

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Lin, Youxiu; Zhou, Qian; Zeng, Yongyi; Tang, Dianping

2018-06-02

The authors describe a photoelectrochemical (PEC) immunoassay for determination of aflatoxin B 1 (AFB 1 ) in foodstuff. The competitive immunoreaction is carried out on a microplate coated with a capture antibody against AFB 1 using AFB 1 -bovine serum albumin (BSA)-liposome-coated mesoporous silica nanoparticles (MSN) loaded with L-cysteine as a support. The photocurrent is produced by a photoactive material consisting of cerium-doped Bi 2 MoO 6 . Initially, L-cysteine acting as the electron donor is gated in the pores by interaction between mesoporous silica and liposome. Thereafter, AFB 1 -BSA conjugates are covalently bound to the liposomes. Upon introduction of the analyte (AFB 1 ), the labeled AFB 1 -BSA complex competes with the analyte for the antibody deposited on the microplate. Accompanying with the immunocomplex, the liposomes on the MSNs are lysed upon addition of Triton X-100. This results in the opening of the pores and in a release of L-cysteine. Free cysteine then induces the electron-hole scavenger of the photoactive nanosheets to increase the photocurrent. The photocurrent (relative to background signal) increases with increasing AFB 1 concentration. Under optimum conditions, the photoactive nanosheets display good photoelectrochemical responses, and allow the detection of AFB 1 at a concentration as low as 0.1 pg·mL -1 within a linear response in the 0.3 pg·mL -1 to 10 ng·mL -1 concentration range. Accuracy was evaluated by analyzing naturally contaminated and spiked peanut samples by using a commercial AFB 1 ELISA kit as the reference, and well-matching results were obtained. Graphical abstract Schematic presentation of a photoelectrochemical immunoassay for AFB 1 . It is based on the use of Ce-doped Bi 2 MoO 6 nanosheets and of liposome-coated mesoporous silica nanoparticles loaded with L-cysteine.

Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-β type I receptor inhibitor

International Nuclear Information System (INIS)

Taniguchi, Yukimi; Kawano, Kumi; Minowa, Takuya; Shimojo, Yuki; Maitani, Yoshie; Sugino, Takashi

2010-01-01

Tumor cell targeting of drug carriers is a promising strategy and uses the attachment of various ligands to enhance the therapeutic potential of chemotherapy agents. Folic acid is a high-affinity ligand for folate receptor, which is a functional tumor-specific receptor. The transforming growth factor (TGF)-β type I receptor (TβR-I) inhibitor A-83-01 was expected to enhance the accumulation of nanocarriers in tumors by changing the microvascular environment. To enhance the therapeutic effect of folate-linked liposomal doxorubicin (F-SL), we co-administrated F-SL with A-83-01. Intraperitoneally injected A-83-01-induced alterations in the cancer-associated neovasculature were examined by magnetic resonance imaging (MRI) and histological analysis. The targeting efficacy of single intravenous injections of F-SL combined with A-83-01 was evaluated by measurement of the biodistribution and the antitumor effect in mice bearing murine lung carcinoma M109. A-83-01 temporarily changed the tumor vasculature around 3 h post injection. A-83-01 induced 1.7-fold higher drug accumulation of F-SL in the tumor than liposome alone at 24 h post injection. Moreover F-SL co-administrated with A-83-01 showed significantly greater antitumor activity than F-SL alone. This study shows that co-administration of TβR-I inhibitor will open a new strategy for the use of folate receptor (FR)-targeting nanocarriers for cancer treatment. (author)

Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes.

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Irma Pujol-Autonell

Full Text Available The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes.To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes.A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides.We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion.We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for

Evaluation of 18F-fluorothymidine positron emission tomography ([18F]FLT-PET/CT) methodology in assessing early response to chemotherapy in patients with gastro-oesophageal cancer.

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Sharma, R; Mapelli, P; Hanna, G B; Goldin, R; Power, D; Al-Nahhas, A; Merchant, S; Ramaswami, R; Challapalli, A; Barwick, T; Aboagye, E O

2016-12-01

3'-Deoxy-3'-[ 18 F]fluorothymidine ([ 18 F]FLT) PET has limited utility in abdominal imaging due to high physiological hepatic uptake of a tracer. We evaluated [ 18 F]FLT-PET/CT combined with a temporal-intensity information-based voxel-clustering approach termed kinetic spatial filtering (KSF) to improve tumour visualisation in patients with locally advanced and metastatic gastro-oesophageal cancer and as a marker of early response to chemotherapy. Dynamic [ 18 F]FLT-PET/CT data were collected before and 3 weeks post first cycle of chemotherapy. Changes in tumour [ 18 F]FLT-PET/CT variables were determined. Response was determined on contrast-enhanced CT after three cycles of therapy using RECIST 1.1. Ten patients were included. Following application of the KSF, visual distinction of all oesophageal and/or gastric tumours was observed in [ 18 F]FLT-PET images. Among the nine patients available for response evaluation (RECIST 1.1), three patients had responded (partial response) and six patients were non-responders (stable disease). There was a significant association between Ki-67 and all baseline [ 18 F]FLT-PET parameters. Area under the curve (AUC) from 0 to 1 min was associated with treatment response. The results of this study indicate that application of the KSF allowed accurate visualisation of both primary and metastatic lesions following imaging with the proliferation marker, [ 18 F]FLT-PET/CT. However, [ 18 F]FLT-PET uptake parameters did not correlate with response. Instead, we observe significant changes in tracer delivery following chemotherapy suggesting that further [ 18 F]FLT-PET/CT studies in this tumour type should be undertaken with caution.

Lipossomas: propriedades físico-químicas e farmacológicas, aplicações na quimioterapia à base de antimônio Liposomes: physicochemical and pharmacological properties, applications in antimony-based chemotherapy

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Frédéric Frézard

2005-06-01

Full Text Available The use of organoantimonial complexes in the therapeutic of leishmaniasis and schistosomiasis has been limited mainly by the need for daily parenteral administration, their adverse side-effects and the appearance of drug resistance. Liposome encapsulation has been so far the most effective means to improve the efficacy of pentavalent antimonials against visceral leishmaniasis. Pharmacologically- and pharmaceutically-acceptable liposomal compositions are still being investigated through manipulation of preparation method, lipid composition and vesicle size. Recently, the encapsulation of a trivalent antimonial within "stealth" liposomes was found to reduce its acute toxicity and effectively deliver this compound to the parasite in experimental schistosomiasis.

Liposome based radiosensitizer cancer therapy

DEFF Research Database (Denmark)

Pourhassan, Houman

Liposome-encapsulated chemotherapeutics have been used in the treatment of a variety of cancers and are feasible for use as mono-therapeutics as well as for combination therapy in conjunction with other modalities. Despite widespread use of liposomal drugs in cancer patient care, insufficient drug...... biomolecules. By modulating the liposomal membrane, liposomes can become sensitive towards enzymatically-driven destabilization and/or functionalization, thereby allowing control of the release of encapsulated therapeutics within the diseased tissue upon intrinsic stimulation from tumor-associated enzymes...... in tumor-bearing mice.The safety and efficacy of sPLA2-sensitive liposomal L-OHP was assessed in sPLA2-deficient FaDu hypopharyngeal squamous cell carcinoma and sPLA2-expressing Colo205 colorectal adenocarcinoma. Also, the feasibility of multimodal cancer therapy employing L-OHP encapsulated in MMP...

[Chronic visceral leishmaniasis during chemotherapy for metastatic osteosarcoma].

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Marguglio, A; Hoyoux, C; Dresse, M F; Chantraine, J M; Thiry, A; Gillet, P

1998-03-01

Leishmaniasis refers to a spectrum of diseases caused by Leishmania. Clinically, three types of leishmaniasis can be distinguished: the cutaneous, mucous and visceral leishmaniasis, the latter being caused by Leishmania donovani. An 11-year-old Thai, living in Belgium for 6 years, had surgery for a vertebral osteosarcoma with pulmonary metastases, followed by polychemotherapy, then pulmonary metastasectomy. During a post-chemotherapy bone marrow aplasia, febrile episode with a general condition impairment was noted and first treated by broad-spectrum antibiotherapy, then by amphotericin B, in the absence of any accurate etiology. The outcome first was favorable. Nevertheless, 7 months later, the visceral leishmaniasis diagnosis was made because of the recurrence of the same symptoms. Classical treatments by antimony derivatives (Glucantim), then liposomal amphotericin (Ambisome) proved to be inefficient. A liposomal amphotericin-gamma interferon association suppressed the symptoms without eradicating the parasite. The patient was given a maintenance therapy based on liposomal amphotericin. The stubborn and recurring nature of this chronic visceral leismaniosis can be due to the immune deficit inherent in the polychemotherapy performed in order to treat the metastatic osteosarcoma which currently is in first full remission.

Biophysical characterization of V3-lipopeptide liposomes influencing HIV-1 infectivity

International Nuclear Information System (INIS)

Rizos, Apostolos K.; Baritaki, Stavroula; Tsikalas, Ioannis; Doetschman, David C.; Spandidos, Demetrios A.; Krambovitis, Elias

2007-01-01

The V3-loop of the HIV-1 gp120 alters host cell immune function and modulates infectivity. We investigated biophysical parameters of liposome constructs with embedded lipopeptides from the principle neutralizing domain of the V3-loop and their influence on viral infectivity. Dynamic light scattering measurements showed liposome supramolecular structures with hydrodynamic radius of the order of 900 and 1300 nm for plain and V3-lipopeptide liposomes. Electron paramagnetic resonance measurements showed almost identical local microenvironment. The difference in liposome hydrodynamic radius was attributed to the fluctuating ionic environment of the V3-lipopeptide liposomes. In vitro HIV-1 infectivity assays showed that plain liposomes reduced virus production in all cell cultures, probably due to the hydrophobic nature of the aggregates. Liposomes carrying V3-lipopeptides with different cationic potentials restored and even enhanced infectivity (p < 0.05). These results highlight the need for elucidation of the involvement of lipid bilayers as dynamic components in supramolecular structures and in HIV-1 fusion mechanisms

Liposome-based vascular endothelial growth factor-165 transfection with skeletal myoblast for treatment of ischaemic limb disease.

Science.gov (United States)

Ye, Lei; Haider, Husnain Kh; Esa, Wahidah Bte; Su, Liping; Law, Peter K; Zhang, Wei; Lim, Yeanteng; Poh, Kian Keong; Sim, Eugene K W

2010-01-01

The study aims to use cholesterol (Chol) + DOTAP liposome (CD liposome) based human vascular endothelial growth factor-165 (VEGF(165)) gene transfer into skeletal myoblasts (SkMs) for treatment of acute hind limb ischaemia in a rabbit model. The feasibility and efficacy of CD liposome mediated gene transfer with rabbit SkMs were characterized using plasmid carrying enhanced green fluorescent protein (pEGFP) and assessed by flow cytometry. After optimization, SkMs were transfected with CD lipoplexes carrying plasmid-VEGF(165) (CD-pVEGF(165)) and transplanted into rabbit ischaemic limb. Animals were randomized to receive intramuscular injection of Medium199 (M199; group 1), non-transfected SkM (group 2) or CD-pVEGF(165) transfected SkM (group 3). Flow cytometry revealed that up to 16% rabbit SkMs were successfully transfected with pEGFP. Based on the optimized transfection condition, transfected rabbit SkM expressed VEGF(165) up to day 18 with peak at day 2. SkMs were observed in all cell-transplanted groups, as visualized with 6-diamidino-2-phenylindole and bromodeoxyuridine. Angiographic blood vessel score revealed increased collateral vessel development in group 3 (39.7 +/- 2.0) compared with group 2 (21.6 +/- 1.1%, P limb and may serve as a safe and new therapeutic modality for the repair of acute ischaemic limb disease.

In Vivo 6-([18F]Fluoroacetamido-1-hexanoicanilide PET Imaging of Altered Histone Deacetylase Activity in Chemotherapy-Induced Neurotoxicity

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Nobuyoshi Fukumitsu

2018-01-01

Full Text Available Background. Histone deacetylases (HDACs regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido-1-hexanoicanilide ([18F]FAHA as a positron emission tomography (PET imaging agent for HDAC IIa. Materials and Methods. [18F]FAHA and [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times. Results. The Ki value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g of [18F]FDG was decreased in the brains of animals in Groups A and B. The Ki value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions. [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment.

The Results of Combined External Radiotherapy and Chemotherapy in the Management of Esophageal Cancer

International Nuclear Information System (INIS)

Lee, Hyun Joo; Suh, Hyun Suk; Kim, Jun Hee; Kim, Chul Soo; Kim, Sung Rok; Kim, Re Hwe

1996-01-01

Purpose : To evaluate the role of combination therapy of external radiotherapy and chemotherapy in the management of advanced esophageal cancer as a primary treatment compared with radiation therapy alone. Methods and Materials : A retrospective review of evaluable 55 esophageal cancer patients referred to the Department of Therapeutic Radiology, Paik Hospital for the external radiotherapy between Jul. 1983 and Dec.1994 was undertaken. Combined therapy patients (A group) were 30 and radiation alone patients (B group) were 25. Median age was 60 years old in A group(ranges : 42-81) and 65 years old in B group (ranges : 50-81). The male patients were 53. The fifty patients had squamous cell carcinomas. Radiation doses of 2520-6480c Gy were delivered over a period of 4-7 weeks. using 4MV LIVAC. Chemotherapy was administered in bolus injection before, after, or during the course of external radiotherapy. The local control rate and patterns of failure according to both treatment modalities and 1,2 year survival rates according to prognostic factors (stage, tumor length, radiation dose etc.) were analysed. Results : Median follow up period was 7 months (range : 2-73 months). Median survival was 7.5 months (20 days-29 months) in A group and 5 months(20 days-73 months) in B group. The 1,2 YSRs were 26.7%, 8.9% in A group. 12.7%, 4.3% in B group (p>0.05), respectively. The 1,2 YSRs according to stage(II/III), tumor length (5cm more or less). radiation dose(5000c Gy more or less) of A and B group were analyzed and the differences of survival rates of both treatments were not statistically significant. But among group B, patients who received 5000c Gy or more showed significant survival benefits (p<0.05). The treatment response rates of A and B group were 43.8%, 25.0%, respectively. Complete response rate of 25.0% in A and 8.3% in B were achieved. The local failure and distant metastasis were 52.4%, 23.8% in A group. 64.3%, 14.3% in B group, respectively. The combination

New potential antitumoral fluorescent tetracyclic thieno[3,2-b]pyridine derivatives: interaction with DNA and nanosized liposomes

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Calhelha Ricardo

2011-01-01

Full Text Available Abstract Fluorescence properties of two new potential antitumoral tetracyclic thieno[3,2-b]pyridine derivatives were studied in solution and in liposomes of DPPC (dipalmitoyl phosphatidylcholine, egg lecithin (phosphatidylcholine from egg yolk; Egg-PC and DODAB (dioctadecyldimethylammonium bromide. Compound 1, pyrido[2',3':3,2]thieno[4,5-d]pyrido[1,2-a]pyrimidin-6-one, exhibits reasonably high fluorescence quantum yields in all solvents studied (0.20 ≤ ΦF ≤ 0.30, while for compound 2, 3-[(p-methoxyphenylethynyl]pyrido[2',3':3,2]thieno[4,5-d]pyrido[1,2-a]pyrimidin-6-one, the values are much lower (0.01 ≤ ΦF ≤ 0.05. The interaction of these compounds with salmon sperm DNA was studied using spectroscopic methods, allowing the determination of intrinsic binding constants, K i = (8.7 ± 0.9 × 103 M-1 for compound 1 and K i = (5.9 ± 0.6 × 103 M-1 for 2, and binding site sizes of n = 11 ± 3 and n = 7 ± 2 base pairs, respectively. Compound 2 is the most intercalative compound in salmon sperm DNA (35%, while for compound 1 only 11% of the molecules are intercalated. Studies of incorporation of both compounds in liposomes of DPPC, Egg-PC and DODAB revealed that compound 2 is mainly located in the hydrophobic region of the lipid bilayer, while compound 1 prefers a hydrated and fluid environment.

The comparative effect of wrapping solid gold nanoparticles and hollow gold nanoparticles with doxorubicin-loaded thermosensitive liposomes for cancer thermo-chemotherapy.

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Li, Yanan; He, Dongsheng; Tu, Jiasheng; Wang, Ru; Zu, Chang; Chen, You; Yang, Wenqian; Shi, Di; Webster, Thomas J; Shen, Yan

2018-04-26

Since conventional chemotherapy is a systemic treatment that affects the body globally and will not concentrate inside the tumor, it causes adverse side effects to patients. In this study, doxorubicin (DOX) together with solid gold nanoparticles (GNPs) or hollow gold nanoparticles (HGNPs), respectively, is loaded inside thermosensitive liposomes (GNPs&DOX-TLs and HGNPs&DOX-TLs), where the GNPs and HGNPs act as a "nanoswitch" for killing tumor cells directly by hyperthermia and triggering DOX release from TLs in the tumor quickly by near infrared laser (NIR) illumination. In addition, this study investigated the photothermal transformation ability, NIR triggered drug release behavior, and the intracellular uptake and cytotoxicity of breast tumor cells and the thermo-chemotherapy mediated by the co-delivery of GNPs&DOX-TLs and HGNPs&DOX-TLs. GNPs and HGNPs had very different light-to-heat transduction efficiencies, while the hollow HGNPs had the advantage of NIR surface plasmon tunability, resulting in the photothermal ablation of tumors with 800 nm light penetration in tissue. The prepared HGNPs&DOX-TLs exhibited a spherical shape with a diameter of 190 nm and a ξ potential of -29 mV, which were steadily dispersed for at least one month. The co-encapsulated DOX was released under hyperthermia caused by NIR-responsive HGNPs and the local drug concentration increased along with the disintegration of the liposomal membrane. This co-delivery of HGNPs&DOX-TLs produced a synergistic cytotoxicity response, thereby enhancing anticancer efficacy 8-fold and increasing the survival time compared to GNPs&DOX-TLs. This work suggested that the co-delivery of HGNPs&DOX-TLs followed by burst-release of DOX using NIR-responsive HGNPs sensitized cancer cells to the chemotherapeutic compound, which provided a novel concept for the combination strategy of chemotherapy and photothermal therapy. These results suggest that the markedly improved therapeutic efficacy and decreased systemic

Preliminary individualized chemotherapy for malignant astrocytomas based on O6-methylguanine-deoxyribonucleic acid methyltransferase methylation analysis.

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Watanabe, Takao; Katayama, Yoichi; Ogino, Akiyoshi; Ohta, Takashi; Yoshino, Atsuo; Fukushima, Takao

2006-08-01

O(6)-methylguanine-deoxyribonucleic acid methyltransferase gene (MGMT) methylation is apparently correlated with responsiveness to nitrosourea chemotherapy, suggesting this alkylating agent should be effective against MGMT-methylated tumors. MGMT appears not to be linked to platinum resistance, so platinum chemotherapy should be used for MGMT-unmethylated tumors. This study was a preliminary trial of individualized chemotherapy based on MGMT methylation status in a total of 20 patients with newly diagnosed malignant astrocytomas (9 anaplastic astrocytomas and 11 glioblastomas multiforme). The procarbazine, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea, and vincristine (PAV) regimen was administered to seven patients with MGMT-methylated tumors, and the carboplatin and etoposide (CE) regimen was administered to 13 patients with MGMT-unmethylated tumors. Objective response to the PAV therapy was noted in all three patients with measurable residual tumor (2 complete responses and 1 partial response). Five of the seven patients continued to be disease-free after initiation of the PAV therapy. Objective response to the CE therapy was seen in only one of seven patients with measurable residual tumor (1 partial response). Three of the 13 patients were free from progression, whereas the remaining 10 patients showed early progression. The PAV regimen is effective against MGMT-methylated malignant astrocytomas, but the CE regimen is not useful at the given dose and schedule in MGMT-unmethylated tumors.

A phase I/II trial of beta-(1,3/(1,6 D-glucan in the treatment of patients with advanced malignancies receiving chemotherapy

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Weitberg Alan B

2008-09-01

Full Text Available Abstract β-(1,3/(1,6 D-glucan, a component of the fungal cell wall, has been shown to stimulate the immune system, enhance hematopoiesis, amplify killing of opsonized tumor cells and increase neutrophil chemotaxis and adhesion. In view of these attributes, the β-glucans should be studied for both their therapeutic efficacy in patients with cancer as well as an adjunctive therapy in patients receiving chemotherapy as a maneuver to limit suppression of hematopoiesis. In this study, twenty patients with advanced malignancies receiving chemotherapy were given a β-(1,3/(1,6 D-glucan preparation (MacroForce plus IP6, ImmuDyne, Inc. and monitored for tolerability and effect on hematopoiesis. Our results lead us to conclude that β-glucan is well-tolerated in cancer patients receiving chemotherapy, may have a beneficial effect on hematopoiesis in these patients and should be studied further, especially in patients with chronic lymphocytic leukemia and lymphoma.

Phase behavior of fluorocarbon and hydrocarbon double-chain hydroxylated and galactosylated amphiphiles and bolaamphiphiles. Long-term shelf-stability of their liposomes.

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Clary, L; Gadras, C; Greiner, J; Rolland, J P; Santaella, C; Vierling, P; Gulik, A

1999-06-01

This paper describes the morphological characterization, by freeze-fracture electron microscopy, and the thermotropic phase behavior, by differential scanning calorimetry and/or X-ray scattering, of aqueous dispersions of various hydroxylated and galactosylated double-chain amphiphiles and bolaamphiphiles, several of them containing one or two hydrophobic fluorocarbon chains. Colloidal systems are observed in water with the hydroxylated hydrocarbon or fluorocarbon bolaamphiphiles only when they are dispersed with a co-amphiphile such as rac-1,2-dimyristoylphosphatidylcholine (DMPC) or rac-1,2-distearoylphosphatidylcholine (DSPC). Liposomes are formed providing the relative content of bolaamphiphiles does not exceed 20% mol. Most of these liposomes can be thermally sterilized and stored at room temperature for several months without any significant modification of their size and size distribution. The hydrocarbon galactosylated bolaamphiphile HO[C24][C12]Gal forms in water a lamellar phase (the gel to liquid-crystal phase transition is complete at 45 degrees C) and a Im3m cubic phase above 47 degrees C. The fluorocarbon HO[C24][F6C5]Gal analog displays a more complex and metastable phase behavior. The fluorinated non-bolaform galactosylated [F8C7][C16]AEGal and SerGal amphiphiles form lamellar phases in water. Low amounts (10% molar ratio) of the HO[C24][F6C5]Gal or HO[C24][C12]Gal bolaamphiphiles or of the single-headed [F8C7][C16]AEGal improve substantially the shelf-stability of reference phospholipon/cholesterol 2/1 liposomes. These liposomes when co-formulated with a single-headed amphiphile from the SerGal series are by far less stable.

pH-triggered echogenicity and contents release from liposomes.

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Nahire, Rahul; Hossain, Rayat; Patel, Rupa; Paul, Shirshendu; Meghnani, Varsha; Ambre, Avinash H; Gange, Kara N; Katti, Kalpana S; Leclerc, Estelle; Srivastava, D K; Sarkar, Kausik; Mallik, Sanku

2014-11-03

Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the cellular lysosomes has been successfully used to enhance the rate for releasing contents. However, imparting pH sensitivity to liposomes requires the synthesis of specialized lipids with structures that are substantially modified at a reduced pH. Herein, we report an alternative strategy to render liposomes pH sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at a reduced pH. The gas bubbles also render the liposomes echogenic, allowing ultrasound imaging. To demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells that overexpress the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents released from these liposomes are further enhanced by the application of continuous wave ultrasound (1 MHz), resulting in substantially reduced viability for the pancreatic cancer cells (14%).

The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals.

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Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

2017-01-01

Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood-brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p -aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood-brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p -aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells.

Astragaloside IV liposomes ameliorates adriamycin-induced ...

African Journals Online (AJOL)

Methods: The rats were given a single tail intravenous injection of adriamycin (6 mg/kg) within 1 week, and then divided into four groups including normal, model, benazepril and astragaloside IV liposomes group. They were all orally administered dosage of benazepril and astragaloside IV liposomes once daily for 8 weeks.

Synthesis and preclinical characterization of 1-(6'-deoxy-6'-[18F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-6'-[18F]FAZAL) as a positron emission tomography radiotracer to assess tumor hypoxia.

Science.gov (United States)

Wanek, Thomas; Kreis, Katharina; Križková, Petra; Schweifer, Anna; Denk, Christoph; Stanek, Johann; Mairinger, Severin; Filip, Thomas; Sauberer, Michael; Edelhofer, Patricia; Traxl, Alexander; Muchitsch, Viktoria E; Mereiter, Kurt; Hammerschmidt, Friedrich; Cass, Carol E; Damaraju, Vijaya L; Langer, Oliver; Kuntner, Claudia

2016-11-01

Positron emission tomography (PET) using fluorine-18 ( 18 F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[ 18 F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-[ 18 F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [ 18 F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β-6) in a final radiochemical yield of 12±8% (n=10, based on [ 18 F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/μmol (n=10). Both radiolabeling precursor β-6 and unlabeled reference compound β-1 were prepared in multistep syntheses starting from 1,2:5,6-di-O-isopropylidene-α-d-allofuranose. In vitro experiments demonstrated an interaction of β-1 with SLC29A1 and SLC28A1/2/3 nucleoside transporter as well as hypoxia specific retention of β-[ 18 F]1 in tumor cell lines. In biodistribution studies in healthy mice β-[ 18 F]1 showed homogenous tissue distribution and excellent metabolic stability, which was unaffected by tissue oxygenation. PET studies in tumor bearing mice showed tumor-to-muscle ratios of 2.13±0.22 (n=4) at 2h after administration of β-[ 18 F]1. In ex vivo autoradiography experiments β-[ 18 F]1 distribution closely matched staining with the hypoxia marker pimonidazole. In conclusion, β-[ 18 F]1 shows potential as PET hypoxia radiotracer which merits further investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of liposome-adriamycin (L-ADM) and thermotherapy on glioma cells: an experimental study

OpenAIRE

Zheng-hua SHI; Jian-ning ZHANG

2013-01-01

Objective 　To observe the effects of liposome-adriamycin (L-ADM) and thermotherapy on proliferation and apoptosis of SWO-38 glioma cells. Methods 　The SWO-38 glioma cells were cultivated in vitro. The effects of thermotherapy (43℃), ADM chemotherapy, L-ADM chemotherapy, thermotherapy + ADM chemotherapy, and thermotherapy + L-ADM chemotherapy on the cell proliferation and apoptosis were observed. The working concentration of ADM and L-ADM, and the cell proliferation rate were determined by MTT...

DDA/TDB liposomes containing soluble Leishmania major antigens induced a mixed Th1/Th2 immune response in BALB/c mice

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Mansure Hojatizade

2017-04-01

Full Text Available Objective(s: Leishmaniasis is a complex parasitic disease that represents a major public health problem. Despite numerous attempts over the past decades, yet there is no effective vaccine against human leishmaniasis probably due to the lack of suitable adjuvants. In this study, a first generation liposomal-based Leishmania vaccine was developed using soluble Leishmania major antigens (SLA and á, Ü-trehalose6, 6'-dibehenat (TDB as an immunostimulatory adjuvant. In this liposome structure, the cationic lipid Dimethyldioctadecylammonium (DDA provides intrinsic adjuvant activity and cholesterol was added as a membrane stabilizer. Liposomes containing SLA were prepared.Materials and Methods: BALB/c mice were subcutaneously (sc immunized with Lip (DDA/TDB/CHOL-SLA+, Lip (DDA/TDB-SLA+, Lip (DDA-SLA+, Lip (DDA/CHOL-SLA+, SLA or Tris-HCl buffer. Immunization was done every two weeks for three weeks. The immunized mice were then challenged sc in the left footpad with 1×106 stationary phase L. major promastigotes (50 ìl, at 2 weeks after last booster injection.Results: mice immunized with any of the liposomal formulations containing SLA (Lip-SLA+, substantially increased footpad swelling and parasite loads of foot and spleen with no significant difference compared to Tris-HCl buffer or SLA alone. Lip-SLA+ formulations induced a mixed Th1/Th2 immune response characterized by IFN-ã and IL-4 production as well as high levels of IgG1 anti-Leishmania antibody. Conclusion: immunization with liposomes containing DDA and/or TDB in combination with SLA induces a mixed Th1/Th2 immune response and is not an appropriate strategy for preferential induction of a Th1 response and protection against leishmaniasis.

Liposome-based delivery systems for ginsenoside Rh2: in vitro and in vivo comparisons

Energy Technology Data Exchange (ETDEWEB)

Xu, Linqiang [China Pharmaceutical University, Department of Pharmaceutics, State Key Laboratory of Natural Medicines (China); Yu, Hua [University of Macao, Institute of Chinese Medical Sciences (China); Yin, Shaoping; Zhang, Ruixia; Zhou, Yudan; Li, Juan, E-mail: lijuancpu@163.com [China Pharmaceutical University, Department of Pharmaceutics, State Key Laboratory of Natural Medicines (China)

2015-10-15

The Ginsenoside Rh2 (Rh2) has been shown to possess anti-cancer properties both in vitro and in vivo. However, the poor bioavailability and fast plasma elimination limit the further clinical applications of Rh2 for cancer treatments. In the present study, three types of Rh2-loaded liposomes including Rh2-loaded normal liposome (Rh2-LP), Rh2-loaded cationic liposome (Rh2-CLP), and Rh2-loaded Methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) liposome (Rh2-PLP) have been optimized and prepared with mean particle size of 80–125 nm. Compared to Rh2-LP, surface modifications with mPEG or octadecylamine significantly improve the physicochemical and biological properties both in vitro and in vivo. Moreover, PLP presented better tumor accumulation of the fluorescent cyanine dye, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR) in HepG2-xenografted nude mice than CLP (1.3-fold) or LP (1.6-fold) and prolong the resident time of DiR in tumor and organs (more than 24 h). The in vivo anti-cancer efficacy assessments indicate that Rh2-PLP presents the most activity on suppressing tumor growth in HepG2-xenografted mice than Rh2-LP and Rh2-CLP and without any significant toxicity. Our results indicate that mPEG-PLA modified liposome should be a potential and promising strategy to enhance the therapeutic index for anti-cancer agents.

Octanol-assisted liposome assembly on chip

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Deshpande, Siddharth; Caspi, Yaron; Meijering, Anna E. C.; Dekker, Cees

2016-01-01

Liposomes are versatile supramolecular assemblies widely used in basic and applied sciences. Here we present a novel microfluidics-based method, octanol-assisted liposome assembly (OLA), to form monodisperse, cell-sized (5-20 μm), unilamellar liposomes with excellent encapsulation efficiency. Akin to bubble blowing, an inner aqueous phase and a surrounding lipid-carrying 1-octanol phase is pinched off by outer fluid streams. Such hydrodynamic flow focusing results in double-emulsion droplets that spontaneously develop a side-connected 1-octanol pocket. Owing to interfacial energy minimization, the pocket splits off to yield fully assembled solvent-free liposomes within minutes. This solves the long-standing fundamental problem of prolonged presence of residual oil in the liposome bilayer. We demonstrate the unilamellarity of liposomes with functional α-haemolysin protein pores in the membrane and validate the biocompatibility by inner leaflet localization of bacterial divisome proteins (FtsZ and ZipA). OLA offers a versatile platform for future analytical tools, delivery systems, nanoreactors and synthetic cells.

Preliminary study of corneal penetration of /sup 125/I-labelled idoxuridine liposome

Energy Technology Data Exchange (ETDEWEB)

Dharma, S.K.; Fishman, P.H.; Peyman, G.A.

1986-01-01

We compared corneal penetration of idoxuridine (IDU) to liposome-encapsulated IDU. Liposomes of phosphatidic acid, phosphatidyl choline and alphatocopherol in a molar ratio 1:8:1 were prepared using the reverse phase evaporation method. New Zealand albino rabbits received either 0.1% solution of I/sup 125/-labelled aqueous IDU or liposome-encapsulated IDU topically every 2 min for 6 min. Corneal, aqueous, and vitreous samples were assayed for I/sup 125/ radioactivity at 15 min and at 1, 2, 3, and 6 h following drug application. Our results indicated that corneal penetration of liposomal IDU was significantly increased over the regular form of the drug for a time interval of 6 h.

A preliminary study of corneal penetration of 125I-labelled idoxuridine liposome

International Nuclear Information System (INIS)

Dharma, S.K.; Fishman, P.H.; Peyman, G.A.

1986-01-01

We compared corneal penetration of idoxuridine (IDU) to liposome-encapsulated IDU. Liposomes of phosphatidic acid, phosphatidyl choline and alphatocopherol in a molar ratio 1:8:1 were prepared using the reverse phase evaporation method. New Zealand albino rabbits received either 0.1% solution of I 125 -labelled aqueous IDU or liposome-encapsulated IDU topically every 2 min for 6 min. Corneal, aqueous, and vitreous samples were assayed for I 125 radioactivity at 15 min and at 1, 2, 3, and 6 h following drug application. Our results indicated that corneal penetration of liposomal IDU was significantly increased over the regular form of the drug for a time interval of 6 h. (author)

pH and temperature dual-sensitive liposome gel based on novel cleavable mPEG-Hz-CHEMS polymeric vaginal delivery system

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Chen D

2012-05-01

Full Text Available Daquan Chen,1,2 Kaoxiang Sun,1,2 Hongjie Mu,1 Mingtan Tang,3 Rongcai Liang,1,2 Aiping Wang,1,2 Shasha Zhou,1 Haijun Sun,1 Feng Zhao,1 Jianwen Yao,1 Wanhui Liu1,21School of Pharmacy, Yantai University, 2State Key Laboratory of Longacting and Targeting Drug Delivery Systems, Yantai, 3School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of ChinaBackground: In this study, a pH and temperature dual-sensitive liposome gel based on a novel cleavable hydrazone-based pH-sensitive methoxy polyethylene glycol 2000-hydrazone-cholesteryl hemisuccinate (mPEG-Hz-CHEMS polymer was used for vaginal administration.Methods: The pH-sensitive, cleavable mPEG-Hz-CHEMS was designed as a modified pH-sensitive liposome that would selectively degrade under locally acidic vaginal conditions. The novel pH-sensitive liposome was engineered to form a thermogel at body temperature and to degrade in an acidic environment.Results: A dual-sensitive liposome gel with a high encapsulation efficiency of arctigenin was formed and improved the solubility of arctigenin characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. The dual-sensitive liposome gel with a sol-gel transition at body temperature was degraded in a pH-dependent manner, and was stable for a long period of time at neutral and basic pH, but cleavable under acidic conditions (pH 5.0. Arctigenin encapsulated in a dual-sensitive liposome gel was more stable and less toxic than arctigenin loaded into pH-sensitive liposomes. In vitro drug release results indicated that dual-sensitive liposome gels showed constant release of arctigenin over 3 days, but showed sustained release of arctigenin in buffers at pH 7.4 and pH 9.0.Conclusion: This research has shed some light on a pH and temperature dual-sensitive liposome gel using a cleavable mPEG-Hz-CHEMS polymer for vaginal delivery.Keywords: mPEG-Hz-CHEMS polymer, pH-sensitive liposomes, thermosensitive

Liposome-based drug delivery in breast cancer treatment

International Nuclear Information System (INIS)

Park, John W

2002-01-01

Drug delivery systems can in principle provide enhanced efficacy and/or reduced toxicity for anticancer agents. Long circulating macromolecular carriers such as liposomes can exploit the 'enhanced permeability and retention' effect for preferential extravasation from tumor vessels. Liposomal anthracyclines have achieved highly efficient drug encapsulation, resulting in significant anticancer activity with reduced cardiotoxicity, and include versions with greatly prolonged circulation such as liposomal daunorubicin and pegylated liposomal doxorubicin. Pegylated liposomal doxorubucin has shown substantial efficacy in breast cancer treatment both as monotherapy and in combination with other chemotherapeutics. Additional liposome constructs are being developed for the delivery of other drugs. The next generation of delivery systems will include true molecular targeting; immunoliposomes and other ligand-directed constructs represent an integration of biological components capable of tumor recognition with delivery technologies

Liposomal nanoparticles encapsulating iloprost exhibit enhanced vasodilation in pulmonary arteries

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Jain PP

2014-07-01

Full Text Available Pritesh P Jain,1 Regina Leber,1,2 Chandran Nagaraj,1 Gerd Leitinger,3 Bernhard Lehofer,4 Horst Olschewski,1,5 Andrea Olschewski,1,6 Ruth Prassl,1,4 Leigh M Marsh11Ludwig Boltzmann Institute for Lung Vascular Research, 2Biophysics Division, Institute of Molecular Biosciences, University of Graz, 3Research Unit Electron Microscopic Techniques, Institute of Cell Biology, Histology, and Embryology, 4Institute of Biophysics, 5Division of Pulmonology, Department of Internal Medicine, 6Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, AustriaAbstract: Prostacyclin analogues are standard therapeutic options for vasoconstrictive diseases, including pulmonary hypertension and Raynaud’s phenomenon. Although effective, these treatment strategies are expensive and have several side effects. To improve drug efficiency, we tested liposomal nanoparticles as carrier systems. In this study, we synthesized liposomal nanoparticles tailored for the prostacyclin analogue iloprost and evaluated their pharmacologic efficacy on mouse intrapulmonary arteries, using a wire myograph. The use of cationic lipids, stearylamine, or 1,2-di-(9Z-octadecenoyl-3-trimethylammonium-propane (DOTAP in liposomes promoted iloprost encapsulation to at least 50%. The addition of cholesterol modestly reduced iloprost encapsulation. The liposomal nanoparticle formulations were tested for toxicity and pharmacologic efficacy in vivo and ex vivo, respectively. The liposomes did not affect the viability of human pulmonary artery smooth muscle cells. Compared with an equivalent concentration of free iloprost, four out of the six polymer-coated liposomal formulations exhibited significantly enhanced vasodilation of mouse pulmonary arteries. Iloprost that was encapsulated in liposomes containing the polymer polyethylene glycol exhibited concentration-dependent relaxation of arteries. Strikingly, half the concentration of iloprost in liposomes elicited

Gemcitabine treatment of rat soft tissue sarcoma with phosphatidyldiglycerol-based thermosensitive liposomes.

Science.gov (United States)

Limmer, Simone; Hahn, Jasmin; Schmidt, Rebecca; Wachholz, Kirsten; Zengerle, Anja; Lechner, Katharina; Eibl, Hansjörg; Issels, Rolf D; Hossann, Martin; Lindner, Lars H

2014-09-01

The pyrimidine analogue gemcitabine (dFdC) is frequently used in the treatment of patients with solid tumors. However, after i.v. application dFdC is rapidly inactivated by metabolization. Here, the potential of thermosensitive liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG2-TSL) were investigated as carrier and targeting system for delivery of dFdC in combination with local hyperthermia (HT). DPPG2-TSL were prepared by the lipid film hydration and extrusion method and characterized by dynamic light scattering, thin layer chromatography, phosphate assay and HPLC. In vivo experiments were performed in Brown Norway rats with a syngeneic soft tissue sarcoma. Local HT treatment was performed by light exposure. DPPG2-TSL were stable at 37°C in serum and showed a temperature dependent dFdC release >40°C. Plasma half-life of dFdC was strongly increased from 0.07 h (non-liposomal) to 0.53 h (liposomal, vesicle size 105 nm) or 2.59 h (liposomal, 129 nm). Therapy of BN175 tumors with dFdC encapsulated in DPPG2-TSL + HT showed significant improvement in tumor growth delay compared to non-liposomal dFdC without HT (p < 0.05), non-liposomal dFdC with HT (p < 0.01), and liposomal dFdC without HT (p < 0.05), respectively. Gemcitabine encapsulated in DPPG2-TSL in combination with local HT is a promising tool for the treatment of solid tumors. Therefore, these encouraging results ask for further investigation and evaluation.

Light-triggered liposomal cargo delivery platform incorporating photosensitizers and gold nanoparticles for enhanced singlet oxygen generation and increased cytotoxicity

Science.gov (United States)

Kautzka, Zofia; Clement, Sandhya; Goldys, Ewa M.; Deng, Wei

2018-02-01

We developed light-triggered liposomes incorporating gold nanoparticles and Rose Bengal (RB), a well-known photosensitizer used for photodynamic therapy. Singlet oxygen generated by these liposomes with 532 nm light illumination was characterized by adjusting the molar ratio of lipids and gold nanoparticles while keeping the amount of RB constant. Gold nanoparticles were found to enhance the singlet oxygen generation rate, with a maximum enhancement factor of 1.75 obtained for the molar ratio of HSPC: PE-NH2: gold of 57:5:17 compared with liposomes loaded with RB alone. The experimental results could be explained by the local electric field enhancement caused by gold nanoparticles. We further assessed cellular cytotoxicity of these liposomes by encapsulating an antitumor drug, doxorubicin (Dox); such Dox loaded liposomes were applied to human colorectal cancer cells, HCT116, and exposed to light. Gold-loaded liposomes containing RB and Dox where Dox release was triggered by light were found to exhibit higher cytotoxicity, compared to the liposomes loaded with RB and Dox alone. Our results indicate that gold-loaded liposomes incorporating photosensitizers may have improved therapeutic efficacy in photodynamic therapy and chemotherapy.

Ultrasound-mediated drug delivery using liposomes modified with a thermosensitive polymer.

Science.gov (United States)

Ninomiya, Kazuaki; Kawabata, Shinya; Tashita, Hiroyuki; Shimizu, Nobuaki

2014-01-01

Ultrasound-mediated drug delivery was established using liposomes that were modified with the thermosensitive polymer (TSP) poly(NIPMAM-co-NIPAM), which sensitized the liposomes to high temperatures. TSP-modified liposomes (TSP liposomes) released encapsulated calcein under 1 MHz ultrasound irradiation at 0.5 W/cm(2) for 120 s as well as the case under incubation at 42 °C for 15 min. In addition, uptake of the drug released from TSP liposomes by cancer cells was enhanced by ultrasound irradiation. In a cell injury assay using doxorubicin (DOX)-loaded TSP liposomes and ultrasound irradiation, cell viability of HepG2 cells at 6 h after ultrasound irradiation (1 MHz, 0.5 W/cm(2) for 30 s) with DOX-loaded TSP liposomes (TSP/lipid ratio=1) was 60%, which was significantly lower than that of the control conditions such as DOX-loaded TSP liposomes alone and DOX-loaded intact liposomes under ultrasound irradiation. Copyright © 2013 Elsevier B.V. All rights reserved.

Crystal structures of LiCsTiF6 and Cs2TiF6 and interval mobility of complex anions

International Nuclear Information System (INIS)

Popov, D.Yu.; Kavun, V.Ya.; Gerasimenko, A.V.; Sergienko, V.I.; Antokhina, T.F.

2002-01-01

The structure of LiCsTiF 6 (1) and Cs 2 TiF 6 (2) monocrystals was studied by the method of X-ray diffraction analysis. Crystal lattice parameters for compound 1 are: a = 9.251 (1), b = 11.920 (1), c = 10.271 (1), sp.gr. Pbcn, Z = 8; for compound 2: a = 6.213 (1), c = 5.004 (1), sp.gr. P3-bar m1, Z = 1. Three-dimensional frame of bound titanium octahedrons and slightly distorted lithium tetragonal pyramids with Li-F distance ranging from 1.86 to 2.24 A is the crystal structure base of compound 1. The structure of compound 2 is made of dose-packed CsF 3 layers and TiF 6 2- octahedrons located between the layers. The types of internal motion of the complex anions were determined by 10 F NMR method, their activation energy in crystals 1 and 2 in the temperature range of 200-500 K being estimated [ru

Fliposomes: pH-triggered conformational flip of new trans-2-aminocyclohexanol-based amphiphiles causes instant cargo release in liposomes.

Science.gov (United States)

Liu, Xin; Zheng, Yu; Samoshina, Nataliya M; Franz, Andreas H; Guo, Xin; Samoshin, Vyacheslav V

2012-12-01

A new type of pH-sensitive liposomes (fliposomes) was designed based on the amphiphiles that are able to perform a pH-triggered conformational flip (flipids). This flip disrupts the liposome membrane and causes rapid release of the liposome cargo, specifically in response to lowered pH. The flipids (1) and (2) are equipped with a trans-2-aminocyclohexanol conformational switch. pH-sensitive fliposomes containing one or both of these flipids, as well as POPC and PEG ceramide, were constructed and characterized. These compositions were stable at 4°C and pH 7.4 for several months. Fliposomes loaded with ANTS/DPX performed an unusually quick content release within a few seconds at pH below 8.5 (in case of 2) and 6.0 (in case of 1). This difference in pH sensitivity demonstrates a potential for the custom design of flipids by variation of the amino group to target areas with specific pH values. The pH titration curves for the fliposome leakage parallel the curves for the acid-induced conformational flip of 1 and 2 studied by ¹H NMR. A plausible mechanism of pH sensitivity starts with an acid-triggered conformational flip of 1 or 2, which changes the molecular size and shape, shortens the lipid tails, and perturbs the liposome membrane, resulting in the content leakage.

Evaluation of the physicochemical properties of liposomes as potential carriers of anticancer drugs: spectroscopic study

International Nuclear Information System (INIS)

Pentak, Danuta

2016-01-01

Vesicle size and composition are a critical parameter for determining the circulation half-life of liposomes. Size influences the degree of drug encapsulation in liposomes. The geometry, size, and properties of liposomes in an aqueous environment have to be described to enable potential applications of liposome systems as drug carriers. The characteristics of multiple thermotropic phase transitions are also an important consideration in liposomes used for analytical and bioanalytical purposes. The aim of this study was to evaluate the physicochemical properties of liposomes which accommodate hydrophilic and amphiphilic drugs used in cancer therapy. The studied liposomes were prepared with the involvement of the modified reverse-phase evaporation method (mREV). The prepared liposomes had a diameter of 70–150 nm. The analyzed compounds were 1-β-d-arabinofuranosylcytosine, cyclophosphamide, and ifosfamide. In literature, there is no information about simultaneous incorporation of cytarabine, ifosfamide, and cyclophosphamide, in spite of the fact that these drugs have been used for more than 30 years. A combination of the examined drugs is used in CODOX-M/IVAC therapy. CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) is one of the currently preferred intensive-dose chemotherapy regimens for Burkitt lymphoma (BL). The present research demonstrates the pioneering studies of incorporation of ifosfamide into liposome vesicles, location of and competition between the analyzed drugs and liposome vesicles. The applied methods were nuclear magnetic resonance (NMR), atomic force microscopy (AFM), differential scanning calorimetry (DSC).Graphical Abstract.

Evaluation of the physicochemical properties of liposomes as potential carriers of anticancer drugs: spectroscopic study

Energy Technology Data Exchange (ETDEWEB)

Pentak, Danuta, E-mail: danuta.pentak@us.edu.pl [University of Silesia, Department of Materials Chemistry and Chemical Technology, Institute of Chemistry (Poland)

2016-05-15

Vesicle size and composition are a critical parameter for determining the circulation half-life of liposomes. Size influences the degree of drug encapsulation in liposomes. The geometry, size, and properties of liposomes in an aqueous environment have to be described to enable potential applications of liposome systems as drug carriers. The characteristics of multiple thermotropic phase transitions are also an important consideration in liposomes used for analytical and bioanalytical purposes. The aim of this study was to evaluate the physicochemical properties of liposomes which accommodate hydrophilic and amphiphilic drugs used in cancer therapy. The studied liposomes were prepared with the involvement of the modified reverse-phase evaporation method (mREV). The prepared liposomes had a diameter of 70–150 nm. The analyzed compounds were 1-β-d-arabinofuranosylcytosine, cyclophosphamide, and ifosfamide. In literature, there is no information about simultaneous incorporation of cytarabine, ifosfamide, and cyclophosphamide, in spite of the fact that these drugs have been used for more than 30 years. A combination of the examined drugs is used in CODOX-M/IVAC therapy. CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) is one of the currently preferred intensive-dose chemotherapy regimens for Burkitt lymphoma (BL). The present research demonstrates the pioneering studies of incorporation of ifosfamide into liposome vesicles, location of and competition between the analyzed drugs and liposome vesicles. The applied methods were nuclear magnetic resonance (NMR), atomic force microscopy (AFM), differential scanning calorimetry (DSC).Graphical Abstract.

Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided platinum-based 2-drug chemotherapy for unresectable nonsmall-cell lung cancer.

Science.gov (United States)

Moon, Yong Wha; Choi, Sung Ho; Kim, Yong Tai; Sohn, Joo Hyuk; Chang, Joon; Kim, Se Kyu; Park, Moo Suk; Chung, Kyung Young; Lee, Hyoun Ju; Kim, Joo-Hang

2007-05-01

The study investigated correlations between adenosine triphosphate / chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-guided platinum-based chemotherapy for unresectable nonsmall-cell lung cancer (NSCLC). The authors performed an in vitro chemosensitivity test, ATP-CRA, to evaluate the chemosensitivities of anticancer drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine for chemonaive, unresectable NSCLC. The cell death rate was determined by measuring the intracellular ATP levels of drug-exposed cells compared with untreated controls. A sensitive drug was defined as a drug producing 30% or more reduction in ATP compared with untreated controls. Assay-guided platinum-based 2-drug chemotherapy was given to patients with pathologically confirmed NSCLC. Thirty-four patients were enrolled. Thirty tumor specimens were obtained by bronchoscopic biopsies and 4 obtained surgically. The median age was 61 years and 27 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The response rate was 43.8%. At a median follow-up period of 16.9 months, the median progression-free and overall survivals were 3.6 and 11.2 months, respectively. Patients were dichotomized into the platinum-sensitive (S; 20 patients) and resistant (R; 14 patients) groups. The positive/negative predictive values were 61.1% and 78.6% with a predictive accuracy of 68.8%. Although without significant differences in pretreatment parameters, the S-group showed better clinical response (P=.036), longer progression-free survival (P=.060), and longer overall survival (P=.025). Despite using bronchoscopic biopsied specimens, ATP-CRA and clinical outcomes correlated well after assay-guided platinum-based 2-drug chemotherapy for unresectable NSCLC. There was a favorable response and survival in the platinum-sensitive vs resistant groups. Copyright (c) 2007 American Cancer Society

Catabolism of 6-ketoprostaglandin F1alpha by the rat kidney cortex.

Science.gov (United States)

Pace-Asciak, C R; Domazet, Z; Carrara, M

1977-05-25

Homogenates of the rat kidney cortex converted 5,8,9,11,12,14,15-hepta-tritiated 6-ketoprostaglandin F 1alpha into one major product identified by gas chromatography-mass spectrometry of the methoxime-methyl ester trimethylsilyl ether derivative as 6,15-diketo-9,11-dihydroxyprost-13-enoic acid. The sequence of derivatisation i.e. methoximation prior to methylation, was crucial as methylation of 15-keto catabolites of the E, F and 6-keto-F series affords degradation products. The corresponding 15-keto-13,14-dihydro catabolite was formed in much smaller quantities. Time course studies indicated that 6-keto-prostaglandin F1alpha was catabolised at a slower rate (about 2-5 fold) than prostaglandin F1alpha. The catabolic activity was blocked by NADH.

Stimuli-responsive Smart Liposomes in Cancer Targeting.

Science.gov (United States)

Jain, Ankit; Jain, Sanjay K

2018-02-08

Liposomes are vesicular carriers which possess aqueous core entrapped within the lipid bilayer. These are carriers of choice because of biocompatible and biodegradable features in addition to flexibility of surface modifications at surface and lipid compositions of lipid bilayers. Liposomes have been reported well for cancer treatment using both passive and active targeting approaches however tumor microenvironment is still the biggest hurdle for safe and effective delivery of anticancer agents. To overcome this problem, stimuli-responsive smart liposomes have emerged as promising cargoes pioneered to anomalous tumor milieu in response to pH, temperature, and enzymes etc. as internal triggers, and magnetic field, ultrasound, and redox potential as external guides for enhancement of drug delivery to tumors. This review focuses on all such stimuli-responsive approaches using fabrication potentiality of liposomes in combination to various ligands, linkers, and PEGylation etc. Scientists engaged in cancer targeting approaches can get benefited greatly with this knowledgeable assemblage of advances in liposomal nanovectors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Physico-chemical studies on the interaction of dendrimers with lipid bilayers. 1. Effect of dendrimer generation and liposome surface charge.

Science.gov (United States)

Roy, Biplab; Panda, Amiya Kumar; Parimi, Srinivas; Ametov, Igor; Barnes, Timothy; Prestidge, Clive A

2014-01-01

Studies on the interaction of different generation poly (amido amine) (PAMAM) dendrimers (2G, 4G and 6G) and liposomes of different compositions were carried out by a combined turbidity, dynamic light scattering and atomic force microscopic measurements. Liposomes comprising soy lecithin (SLC, negative surface charge), 1, 2-palmitoyl-sn-glycero-3-phosphatidylcholine (DPPC, mildly positive surface charge), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol (DPPG, negatively charged) and a biologically simulated mixture of DPPC + DPPG (7:3, M/M, negatively charged) were used as model bilayers. 30 wt% cholesterol was used in each combination as it is known to control the fluidity of membrane bilayers. Silica was used as a negatively charged hard sphere model with an aim to compare the results. Both the turbidity and hydrodynamic diameter values of all the liposomes, except DPPC, passed through maxima upon the progressive addition of PAMAM; the effect was insignificant in case of DPPC. Formation of dendriosome, a complex formed between dendrimer and liposome, resulted in the charge reversal of the negatively charged liposomes. Interaction between PAMAM and liposome was found to be governed by electrostatic as well as hydrogen bonding. Generation dependent PAMAM activity followed the order: 6G >4G>2G in terms of overall dendrimer concentration. However, interestingly, the order was reverse when PAMAM activity was considered in terms of total end group concentrations. AFM studies reveal the rupture of bilayer structure upon addition of dendrimer.

Physical and Oxidative Stability of Uncoated and Chitosan-Coated Liposomes Containing Grape Seed Extract

Directory of Open Access Journals (Sweden)

Jochen Weiss

2013-08-01

Full Text Available Polyphenol-rich grape seed extract (0.1 w/w% was incorporated in liposomes (1 w/w% soy lecithin by high pressure homogenization (22,500 psi and coated with chitosan (0.1 w/w%. Primary liposomes and chitosan-coated secondary liposomes containing grape seed extract showed good physical stability during 98 days of storage. Most of the polyphenols were incorporated in the shell of the liposomes (85.4%, whereas only 7.6% of the polyphenols of grape seed extract were located in the interior of the liposomes. Coating with chitosan did not change the polyphenol content in the liposomes (86.6%. The uncoated liposomes without grape seed extract were highly prone to lipid oxidation. The cationic chitosan coating, however, improved the oxidative stability to some extent, due to its ability to repel pro-oxidant metals. Encapsulated grape seed extract showed high antioxidant activity in both primary and secondary liposomes, which may be attributed to its polyphenol content. In conclusion, the best chemical stability of liposomes can be achieved using a combination of grape seed extract and chitosan.

Evaluation of the immunogenicity of liposome encapsulated HVR1 and NS3 regions of genotype 3 HCV, either singly or in combination

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Gupte Gouri M

2012-03-01

Full Text Available Abstract Background Hepatitis C virus displays a high rate of mutation and exists as a quasispecies in infected patients. In the absence of an effective universal vaccine, genotype-specific vaccine development represents an alternative. We have attempted to develop a genotype 3 based, liposome encapsulated HCV vaccine with hypervariable region-1 (HVR1 and non-structural region-3 (NS3 components. Results HCV RNA extracted from serum samples of 49 chronically infected patients was PCR amplified to obtain HVR1 region. These amplified products were cloned to obtain 20 clones per sample in order to identify the quasispecies pattern. The HVR1 consensus sequence, along with three variants was reverse transcribed to obtain peptides. The peptides were checked for immunoreactivity individually, as a pool or as a single peptide tetramer interspersed with four glycine residues. Anti-HCV positivity varied from 42.6% (tetramer to 92.2% (variant-4 when 115 anti-HCV positive sera representing genotypes 1, 3, 4 and 6 were screened. All the 95 anti-HCV negatives were scored negative by all antigens. Mice were immunized with different liposome encapsulated or Al(OH3 adjuvanted formulations of HVR1 variants and recombinant NS3 protein, and monitored for anti-HVR1 and anti-NS3 antibody titres, IgG isotypes and antigen specific cytokine levels. A balanced Th1/Th2 isotyping response with high antibody titres was observed in most of the liposome encapsulated antigen groups. The effect of liposomes and aluminium hydroxide on the expression of immune response genes was studied using Taqman Low Density Array. Both Th1 (IFN-gamma, Il18 and Th2 (Il4 genes were up regulated in the liposome encapsulated HVR1 variant pool-NS3 combination group. In-vitro binding of the virus to anti-HVR1 antibodies was demonstrated. Conclusion The optimum immunogen was identified to be combination of peptides of HVR1 consensus sequence and its variants along with pNS3 encapsulated in liposomes

Successful haploidentical stem cell transplantation with prophylactic administration of liposomal amphotericin B after invasive pulmonary zygomycosis

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Testuro Ochi

2017-12-01

Full Text Available A 54-year-old woman with acute myeloid leukemia (AML achieved complete remission by induction chemotherapy, but developed zygomycosis after consolidation therapy. As zygomycosis could not be cured by liposomal amphotericin B and micafungin, left lower lobectomy was performed. As AML relapsed 7 months after onset, she received haploidentical stem cell transplantation under administration of liposomal amphotericin B. Despite experiencing severe acute graft-versus-host disease, she remains alive with no relapse of either zygomycosis or AML. Keywords: Zygomycosis, Acute myeloid leukemia, Liposomal amphotericin B, Stem cell transplantation

Preparation of 99mTc-HYNIC-PEG-liposomes for imaging of the focal sites infection

International Nuclear Information System (INIS)

Hong, Jun Pyo; Awh, Ok Doo; Kim, Hyun Suk; Lee, Eun Sook; Lee, Tae Sup; Choi, Tae Hyun; Choi, Chang Woon; Lim, Sang Moo

2002-01-01

A new linker, hydrazino nicotinamide (HYNIC), was recently introduced for labelling of liposome with 99m Tc. In this study we synthesized HYNIC derivatized PEG (polyethylene glycol)-liposomes radiolabeled with 99m Tc. In order to synthesize HYNIC-DSPE (distearoyl phosphatidyl ethanolamine) which is a crucial component for 99m Tc chelation, first of all succinimidyl 6-BOC-hydrazinopyridine-3-carboxylic acid was synthesized from 6-chloronicotinic acid by three sequential reactions. A DSPE derivative of succinimidyl 6-BOC-hydrazinopyridine-3-carboxylic acid was transformed into HYNIC-DSPE by HCI/dioxane. HYNIC-PEG-liposomes were prepared by hydration of the dried lipid mixture of EPC (egg phosphatidyl choline): PEG-DSPE : HYNIC-DSPE: cholesterol (1.85:0.15:0.07:1, molar ratio). The HYNIC-PEG-liposomes were labeled with 99m Tc in the presence of SnCl 2 ·2H 2 O (a reducing agent) and tricine (a colignad). To investigate the level of in vivo transchelation of 99m Tc in the liposomes, the 99m Tc-HYNIC-PEG-liposomes were incubated with a molar excess of DTPA, cysteine or glutathione solutions at 37 .deg. C for 24 hours. 6-BOC-hydrazinopyridine-3-carboxylic acid was synthesized with 77.3% overall yield. The HYNIC concentration in the PEG-coated liposome dispersion was 1.08 mM. In condition of considering the measured liposome size of 106 nm, the phospholipid concentration of 77.5 μmol/ ml and the liposomal particle number of 5.2x10 14 liposomes/ml, it is corresponded to approximate 1,250 nicotinyl hydrazine group per liposome in HYNIC-PEG-liposome. The removal of free 99m Tc was not necessary because the labeling efficiency were above 99%. The radiolabeled liposomes maintained 98%, 96% and 99%, respectively, of radioactivity after incubation with transchelators. The radiolabeled liposomes possessed above 90% of the radioactivity in serum. These results suggest that the HYNIC can be synthesized easily and applied in labelling of PEG-liposomes with 99m Tc

trimethylammoniumpropane-based Liposomes

African Journals Online (AJOL)

mechanisms to introduce therapeutic agents into the body. Currently, the ... Liposomes are biodegradable and non-toxic and can elicit both ... buffered saline by dissolving a vial in 40 ml phosphate ... vaccines were processed using copper grids to adsorb the .... time-dependent fluctuations in the intensity of scattered light ...

Protease-Sensitive Liposomes in Chemotherapy & Chemoradiotherapy: From Material Development to In Vivo Application in Tumor-Bearing Mice

DEFF Research Database (Denmark)

Brogaard, Rikke Yding; Melander, Fredrik

to enhance therapeutic efficacies. In this thesis, the development, characterization, and evaluation of an advanced liposomal DDS and its potential in chemoradiotherapy is presented from material development to in vivo application in tumor*bearing mice. In the first part of the thesis, we report the design...... concept of the liposomal DDS, which leads to rapid cellular uptake. Various lipid compositions are tested in uptake and cytotoxicity experiments in vitro, followed by in vivo experiments where the ability of the liposomal DDS to accumulate in tumors together with its anti*cancer activity is explored...... in tumor*bearing mice. The in vivo data demonstrates superior anti*cancer activity relative to the free drug and to conventional, long circulating liposomes. This indicates that the MMP*sensitive liposomal DDS holds potential in therapeutic applications. In the second part of the thesis, the potential...

Calcium-Responsive Liposomes via a Synthetic Lipid Switch.

Science.gov (United States)

Lou, Jinchao; Carr, Adam J; Watson, Alexa J; Mattern-Schain, Samuel I; Best, Michael D

2018-03-07

Liposomal drug delivery would benefit from enhanced control over content release. Here, we report a novel avenue for triggering release driven by chemical composition using liposomes sensitized to calcium-a target chosen due to its key roles in biology and disease. To demonstrate this principle, we synthesized calcium-responsive lipid switch 1, designed to undergo conformational changes upon calcium binding. The conformational change perturbs membrane integrity, thereby promoting cargo release. This was shown through fluorescence-based release assays via dose-dependent response depending on the percentage of 1 in liposomes, with minimal background leakage in controls. DLS experiments indicated dramatic changes in particle size upon treatment of liposomes containing 1 with calcium. In a comparison of ten naturally occurring metal cations, calcium provided the greatest release. Finally, STEM images showed significant changes in liposome morphology upon treatment of liposomes containing 1 with calcium. These results showcase lipid switches driven by molecular recognition principles as an exciting avenue for controlling membrane properties. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ultraviolet radiation-induced lipid peroxidation in liposomal membrane: modification by capsaicin

International Nuclear Information System (INIS)

De, A.K.; Ghosh, J.J.; Mandal, T.K.

1993-01-01

Ultraviolet-radiation has been reported to cause lipid peroxidation in the liposomal membrane. In the present study, treatment with capsaicin, (8-methyl-n-vanillyl-6-nonenamide), the pungent principle of red hot pepper, was shown to modify UV-induced lipid peroxidation in the liposomal membrane. Treatment with low doses of capsaicin (less than 0.1 μg/mL of phosphatidyl choline liposome) produced a significant increase in UV-induced lipid peroxidation, while high doses (0.1-0.5 μg/mL of PC liposome) caused a significant decrease of UV-induced peroxidation

Ultraviolet radiation-induced lipid peroxidation in liposomal membrane: modification by capsaicin

Energy Technology Data Exchange (ETDEWEB)

De, A. K.; Ghosh, J. J.; Mandal, T. K. [University College of Science, Department of Biochemistry, 35 Ballygunge Circular Road, Calcutta 700-019 (India)

1993-07-01

Ultraviolet-radiation has been reported to cause lipid peroxidation in the liposomal membrane. In the present study, treatment with capsaicin, (8-methyl-n-vanillyl-6-nonenamide), the pungent principle of red hot pepper, was shown to modify UV-induced lipid peroxidation in the liposomal membrane. Treatment with low doses of capsaicin (less than 0.1 μg/mL of phosphatidyl choline liposome) produced a significant increase in UV-induced lipid peroxidation, while high doses (0.1-0.5 μg/mL of PC liposome) caused a significant decrease of UV-induced peroxidation.

Design and syntheses of mono and multivalent mannosyl-lipoconjugates for targeted liposomal drug delivery.

Science.gov (United States)

Štimac, Adela; Cvitaš, Jelena TrmĿiĿ; Frkanec, Leo; Vugrek, Oliver; Frkanec, Ruža

2016-09-10

Multivalent mannosyl-lipoconjugates may be of interest for glycosylation of liposomes and targeted drug delivery because the mannose specifically binds to C-type lectin receptors on the particular cells. In this paper syntheses of two types of novel O-mannosides are presented. Conjugates 1 and 2 with a COOH- and NH2-functionalized spacer and the connection to a lysine and FmocNH-PEG-COOH, are described. The coupling reactions of prepared intermediates 6 and 4 with a PEGylated-DSPE or palmitic acid, respectively, are presented. Compounds 5, mono-, 8, di- and 12, tetravalent mannosyl-lipoconjugates, were synthesized. The synthesized compounds were incorporated into liposomes and liposomal preparations featuring exposed mannose units were characterized. Carbohydrate liposomal quartz crystal microbalance based assay has been established for studying carbohydrate-lectin binding. It was demonstrated that liposomes with incorporated mannosyl-lipoconjugates were effectively recognized by Con A and have great potential to be used for targeted liposomal drug delivery systems. Copyright © 2016 Elsevier B.V. All rights reserved.

Superconductivity of Hg3NbF6 and Hg3TaF6

International Nuclear Information System (INIS)

Datars, W.R.; Morgan, K.R.; Gillespie, R.J.

1983-01-01

Low-temperature ac susceptibility measurements show that two new metallic compounds, Hg 3 TaF 6 and Hg 3 NbF 6 , are superconductors with a critical temperature of 7.0 K. Critical fields are 20% higher in Hg 3 TaF 6 but the temperature dependence of the critical field of the compounds is very similar down to 1.35 K. The critical field extrapolated to T = 0 K is 0.17 T for Hg 3 TaF 6 and 0.13 T for Hg 3 NbF 6

Atmospheric histories and growth trends of C4F10, C5F12, C6F14, C7F16 and C8F18

Directory of Open Access Journals (Sweden)

R. F. Weiss

2012-05-01

Full Text Available Atmospheric observations and trends are presented for the high molecular weight perfluorocarbons (PFCs: decafluorobutane (C4F10, dodecafluoropentane (C5F12, tetradecafluorohexane (C6F14, hexadecafluoroheptane (C7F16 and octadecafluorooctane (C8F18. Their atmospheric histories are based on measurements of 36 Northern Hemisphere and 46 Southern Hemisphere archived air samples collected between 1973 to 2011 using the Advanced Global Atmospheric Gases Experiment (AGAGE "Medusa" preconcentration gas chromatography-mass spectrometry systems. A new calibration scale was prepared for each PFC, with estimated accuracies of 6.8% for C4F10, 7.8% for C5F12, 4.0% for C6F14, 6.6% for C7F16 and 7.9% for C8F18. Based on our observations the 2011 globally averaged dry air mole fractions of these heavy PFCs are: 0.17 parts-per-trillion (ppt, i.e., parts per 1012 for C4F10, 0.12 ppt for C5F12, 0.27 ppt for C6F14, 0.12 ppt for C7F16 and 0.09 ppt for C8F18. These atmospheric mole fractions combine to contribute to a global average radiative forcing of 0.35 mW m−2, which is 6% of the total anthropogenic PFC radiative forcing (Montzka and Reimann, 2011; Oram et al., 2012. The growth rates of the heavy perfluorocarbons were largest in the late 1990s peaking at 6.2 parts per quadrillion (ppq, i.e., parts per 1015 per year (yr for C4F10, at 5.0 ppq yr−1 for C5F12 and 16.6 ppq yr−1 for C6F14 and in the early 1990s for C7F16 at 4.7 ppq yr−1 and in the mid 1990s for C8F18 at 4.8 ppq yr−1. The 2011 globally averaged mean atmospheric growth rates of these PFCs are subsequently lower at 2.2 ppq yr−1 for C4F10, 1.4 ppq yr−1 for C5F12, 5.0 ppq yr−1 for C6F14, 3.4 ppq yr−1 for C7F16 and 0.9 ppq yr−1 for C8F18. The more recent slowdown in the growth rates suggests that emissions are declining as compared to the 1980s and 1990s.

Correlation between radioactivity and chemotherapeutics of the 111In-VNB-liposome in pharmacokinetics and biodistribution in rats

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Tsai TH

2012-02-01

Full Text Available Wen-Chuan Lee1,*, Chih-Hsien Chang2,3,*, Chih-Min Huang1, Yu-Tse Wu1, Liang-Cheng Chen2, Chung-Li Ho2, Tsui-Jung Chang2, Te-Wei Lee2, Tung-Hu Tsai1,41Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, 2Division of Isotope Application, Institute of Nuclear Energy Research, Taoyuan, 3Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 4Department of Education and Research, Taipei City Hospital, Taipei, Taiwan*These authors contributed equally to this workBackground: The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [111In-VNB-liposome] has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the 111In-VNB-liposome.Methods: The VNB-liposome and 111In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the 111In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111.Results: High uptake of the 111In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97 between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the 111In-VNB-liposome.Conclusion: A significant positive correlation between the pharmacokinetics and biodistribution of 111Indium radioactivity and vinorelbine in blood, spleen

Solid tumors after chemotherapy or surgery for testicular nonseminoma: a population-based study.

Science.gov (United States)

Fung, Chunkit; Fossa, Sophie D; Milano, Michael T; Oldenburg, Jan; Travis, Lois B

2013-10-20

Increased risks of solid tumors after older radiotherapy strategies for testicular cancer (TC) are well established. Few population-based studies, however, focus on solid cancer risk among survivors of TC managed with nonradiotherapy approaches. We quantified the site-specific risk of solid cancers among testicular nonseminoma patients treated in the modern era of cisplatin-based chemotherapy, without radiotherapy. Standardized incidence ratios (SIRs) for solid tumors were calculated for 12,691 patients with testicular nonseminoma reported to the population-based Surveillance, Epidemiology, and End Results program (1980 to 2008) and treated initially with either chemotherapy (n = 6,013) or surgery (n = 6,678) without radiotherapy. Patients accrued 116,073 person-years of follow-up. Two hundred ten second solid cancers were observed. No increased risk followed surgery alone (SIR, 0.93; 95% CI, 0.76 to 1.14; n = 99 solid cancers), whereas significantly increased 40% excesses (SIR, 1.43; 95% CI, 1.18 to 1.73; n = 111 solid cancers) occurred after chemotherapy. Increased risks of solid cancers after chemotherapy were observed in most follow-up periods (median latency, 12.5 years), including more than 20 years after treatment (SIR, 1.54; 95% CI, 0.96 to 2.33); significantly increased three- to seven-fold risks occurred for cancers of the kidney (SIR, 3.37; 95% CI, 1.79 to 5.77), thyroid (SIR, 4.40; 95% CI, 2.19 to 7.88), and soft tissue (SIR, 7.49; 95% CI, 3.59 to 13.78). To our knowledge, this is the first large population-based series reporting significantly increased risks of solid cancers among patients with testicular nonseminoma treated in the modern era of cisplatin-based chemotherapy. Subsequent analytic studies should focus on the evaluation of dose-response relationships, types of solid cancers, latency patterns, and interactions with other possible factors, including genetic susceptibility.

Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia

Directory of Open Access Journals (Sweden)

Salade L

2017-11-01

Full Text Available Laurent Salade,1 Nathalie Wauthoz,1 Magali Deleu,2 Marjorie Vermeersch,3 Carine De Vriese,1 Karim Amighi,1 Jonathan Goole1 1Laboratoire de Pharmacie Galénique et de Biopharmacie, Université libre de Bruxelles (ULB, Brussels, 2Laboratoire de Biophysique Moléculaire aux Interfaces, Gembloux Agro-Bio Tech, Université de Liège, Gembloux, 3Centre for Microscopy and Molecular Imaging (CMMI, Charleroi, Belgium Abstract: The aim of the present study was to develop a ghrelin-containing formulation based on liposomes coated with chitosan intended for nose–brain delivery for the treatment of cachexia. Among the three types of liposomes developed, anionic liposomes provided the best results in terms of encapsulation efficiency (56% and enzymatic protection against trypsin (20.6% vs 0% for ghrelin alone and carboxylesterase (81.6% vs 17.2% for ghrelin alone. Ghrelin presented both electrostatic and hydrophobic interactions with the anionic lipid bilayer, as demonstrated by isothermal titration calorimetry. Then, anionic liposomes were coated with N-(2-hydroxypropyl-3-trimethyl ammonium chitosan chloride. The coating involved a size increment from 146.9±2.7 to 194±6.1 nm, for uncoated and coated liposomes, respectively. The ζ-potential was similarly increased from -0.3±1.2 mV to 6±0.4 mV before and after coating, respectively. Chitosan provided mucoadhesion, with an increase in mucin adsorption of 22.9%. Enhancement of permeation through the Calu3 epithelial monolayer was also observed with 10.8% of ghrelin recovered in the basal compartment in comparison to 0% for ghrelin alone. Finally, aerosols generated from two nasal devices (VP3 and SP270 intended for aqueous dispersion were characterized with either coated or uncoated liposomes. Contrarily to the SP270 device, VP3 device showed minor changes between coated and uncoated liposome aerosols, as shown by their median volume diameters of 38.4±5.76 and 37.6±5.74 µm, respectively. Overall, the

[Preparation of diclofenac sodium liposomes and its ocular pharmacokinetics].

Science.gov (United States)

Sun, Kao-xiang; Wang, Ai-ping; Huang, Li-jun; Liang, Rong-cai; Liu, Ke

2006-11-01

To prepare diclofenac sodium liposomes and observe its ocular pharmacokinetics in rabbits. The diclofenac sodium cationic liposomes were prepared by reverse-phase evaporation methods and the formula of liposome was optimized with uniform design. HPLC method was established and validated for the determination of diclofenac sodium in precornea, cornea and aqueous humor of rabbit eye. Liposome and eyedrop solution 50 microL with total 50 microg diclofenac sodium were instilled to eyes of rabbits, separately. Samples of tear, cornea and aqueous humor were collected at different time intervals after rabbits were sacrificed. The ocular pharmacokinetics was investigated by the concentration-time data of tear, cornea and aqueous humor. The mean particle size of the diclofenac sodium liposomes was 226.5 nm with zeta potential of + 18. 1 mV. The entrapment efficiency reached 63%. Compared with solution, liposome was characterized by slower clearance in precornea. The concentration of diclotenac in cornea and aqueous humor instilled with liposome were higher than that with eye-drop solution. Cmax of diclofenac sodium in aqueous humor instilled with liposome and eye-drop solution were (0.69 +/- 0.25) and (0.48 +/- 0.19) microg x mL(-1) and (36.68 +/- 11.7) and (21.82 +/- 8.6) microg x g(-1) in cornea, respectively. But no significant difference were found to Tmax in aqueous humor and cornea between liposome and eyedrop, T(1/2) of diclofenac in aqueous humor and cornea with liposoine were longer than that with eye-drop solution. The ocular bioavailability of liposome in aqueous humor was 211% compared with that of eyedrop. Diclofenac sodium cationic liposomes can increase the corneal contact time, enhance the corneal permeability of diclofenac sodium and improve its ocular bioavailability.

Prevention of blood transfusion with intravenous iron in gynecologic cancer patients receiving platinum-based chemotherapy.

Science.gov (United States)

Athibovonsuk, Punnada; Manchana, Tarinee; Sirisabya, Nakarin

2013-12-01

To compare the efficacy of intravenous iron and oral iron for prevention of blood transfusions in gynecologic cancer patients receiving platinum-based chemotherapy. Sixty-four non anemic gynecologic cancer patients receiving adjuvant platinum-based chemotherapy were stratified and randomized according to baseline hemoglobin levels and chemotherapy regimen. The study group received 200mg of intravenous iron sucrose immediately after each chemotherapy infusion. The control group received oral ferrous fumarate at a dose of 200mg three times a day. Complete blood count was monitored before each chemotherapy infusion. Blood transfusions were given if hemoglobin level was below 10mg/dl. There were 32 patients in each group. No significant differences in baseline hemoglobin levels and baseline characteristics were demonstrated between both groups. Nine patients (28.1%) in the study group and 18 patients (56.3%) in the control group required blood transfusion through 6 cycles of chemotherapy (p=0.02). Fewer median number of total packed red cell units were required in the study group compared to the control group (0 and 0.5 unit, respectively, p=0.04). Serious adverse events and hypersensitivity reactions were not reported. However, constipation was significantly higher in the control group (3.1% and 40.6%, p=gynecologic cancer patients receiving platinum-based chemotherapy, associated with less constipation than the oral formulation. © 2013 Elsevier Inc. All rights reserved.

Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors.

Science.gov (United States)

Kesler, Shelli R; Blayney, Douglas W

2016-02-01

Chemotherapy exposure is a known risk factor for cancer-related cognitive impairments. Anthracycline-based regimens are commonly used chemotherapies that have been shown to be associated with cognitive impairment and brain changes in clinical studies. To directly compare the effects of anthracycline and nonanthracycline regimens on cognitive status and functional brain connectivity. In this observational study, we retrospectively examined cognitive and resting state functional magnetic resonance imaging data acquired from 62 primary breast cancer survivors (mean [SD] age, 54.7 [8.5] years) who were more than 2 years off-therapy, on average. Twenty of these women received anthracycline-based chemotherapy as part of their primary treatment, 19 received nonanthracycline regimens, and 23 did not receive any chemotherapy. Participants were enrolled at a single academic institution (Stanford University) from 2008 to 2014, and the study analyses were performed at this time. Cognitive status was measured using standardized neuropsychological tests, and functional brain connectivity was evaluated using resting state functional magnetic resonance imaging with a focus on the brain's default mode network. The anthracycline group demonstrated significantly lower verbal memory performance including immediate recall (F = 3.73; P = .03) and delayed recall (F = 11.11; P < .001) as well as lower left precuneus connectivity (F = 7.48; P = .001) compared with the other 2 groups. Patient-reported outcomes related to cognitive dysfunction (F = 7.27; P = .002) and psychological distress (F = 5.64; P = .006) were similarly elevated in both chemotherapy groups compared with the non-chemotherapy-treated controls. These results suggest that anthracyclines may have greater negative effects than nonanthracycline regimens on particular cognitive domains and brain network connections. Both anthracycline and nonanthracycline regimens may have nonspecific effects on other cognitive

[Liposome-mediated glial growth factor 2 gene therapy in brain injury: an experimental study with rats].

Science.gov (United States)

Xue, Ya-jun; Dong, Yan; Han, Xi; Wei, Mei-yang; Ge, Jun-hui; Cai, Ru-jue; Hu, Guo-han; Luo, Chun; Zhu, Cheng; Lu, Yi-cheng

2006-09-05

To explore the protective effect of glial growth factor-2 (GGF2) on brain injury. Thirty-four SD rats underwent lateral fluid percussion to establish brain injury models and then were randomly divided into 4 groups: treatment group (n = 10, the plasmid pEGFP-N1-GGF2 mixed with liposome was injected into the brain tissue directly), vector control group (n = 10, the vector pEGFP-N1 mixed with liposome was injected into the brain tissue directly), liposome control group (n = 10, liposome was injected), and sham operation group (n = 4). Three assessment tasks were performed for neurobehavioral evaluation: Clivas Test, Beam Balance Test and Beam Walking Test. 10 days after brain injury, the rats were sacrificed and their brains were embedded in paraffin for HE staining, Nissle staining and immunohistochemical examination of MBP, NSE, and GFAP. The Clivas test score of the treatment group was 66.25 +/- 3.54, significantly higher than those of the vector control group and. liposome control group (58.31 +/- 3.72 and 57.21 +/- 3.93 respectively, both P beam test score of the treatment group was 2.59 +/- 0.21, significantly lower than those the vector control group and liposome control group (3.41 +/- 0.25 and 3.24 +/- 0.22 respectively, both P walking test score of the treatment group was 20.15 +/- 2.59, significantly lower than those of control group and liposome control group (27.00 +/- 3.47 and 27.80 +/- 3.00 respectively, both P beam walking test was the greatest. The neuron number in the external granular layer and external pyramidal layer in cortex of the treatment group was 98 +/- 10, significantly more than those of the vector control group and liposome group (75 +/- 7 and 67 +/- 8, both P < 0.05). The neuron number in the internal pyramidal layer in cortex of the treatment group was 37 +/- 4, significantly more than those of the vector control group and liposome group (19 +/- 3 and 23 +/- 4 respectively, both P < 0.05). The neuron number in the CA1 region in

Crystal structure of difluorochloronium hexafluoroniobate and hexafluorotantalate, ClF2NbF6 and ClF2TaF6

International Nuclear Information System (INIS)

Ehllern, A.M.; Antipin, M.Yu.; Sharabarin, A.V.; Struchkov, Yu.T.

1991-01-01

Crystal structure of ClF 2 NbF 6 (1) and ClF 2 TaF 6 (2) were investigated by the method of X-ray diffraction analysis. Salts 1 and 2 are isostructural, crystals are rhombic: a = 9.981(2) and 10.049(2), b = 5.781(1) and 5.775(1), c = 10.552(2) and 10.670(2) A, V = 608.9(3) and 619.2(3) A 3 , Z = 4, d calcd 3.058 and 3.952 g/cm 3 , sp. gr. Pcca. Both salts are characterized by ionic structure. Bond lengths and valent angles, general view of 1 crystal structure are presented

Improved permeability of acyclovir: optimization of mucoadhesive liposomes using the phospholipid vesicle-based permeation assay.

Science.gov (United States)

Naderkhani, Elenaz; Erber, Astrid; Škalko-Basnet, Nataša; Flaten, Gøril Eide

2014-02-01

The antiviral drug acyclovir (ACV) suffers from poor solubility both in lipophilic and hydrophilic environment, leading to low and highly variable bioavailability. To overcome these limitations, this study aimed at designing mucoadhesive ACV-containing liposomes to improve its permeability. Liposomes were prepared from egg phosphatidylcholine (E-PC) and E-PC/egg phosphatidylglycerol (E-PC/E-PG) and their surfaces coated with Carbopol. All liposomal formulations were fully characterized and for the first time the phospholipid vesicle-based permeation assay (PVPA) was used for testing in vitro permeability of drug from mucoadhesive liposome formulations. The negatively charged E-PC/E-PG liposomes could encapsulate more ACV than neutral E-PC liposomes. Coating with Carbopol increased the entrapment in the neutral E-PC liposomes. The incorporation of ACV into liposomes exhibited significant increase in its in vitro permeability, compared with its aqueous solution. The neutral E-PC liposomal formulations exhibited higher ACV permeability values compared with charged E-PC/E-PG formulations. Coating with Carbopol significantly enhanced the permeability from the E-PC/E-PG liposomes, as well as sonicated E-PC liposomes, which showed the highest permeability of all tested formulations. The increased permeability was according to the formulations' mucoadhesive properties. This indicates that the PVPA is suitable to distinguish between permeability of ACV from different mucoadhesive liposome formulations developed for various routes of administration. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Influence of trehalose 6,6'-diester (TDX) chain length on the physicochemical and immunopotentiating properties of DDA/TDX liposomes

DEFF Research Database (Denmark)

Kallerup, Rie Selchau; Madsen, Cecilie Maria; Schiøth, Mikkel Lohmann

2015-01-01

Linking physicochemical characterization to functional properties is crucial for defining critical quality attributes during development of subunit vaccines toward optimal safety and efficacy profiles. We investigated how the trehalose 6,6'-diester (TDX) chain length influenced the physicochemical...... and immunopotentiating properties of the clinically tested liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and analogues of trehalose-6,6'-dibehenate (TDB). TDB analogues with symmetrically shortened acyl chains [denoted X: arachidate (A), stearate (S), palmitate (P), myristate (Myr) and laurate...

New Transfection Agents Based on Liposomes Containing Biosurfactant MEL-A.

Science.gov (United States)

Nakanishi, Mamoru; Inoh, Yoshikazu; Furuno, Tadahide

2013-08-16

Nano vectors are useful tools to deliver foreign DNAs, oligonucleotides, and small interfering double-stranded RNAs (siRNAs) into mammalian cells with gene transfection and gene regulation. In such experiments we have found the liposomes with a biosurfacant mannosylerythriol lipid (MEL-A) are useful because of their high transfer efficiency, and their unique mechanism to transfer genes to target cells with the lowest toxicity. In the present review we will describe our current work, which may contribute to the great advance of gene transfer to target cells and gene regulations. For more than two decades, the liposome technologies have changed dramatically and various methods have been proposed in the fields of biochemistry, cell biology, biotechnology, and so on. In addition, they were towards to pharmaceutics and clinical applications. The liposome technologies were expected to use gene therapy, however, they have not reached a requested goal as of yet. In the present paper we would like to present an approach using a biosurfactant, MEL-A, which is a surface-active compound produced by microorganisms growing on water-insoluble substrates and increases efficiency in gene transfection. The present work shows new transfection agents based on liposomes containing biosurfactant MEL-A.

The Role of Liposomal Bupivacaine in Value-Based Care.

Science.gov (United States)

Iorio, Richard

Multimodal pain control strategies are crucial in reducing opioid use and delivering effective pain management to facilitate improved surgical outcomes. The utility of liposomal bupivacaine in enabling effective pain control in multimodal strategies has been demonstrated in several studies, but others have found the value of liposomal bupivacaine in such approaches to be insignificant. At New York University Langone Medical Center, liposomal bupivacaine injection and femoral nerve block were compared in their delivery of efficacious and cost-effective multimodal analgesia among patients undergoing total joint arthroplasty (TJA). Retrospective analysis revealed that including liposomal bupivacaine in a multimodal pain control protocol for TJA resulted in improved quality and efficiency metrics, decreased narcotic use, and faster mobilization, all relative to femoral nerve block, and without a significant increase in admission costs. In addition, liposomal bupivacaine use was associated with elimination of the need for patient-controlled analgesia in TJA. Thus, at Langone Medical Center, the introduction of liposomal bupivacaine to TJA has been instrumental in achieving adequate pain control, delivering high-level quality of care, and controlling costs.

Tandem repeat variation near the HIC1 (hypermethylated in cancer 1) promoter predicts outcome of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.

Science.gov (United States)

Okazaki, Satoshi; Schirripa, Marta; Loupakis, Fotios; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Berger, Martin D; Miyamoto, Yuji; Suenaga, Mitsukuni; Iqubal, Syma; Barzi, Afsaneh; Cremolini, Chiara; Falcone, Alfredo; Battaglin, Francesca; Salvatore, Lisa; Borelli, Beatrice; Helentjaris, Timothy G; Lenz, Heinz-Josef

2017-11-15

The hypermethylated in cancer 1/sirtuin 1 (HIC1/SIRT1) axis plays an important role in regulating the nucleotide excision repair pathway, which is the main oxaliplatin-induced damage-repair system. On the basis of prior evidence that the variable number of tandem repeat (VNTR) sequence located near the promoter lesion of HIC1 is associated with HIC1 gene expression, the authors tested the hypothesis that this VNTR is associated with clinical outcome in patients with metastatic colorectal cancer who receive oxaliplatin-based chemotherapy. Four independent cohorts were tested. Patients who received oxaliplatin-based chemotherapy served as the training cohort (n = 218), and those who received treatment without oxaliplatin served as the control cohort (n = 215). Two cohorts of patients who received oxaliplatin-based chemotherapy were used for validation studies (n = 176 and n = 73). The VNTR sequence near HIC1 was analyzed by polymerase chain reaction analysis and gel electrophoresis and was tested for associations with the response rate, progression-free survival, and overall survival. In the training cohort, patients who harbored at least 5 tandem repeats (TRs) in both alleles had a significantly shorter PFS compared with those who had fewer than 4 TRs in at least 1 allele (9.5 vs 11.6 months; hazard ratio, 1.93; P = .012), and these findings remained statistically significant after multivariate analysis (hazard ratio, 2.00; 95% confidence interval, 1.13-3.54; P = .018). This preliminary association was confirmed in the validation cohort, and patients who had at least 5 TRs in both alleles had a worse PFS compared with the other cohort (7.9 vs 9.8 months; hazard ratio, 1.85; P = .044). The current findings suggest that the VNTR sequence near HIC1 could be a predictive marker for oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Cancer 2017;123:4506-14. © 2017 American Cancer Society. © 2017 American Cancer Society.

New organic superconductors beta-(BDA-TTP)2X [BDA-TTP + 2,5-bis(1,3-dithian-2ylidene)-1,3,4,6-tetrathiapentalene; X(-) = SbF6(-), AsF6(-), and PF6(-)].

Science.gov (United States)

Yamada, J; Watanabe, M; Akutsu, H; Nakatsuji, S; Nishikawa, H; Ikemoto, I; Kikuchi, K

2001-05-09

The synthesis, electrochemical properties, and molecular structure of a new pi-electron donor, 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA-TTP), is described. In contrast to the hitherto-known tetrachalcogenafulvalene pi-donors providing organic superconductors, this donor contains only the bis-fused 1,3-dithiole-2-ylidene unit as a pi-electron system, yet produces a series of ambient-pressure superconductors beta-(BDA-TTP)2X [X = SbF6 (magnetic T(c) = 6.9 K, resistive T(c) = 7.5 K), AsF6 (magnetic T(c) = 5.9 K, resistive T(c) = 5.8 K), and PF6 (magnetic T(c) = 5.9 K)], which are isostructural. The values of the intermolecular overlap integrals calculated on the donor layers of these superconductors suggest a two-dimensional (2D) electronic structure with loose donor packing. Tight-binding band calculations also indicate that these superconductors have the 2D band dispersion relations and closed Fermi surfaces.

S-1 monotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck after progression on platinum-based chemotherapy

International Nuclear Information System (INIS)

Yokota, Tomoya; Onozawa, Yusuke; Boku, Narikazu

2011-01-01

Platinum compounds play pivotal roles in treatment for squamous cell carcinoma of the head and neck. The objective was to evaluate the efficacy of S-1 monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy. We retrospectively analyzed 39 consecutive patients with recurrent or metastatic squamous cell carcinoma of the head and neck who received S-1 monotherapy after failure of platinum-based chemotherapy or chemoradiotherapy at the Shizuoka Cancer Center between August 2003 and October 2010. S-1 was given orally twice daily (80 mg/m 2 /day) for 28 days followed by a 14-day rest. The median follow-up period in survivors was 31.5 months. Among 38 patients with measurable lesions, 9 (24%) showed partial response and 15 (39%) showed stable disease. The median progression-free survival was 4.9 months and the median overall survival was 13.2 months. The median progression-free survival for oropharyngeal cancer (n=7) was significantly longer than for other cancers (n=32) (14.9 vs. 4.7 months, P=0.035). The response rate in patients with a recurrence-free interval since the last platinum administration >6.0 months was significantly better than with a recurrence-free interval 6.0 months also showed a significantly better progression-free survival (6.0 vs. 2.6 months, P=0.045). The frequency of Grade 3/4 toxicities was less than 10%. S-1 monotherapy shows promising signs of efficacy and tolerability in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy in this retrospective cohort and warrants further investigation in this population. (author)

Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia.

Science.gov (United States)

Salade, Laurent; Wauthoz, Nathalie; Deleu, Magali; Vermeersch, Marjorie; De Vriese, Carine; Amighi, Karim; Goole, Jonathan

2017-01-01

The aim of the present study was to develop a ghrelin-containing formulation based on liposomes coated with chitosan intended for nose-brain delivery for the treatment of cachexia. Among the three types of liposomes developed, anionic liposomes provided the best results in terms of encapsulation efficiency (56%) and enzymatic protection against trypsin (20.6% vs 0% for ghrelin alone) and carboxylesterase (81.6% vs 17.2% for ghrelin alone). Ghrelin presented both electrostatic and hydrophobic interactions with the anionic lipid bilayer, as demonstrated by isothermal titration calorimetry. Then, anionic liposomes were coated with N -(2-hydroxy) propyl-3-trimethyl ammonium chitosan chloride. The coating involved a size increment from 146.9±2.7 to 194±6.1 nm, for uncoated and coated liposomes, respectively. The ζ-potential was similarly increased from -0.3±1.2 mV to 6±0.4 mV before and after coating, respectively. Chitosan provided mucoadhesion, with an increase in mucin adsorption of 22.9%. Enhancement of permeation through the Calu3 epithelial monolayer was also observed with 10.8% of ghrelin recovered in the basal compartment in comparison to 0% for ghrelin alone. Finally, aerosols generated from two nasal devices (VP3 and SP270) intended for aqueous dispersion were characterized with either coated or uncoated liposomes. Contrarily to the SP270 device, VP3 device showed minor changes between coated and uncoated liposome aerosols, as shown by their median volume diameters of 38.4±5.76 and 37.6±5.74 µm, respectively. Overall, the results obtained in this study show that the developed formulation delivered by the VP3 device can be considered as a potential candidate for nose-brain delivery of ghrelin.

Chemotherapy for intracranial ependymoma in adults

International Nuclear Information System (INIS)

Gramatzki, Dorothee; Roth, Patrick; Felsberg, Jörg; Hofer, Silvia; Rushing, Elisabeth J.; Hentschel, Bettina; Westphal, Manfred; Krex, Dietmar; Simon, Matthias; Schnell, Oliver; Wick, Wolfgang; Reifenberger, Guido; Weller, Michael

2016-01-01

Ependymal tumors in adults are rare, accounting for less than 4 % of primary tumors of the central nervous system in this age group. The low prevalence of intracranial ependymoma in adults limits the ability to perform clinical trials. Therefore, treatment decisions are based on small, mostly retrospective studies and the role of chemotherapy has remained unclear. We performed a retrospective study on 17 adult patients diagnosed with intracranial World Health Organisation grade II or III ependymoma, who were treated with chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by applying Macdonald criteria. Progression-free (PFS) and overall survival (OS) were calculated from start of chemotherapy, using the Kaplan-Meier method. Eleven patients had supratentorial and 6 infratentorial tumors. Ten patients were treated with temozolomide (TMZ), 3 with procarbazine/lomustine/vincristine (PCV), 3 with platinum-based chemotherapy and 1 patient received epirubicin/ifosfamide. Response rates were as follows: TMZ 8/10 stable disease; PCV 3/3 stable disease; platinum-based chemotherapy 1/3 partial response; epirubicin/ifosfamide 1/1 complete response. PFS rates at 6, 12 and 24 months were 52.9, 35.3 and 23.5 %. OS rates at 6, 12 and 24 months were 82.4, 82.4 and 70.1 %. There was no indication for a favourable prognostic role of O 6 -methylguanyl-DNA-methyltransferase (MGMT) promoter methylation which was detected in 3/12 investigated tumors. Survival outcomes in response to chemotherapy in adult intracranial ependymoma patients vary substantially, but individual patients may respond to any kind of chemotherapy. There were too few patients to compare survival data between chemotherapeutic subgroups. The online version of this article (doi:10.1186/s12885-016-2323-0) contains supplementary material, which is available to authorized users

Octanol-assisted liposome assembly on chip

NARCIS (Netherlands)

Deshpande, S.R.; Caspi, Y.; Meijering, A.E.C.; Dekker, C.

2016-01-01

Liposomes are versatile supramolecular assemblies widely used in basic and applied sciences. Here we present a novel microfluidics-based method, octanol-assisted liposome assembly (OLA), to form monodisperse, cell-sized (5–20 μm), unilamellar liposomes with excellent encapsulation efficiency. Akin

Plasmon resonant liposomes for controlled drug delivery

Science.gov (United States)

Knights-Mitchell, Shellie S.; Romanowski, Marek

2015-03-01

Nanotechnology use in drug delivery promotes a reduction in systemic toxicity, improved pharmacokinetics, and better drug bioavailability. Liposomes continue to be extensively researched as drug delivery systems (DDS) with formulations such as Doxil® and Ambisome® approved by FDA and successfully marketed in the United States. However, the limited ability to precisely control release of active ingredients from these vesicles continues to challenge the broad implementation of this technology. Moreover, the full potential of the carrier to sequester drugs until it can reach its intended target has yet to be realized. Here, we describe a liposomal DDS that releases therapeutic doses of an anticancer drug in response to external stimulus. Earlier, we introduced degradable plasmon resonant liposomes. These constructs, obtained by reducing gold on the liposome surface, facilitate spatial and temporal release of drugs upon laser light illumination that ultimately induces an increase in temperature. In this work, plasmon resonant liposomes have been developed to stably encapsulate and retain doxorubicin at physiological conditions represented by isotonic saline at 37o C and pH 7.4. Subsequently, they are stimulated to release contents either by a 5o C increase in temperature or by laser illumination (760 nm and 88 mW/cm2 power density). Successful development of degradable plasmon resonant liposomes responsive to near-infrared light or moderate hyperthermia can provide a new delivery method for multiple lipophilic and hydrophilic drugs with pharmacokinetic profiles that limit clinical utility.

Antitumor effect of iRGD-modified liposomes containing conjugated linoleic acid–paclitaxel (CLA-PTX on B16-F10 melanoma

Directory of Open Access Journals (Sweden)

Du R

2014-06-01

Full Text Available Ruo Du,1 Ting Zhong,1 Wei-Qiang Zhang,1 Ping Song,1 Wen-Ding Song,1 Yang Zhao,1 Chao-Wang,1 Yi-Qun Tang,3 Xuan Zhang,1,2 Qiang Zhang1,2 1Department of Pharmaceutics, 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 3Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: In the present study, we prepared a novel delivery system of iRGD (CRGDK/RGPD/EC-modified sterically stabilized liposomes (SSLs containing conjugated linoleic acid–paclitaxel (CLA-PTX. The anti-tumor effect of iRGD-SSL-CLA-PTX was investigated on B16-F10 melanoma in vitro and in vivo. The in vitro targeting effect of iRGD-modified SSLs was investigated in a real-time confocal microscopic analysis experiment. An endocytosis-inhibition assay was used to evaluate the endocytosis pathways of the iRGD-modified SSLs. In addition, the in vitro cellular uptake and in vitro cytotoxicity of iRGD-SSL-CLA-PTX were evaluated in B16-F10 melanoma cells. In vivo biodistribution and in vivo antitumor effects of iRGD-SSL-CLA-PTX were investigated in B16-F10 tumor-bearing mice. The induction of apoptosis by iRGD-SSL-CLA-PTX was evaluated in tumor-tissue sections. Real-time confocal microscopic analysis results indicated that the iRGD-modified SSLs internalized into B16-F10 cells faster than SSLs. The identified endocytosis pathway of iRGD-modified SSLs indicated that energy- and lipid raft-mediated endocytosis played a key role in the liposomes’ cellular uptake. The results of the cellular uptake experiment indicated that the increased cellular uptake of CLA-PTX in the iRGD-SSL-CLA-PTX-treated group was 1.9-, 2.4-, or 2.1-fold compared with that in the CLA-PTX group after a 2-, 4-, or 6-hour incubation, respectively. In the biodistribution test, the CLA-PTX level in tumor tissues from iRGD-SSL-CLA-PTX-treated mice at 1 hour (1.84±0.17 µg/g and 4 hours (1.17±0

Body distributioin of RGD-mediated liposome in brain-targeting drug delivery.

Science.gov (United States)

Qin, Jing; Chen, DaWei; Hu, Haiyang; Qiao, MingXi; Zhao, XiuLi; Chen, Baoyu

2007-09-01

RGD conjugation liposomes (RGD-liposomes) were evaluated for brain-targeting drug delivery. The flow cytometric in vitro study demonstrated that RGD-liposomes could bind to monocytes and neutrophils effectively. Ferulic acid (4-hydroxy-3-methoxycinnamic, FA) was loaded into liposomes. Rats were subjected to intrastriatal microinjections of 100 units of human recombinant IL-1beta to produce brain inflammation and caudal vein injection of three formulations (FA solution, FA liposome and RGD-coated FA liposome). Animals were sacrificed 15, 30, 60 and 120 min after administration to study the body distribution of the FA in the three formulations. HPLC was used to determine the concentration of FA in vivo with salicylic acid as internal standard. The results of body distribution indicated that RGD-coated liposomes could be mediated into the brain with a 6-fold FA concentration compared to FA solution and 3-fold in comparison to uncoated liposome. Brain targeted delivery was achieved and a reduction in dosage might be allowed.

Chemical coupling of thiolated chitosan to preformed liposomes improves mucoadhesive properties

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Gradauer K

2012-05-01

Full Text Available Kerstin Gradauer,1 Caroline Vonach,1 Gerd Leitinger,2,3 Dagmar Kolb,2,3 Eleonore Fröhlich,3 Eva Roblegg,4 Andreas Bernkop-Schnürch,5 Ruth Prassl1,61Institute of Biophysics and Nanosystems Research, Austrian Academy of Sciences, Graz, Austria; 2Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria; 3Center for Medical Research, Medical University of Graz, Graz, Austria; 4Institute of Pharmaceutical Sciences/Pharmaceutical Technology, Karl-Franzens University, Graz, Austria; 5Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria; 6Ludwig Boltzmann Institute for Lung Vascular Research, Graz, AustriaAim: To develop mucoadhesive liposomes by anchoring the polymer chitosan-thioglycolic acid (chitosan-TGA to the liposomal surface to target intestinal mucosal membranes.Methods: Liposomes consisting of phosphatidylcholine (POPC and a maleimide-functionalized lipid were incubated with chitosan-TGA, leading to the formation of a thioether bond between free SH-groups of the polymer and maleimide groups of the liposome. Uncoated and newly generated thiomer-coated liposomes were characterized according to their size, zeta potential, and morphology using photon correlation spectroscopy and transmission electron microscopy. The release behavior of calcitonin and the fluorophore/quencher-couple ANTS/DPX (8-aminonaphthalene-1,3,6-trisulfonic acid/p-xylene-bis- pyridinium bromide from coated and uncoated liposomes, was investigated over 24 hours in simulated gastric and intestinal fluids. To test the mucoadhesive properties of thiomer-coated and uncoated liposomes in-vitro, we used freshly excised porcine small intestine.Results: Liposomes showed a concentration-dependent increase in size – from approximately 167 nm for uncoated liposomes to 439 nm for the highest thiomer concentration used in this study. Likewise, their zeta potentials gradually increased from

Liposomal flucytosine capped with gold nanoparticle formulations for improved ocular delivery

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Salem HF

2016-01-01

Full Text Available Heba F Salem,1 Sayed M Ahmed,2 Mahmoud M Omar3 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt; 2Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 3Department of Industrial Pharmacy, Faculty of Pharmacy, Deraya University, El-Minia, Egypt Abstract: Nanoliposomes have an organized architecture that provides versatile functions. In this study, liposomes were used as an ocular carrier for nanogold capped with flucytosine antifungal drug. Gold nanoparticles were used as a contrasting agent that provides tracking of the drug to the posterior segment of the eye for treating fungal intraocular endophthalmitis. The nanoliposomes were prepared with varying molar ratios of lecithin, cholesterol, Span 60, a positive charge inducer (stearylamine, and a negative charge inducer (dicetyl phosphate. Formulation F6 (phosphatidylcholine, cholesterol, Span 60, and stearylamine at a molar ratio of 1:1:1:0.15 demonstrated the highest extent of drug released, which reached 7.043 mg/h. It had a zeta potential value of 42.5±2.12 mV and an average particle size approaching 135.1±12.0 nm. The ocular penetration of the selected nanoliposomes was evaluated in vivo using a computed tomography imaging technique. It was found that F6 had both the highest intraocular penetration depth (10.22±0.11 mm as measured by the computed tomography and the highest antifungal efficacy when evaluated in vivo using 32 infected rabbits’ eyes. The results showed a strong correlation between the average intraocular penetration of the nanoparticles capped with flucytosine and the percentage of the eyes healed. After 4 weeks, all the infected eyes (n=8 were significantly healed (P<0.01 when treated with liposomal formulation F6. Overall, the nanoliposomes encapsulating flucytosine have been proven efficient in treating the infected rabbits’ eyes, which proves the efficiency of the

18F-fluorodeoxyglucose positron emission tomography optimizes neoadjuvant chemotherapy for primary breast cancer to achieve pathological complete response

International Nuclear Information System (INIS)

Ueda, Shigeto; Saeki, Toshiaki; Shigekawa, Takashi

2012-01-01

The background of this study was to assess the usefulness of positron emission tomography combined with computed tomography using 18 F-fluorodeoxyglucose (FDG positron emission tomography (PET)/CT) for optimizing chemotherapy during neoadjuvant chemotherapy for primary breast cancer. One hundred and eight patients (110 tumors) with breast cancer (≥2 cm, stages II and III) received neoadjuvant chemotherapy consisting of an anthracycline-based regimen and taxane. The maximal value of the baseline standardized uptake value (SUV) and the change in SUV after four cycles of an anthracycline-based regimen relative to baseline SUV were assessed for predicting pathological complete response (pCR) after sequential taxane. Tumors with pCR had significantly higher baseline SUV (9.3±3.7 SD) compared to those with non-pCR (7.2±3.8 SD) (p=0.02), but there was a considerable overlap between two groups. On PET scan after four cycles of chemotherapy, thirty-three patients (33.7%) with a 72.1% or greater reduction in SUV were considered as responders and the performance in predicting pCR had a sensitivity of 88.9% and specificity of 78.7%. The baseline SUV could not be a useful indicator for predicting pCR due to the wide range in sensitivity. On the other hand, a relative change in SUV after completion of an anthracycline-based regimen could be useful for predicting pCR. (author)

New Transfection Agents Based on Liposomes Containing Biosurfactant MEL-A

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Tadahide Furuno

2013-08-01

Full Text Available Nano vectors are useful tools to deliver foreign DNAs, oligonucleotides, and small interfering double-stranded RNAs (siRNAs into mammalian cells with gene transfection and gene regulation. In such experiments we have found the liposomes with a biosurfacant mannosylerythriol lipid (MEL-A are useful because of their high transfer efficiency, and their unique mechanism to transfer genes to target cells with the lowest toxicity. In the present review we will describe our current work, which may contribute to the great advance of gene transfer to target cells and gene regulations. For more than two decades, the liposome technologies have changed dramatically and various methods have been proposed in the fields of biochemistry, cell biology, biotechnology, and so on. In addition, they were towards to pharmaceutics and clinical applications. The liposome technologies were expected to use gene therapy, however, they have not reached a requested goal as of yet. In the present paper we would like to present an approach using a biosurfactant, MEL-A, which is a surface-active compound produced by microorganisms growing on water-insoluble substrates and increases efficiency in gene transfection. The present work shows new transfection agents based on liposomes containing biosurfactant MEL-A.

Comparing Intra-Arterial Chemotherapy Combined With Intravesical Chemotherapy Versus Intravesical Chemotherapy Alone: A Randomised Prospective Pilot Study for T1G3 Bladder Transitional Cell Carcinoma After Bladder-Preserving Surgery

Energy Technology Data Exchange (ETDEWEB)

Chen, Junxing, E-mail: Junxingchen@hotmail.com; Yao, Zhijun, E-mail: yaozhijun1985@qq.com; Qiu, Shaopeng, E-mail: qiushp@mail.sysu.edu.cn; Chen, Lingwu, E-mail: chenlingwu@hotmail.com [First Affiliated Hospital of Sun Yat-Sen University, Department of Urology (China); Wang, Yu, E-mail: zsyyjr@163.com; Yang, Jianyong, E-mail: yangjianyong_2011@163.com; Li, Jiaping, E-mail: jpli3s@126.com [First Affiliated Hospital of Sun Yat-Sen University, Department of Interventional Oncology (China)

2013-12-15

Purpose: To compare the efficacy of intra-arterial chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder transitional cell carcinoma (BTCC) followed by bladder-preserving surgery. Materials and Methods: Sixty patients with T1G3 BTCC were randomly divided into two groups. After bladder-preserving surgery, 29 patients (age 30-80 years, 24 male and 5 female) received intra-arterial chemotherapy in combination with intravesical chemotherapy (group A), whereas 31 patients (age 29-83 years, 26 male and 5 female) were treated with intravesical chemotherapy alone (group B). Twenty-nine patients were treated with intra-arterial epirubicin (50 mg/m{sup 2}) + cisplatin (60 mg/m{sup 2}) chemotherapy 2-3 weeks after bladder-preserving surgery once every 4-6 weeks. All of the patients received the same intravesical chemotherapy: An immediate prophylactic was administered in the first 6 h. After that, therapy was administered one time per week for 8 weeks and then one time per month for 8 months. The instillation drug was epirubicin (50 mg/m{sup 2}) and lasted for 30-40 min each time. The end points were tumour recurrence (stage Ta, T1), tumour progression (to T2 or greater), and disease-specific survival. During median follow-up of 22 months, the overall survival rate, tumour-specific death rate, recurrence rate, progression rate, time to first recurrence, and adverse reactions were compared between groups. Results: The recurrence rates were 10.3 % (3 of 29) in group A and 45.2 % (14 of 31) in group B, and the progression rates were 0 % (0 of 29) in group A and 22.6 % (7 of 31) in group B. There was a significant difference between the two groups regarding recurrence (p = 0.004) and progression rates (p = 0.011). Median times to first recurrence in the two groups were 15 and 6.5 months, respectively. The overall survival rates were 96.6 and 87.1 %, and the tumour-specific death rates were 0 % (0 of 29) and 13.5 % (4 of 31

Monitoring 5-fluorouracil in patients undergoing chemotherapy by means of F-19 MR spectroscopy

International Nuclear Information System (INIS)

Wolf, W.; Albright, M.J.; Silver, M.S.; Starewicz, P.M.; Weber, H.; Reichardt, U.; Saver, R.

1986-01-01

F-19 MR spectroscopy allows direct observation of fluorinated drugs and their metabolites in the human body without background signal from the tissue. In addition, unlike F-18, specific chemical structure information is available in vivo. The behavior of a well-known fluorinated chemotherapeutic drug, 5-fluorouracil (5-FU), and its metabolites was observed noninvasively in patients undergoing cancer chemotherapy. The time course of the drug's metabolism was examined and half-life values of the unmetabolized 5-FU in the liver were calculated from the F-19 peak intensity. Half-life values of the unmetabolized 5-FU in the liver were in the range of 15-30 minutes. Interpatient variations were correlated with the chemotherapy results. F-19 MR spectroscopy is feasible in humans and allows determination of the time course of the metabolism of fluorinated drugs in individual patients

Pegylated liposomal doxorubicin in malignant pleural mesothelioma: a possible guardian for long-term survival

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Zarogoulidis P

2012-09-01

Full Text Available Paul Zarogoulidis,1,2 Maria Mavroudi,1 Konstantinos Porpodis,1 Kalliopi Domvri,1 Antonios Sakkas,3 Nikolaos Machairiotis,1 Aikaterini Stylianaki,1 Anastasios Tsiotsios,1 Nikolaos Courcoutsakis,4 Konstantinos Zarogoulidis11Pulmonary Department-Oncology Unit, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Pulmonary Department-Interventional Unit, Ruhrland Klinik, University of Essen, Essen, Germany; 3Department of Pathology, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 4Department of Radiology, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, GreeceAbstract: Malignant pleural mesothelioma is a rare and aggressive malignancy of the pleura correlated with exposure to asbestos, with a medium survival of 11–12 months after diagnosis. A case of a 67-year-old male who had previously worked in the asbestos industry and is a current smoker is reported. The computed tomography evaluation revealed a right pleural mass with pleural thickening, and the pleural biopsy confirmed a diagnosis of malignant pleural mesothelioma. He was treated with chemotherapy consisting of etoposide, paclitaxel, and pegylated liposomal doxorubicin hydrochloride. After completion of chemotherapy, radiologic evaluation confirmed a reduction of pleural thickening and improvement in his symptoms. A complete presentation of each drug formulation and characteristics are also included in this paper. The patient’s follow-up is continuing, and computed tomography reveals stable disease 9 years after initial examination.Keywords: mesothelioma, asbestos, pegylated liposomal doxorubicin

A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin

International Nuclear Information System (INIS)

Ono, K; Sato, T; Iyama, S; Tatekoshi, A; Hashimoto, A; Kamihara, Y; Horiguchi, H; Kikuchi, S; Kawano, Y; Takada, K; Hayashi, T; Miyanishi, K; Sato, Y; Takimoto, R; Kobune, M; Kato, J

2014-01-01

Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death

Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses.

Science.gov (United States)

Kaur, Randip; Henriksen-Lacey, Malou; Wilkhu, Jitinder; Devitt, Andrew; Christensen, Dennis; Perrie, Yvonne

2014-01-06

Cholesterol is an abundant component of mammalian cell membranes and has been extensively studied as an artificial membrane stabilizer in a wide range of phospholipid liposome systems. In this study, the aim was to investigate the role of cholesterol in cationic liposomal adjuvant system based on dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB) which has been shown as a strong adjuvant system for vaccines against a wide range of diseases. Packaging of cholesterol within DDA:TDB liposomes was investigated using differential scanning calorimetery and surface pressure-area isotherms of lipid monolayers; incorporation of cholesterol into liposomal membranes promoted the formation of a liquid-condensed monolayer and removed the main phase transition temperature of the system, resulting in an increased bilayer fluidity and reduced antigen retention in vitro. In vivo biodistribution studies found that this increase in membrane fluidity did not alter deposition of liposomes and antigen at the site of injection. In terms of immune responses, early (12 days after immunization) IgG responses were reduced by inclusion of cholesterol; thereafter there were no differences in antibody (IgG, IgG1, IgG2b) responses promoted by DDA:TDB liposomes with and without cholesterol. However, significantly higher levels of IFN-gamma were induced by DDA:TDB liposomes, and liposome uptake by macrophages in vitro was also shown to be higher for DDA:TDB liposomes compared to their cholesterol-containing counterparts, suggesting that small changes in bilayer mechanics can impact both cellular interactions and immune responses.

Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2-3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells.

Science.gov (United States)

Juang, Vivian; Lee, Hsin-Pin; Lin, Anya Maan-Yuh; Lo, Yu-Li

Antimicrobial peptides (AMPs) have been recently evaluated as a new generation of adjuvants in cancer chemotherapy. In this study, we designed PEGylated liposomes encapsulating epirubicin as an antineoplastic agent and tilapia hepcidin 2-3, an AMP, as a multidrug resistance (MDR) transporter suppressor and an apoptosis/autophagy modulator in human cervical cancer HeLa cells. Cotreatment of HeLa cells with PEGylated liposomal formulation of epirubicin and hepcidin 2-3 significantly increased the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or hepcidin 2-3 were found to noticeably escalate the intracellular H 2 O 2 and O 2 - levels of cancer cells. Furthermore, these treatments considerably reduced the mRNA expressions of MDR protein 1, MDR-associated protein (MRP) 1, and MRP2. The addition of hepcidin 2-3 in liposomes was shown to markedly enhance the intracellular epirubicin uptake and mainly localized into the nucleus. Moreover, this formulation was also found to trigger apoptosis and autophagy in HeLa cells, as validated by significant increases in the expressions of cleaved poly ADP ribose polymerase, caspase-3, caspase-9, and light chain 3 (LC3)-II, as well as a decrease in mitochondrial membrane potential. The apoptosis induction was also confirmed by the rise in sub-G1 phase of cell cycle assay and apoptosis percentage of annexin V/propidium iodide assay. We found that liposomal epirubicin and hepcidin 2-3 augmented the accumulation of GFP-LC3 puncta as amplified by chloroquine, implying the involvement of autophagy. Interestingly, the partial inhibition of necroptosis and the epithelial-mesenchymal transition by this combination was also verified. Altogether, our results provide evidence that coincubation with PEGylated liposomes of hepcidin 2-3 and epirubicin caused programmed cell death in cervical cancer cells through modulation of multiple signaling pathways, including MDR transporters, apoptosis, autophagy, and/or necroptosis

Rh-I-UEA-1 Polymerized Liposomes Target and Image Adenomatous Polyps in the APCMin/+ Mouse Using Optical Colonography

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Celeste A. Roney

2011-07-01

Full Text Available Mutated adenomatous polyposis coli (APC genes predispose transformations to neoplasia, progressing to colorectal carcinoma. Early detection facilitates clinical management and therapy. Novel lectin-mediated polymerized targeted liposomes (Rh-I-UEA-1, with polyp specificity and incorporated imaging agents were fabricated to locate and image adenomatous polyps in APCMin/+ mice. The biomarker α-l-fucose covalently joins the liposomal conjugated lectin Ulex europaeus agglutinin (UEA-1, via glycosidic linkage to the polyp mucin layer. Multispectral optical imaging (MSI corroborated a global perspective of specific binding (rhodamine B 532 nm emission, 590–620 nm excitation of targeted Rh-I-UEA-1 polymerized liposomes to polyps with 1.4-fold labeling efficiency. High-resolution coregistered optical coherence tomography (OCT and fluorescence molecular imaging (FMI reveal the spatial correlation of contrast distribution and tissue morphology. Freshly excised APCMin bowels were incubated with targeted liposomes (UEA-1 lectin, control liposomes (no lectin, or iohexol (Omnipaque and imaged by the three techniques. Computed tomographic quantitative analyses did not confirm that targeted liposomes more strongly bound polyps than nontargeted liposomes or iohexol (Omnipaque alone. OCT, with anatomic depth capabilities, along with the coregistered FMI, substantiated Rh-I-UEA-1 liposome binding along the mucinous polyp surface. UEA-1 lectin denotes α-l-fucose biomarker carbohydrate expression at the mucin glycoprotein layer; Rh-I-UEA-1 polymerized liposomes target and image adenomatous polyps in APCMin mice.

Nanoparticle Stabilized Liposomes for Acne Therapy

Science.gov (United States)

Fu, Victoria

Acne vulgaris is a common skin disease that affects over 40 million people in the United States alone. The main cause of acne vulgaris is Propionibacterium acnes (P. acnes), resides deep in the pores and follicles of the skin in order to feed on oil produced by the sebaceous glands. The liposome is a lipid based nanoparticle with numerous advantages over free drug molecules as an acne treatment alternative. Bare liposomes loaded with lauric acid (LipoLA) were found to show strong antimicrobial activity against P. acnes while generating minimal toxicity. However, the platform is limited by the spontaneous tendency of liposomes to fuse with each other. Attaching nanoparticles to the surface of liposomes can overcome this challenge by providing steric repulsion and reduce surface tension. Thus, carboxyl-functionalized gold nanoparticles (AuC) were attached to the surface of liposomes (AuC-liposomes) loaded with doxycycline, a general tetracycline antibiotic. These particles were found to have a diameter of 120 nm and a zeta potential of 20.0 mV. Both fluorescent and antimicrobial studies demonstrated that based on electrostatic interaction, negatively charged AuC attached to the liposome's positively charged surface and stabilized liposomes in a neutral pH environment (pH = 7.4). Upon entering the skin's acidic environment (pH = 4), AuC detached from the liposome's surface and liposomes could fuse with P. acnes residing in the pores. Furthermore, toxicity studies showed that AuC-liposomes did not induce any significant toxicity, while two of the leading over-the-counter therapies, benzoyl peroxide and salicylic acid, generated substantial skin irritation.

EXPERIMENTAL LIPOSOMAL VIRAL VACCINE SAFETY

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Romanova OA

2016-12-01

Full Text Available Introduction. With the transport links development there is rather important issue respiratory viral infections spread, especially influenza. The only method controlling influenza is vaccination. Search and development effective and safe vaccines is important. Material and methods. In base SO "Mechnikov Institute Microbiology and Immunology National Ukrainian Academy Medical Sciences" in the scientific theme "Developing new approaches to creating viral vaccines and study specific activity depending of type and degree component`s modification" was created several experimental influenza vaccine with subsequent component`s modification for selecting the most optimal pattern of safety and immunogenicity. In assessing the influenza vaccine safety is using a few criteria, including, reactivity, as measured by the frequency of local and systemic adverse (negative effects, which due to its introduction, and for lipid content drugs, ability to influence oxidation processes. At present study phase was determined: a systemic reaction and local reaction of delayed-type hypersensitivity (foot pad swelling assay;b lipids and proteins peroxidation processes after administration officinal and experimental vaccines (content protein’s carbonyl groups, lipid’s hydroperoxides, activity of glutathione-peroxidase.Study objects were trivalent seasonal influenza vaccine, "Vaxigrip" (Sanofi Pasteur, S.A., France, "Inflexal V" (Biotech Ltd. Berne, Switzerland and experimental vaccine samples. Highest immunogenicity vaccines had undergone improvements and modifications using adjuvant systems and acylation influenza proteins. Liposomes 2 – the experimental influenza vaccine with a liposome negative charge and antigenic composition like split vaccines "Vaksihryp". Liposomes 2.1 - the adjuvantexperimental influenza vaccine with modifications liposomal components (etoniy and chlorophyllipt molecules embedded in liposomal membrane. Liposomes 2.2 - the adjuvant

Measurement of the figure of merit M for 1-C3F6/SF6 mixtures

DEFF Research Database (Denmark)

Christensen, Jørn Erik Berril; McAllister, Iain Wilson

1997-01-01

High precision measurements of the linear part of the Paschen curve are reported for 1-C3F6/SF6 mixtures. From these measurements, values for the pressure-reduced limiting electric field strength (E/p)lim and the associated figure of merit M are derived. These two parameters can be used to charac......High precision measurements of the linear part of the Paschen curve are reported for 1-C3F6/SF6 mixtures. From these measurements, values for the pressure-reduced limiting electric field strength (E/p)lim and the associated figure of merit M are derived. These two parameters can be used...

Treatment of deep mycoses with liposomal amphotericin B.

Science.gov (United States)

Berenguer, J; Muñoz, P; Parras, F; Fernández-Baca, V; Hernández-Sampelayo, T; Bouza, E

1994-06-01

Amphotericin B is the mainstay of therapy of many deep mycoses, but its use is seriously hampered by dose-limiting nephrotoxicity. In this study a liposomal formulation of amphotericin B was administered to ten patients with proven deep mycoses: invasive aspergillosis (n = 4), deep candidiasis (n = 4) and zygomycosis (n = 2). The mean daily dosage of liposomal amphotericin B was 3.0 mg/kg (range 2.5 to 4 mg/kg), the mean total dosage of liposomal amphotericin B 2,781 mg (range 87 to 5,220 mg) and the mean duration of treatment 17 days (range 3 to 33 days). Treatment with liposomal amphotericin B was associated with little nephrotoxicity and an overall survival rate of 50%. The median increase of serum creatinine from baseline levels was 0.38 mg/dl (-1.2 to 2.6 mg/dl).

Thermoresponsive pegylated bubble liposome nanovectors for efficient siRNA delivery via endosomal escape

KAUST Repository

Alamoudi, Kholod

2017-05-19

Improving the delivery of siRNA into cancer cells via bubble liposomes. Designing a thermoresponsive pegylated liposome through the introduction of ammonium bicarbonate salt into liposomes so as to control their endosomal escape for gene therapy.A sub-200 nm nanovector was fully characterized and examined for cellular uptake, cytotoxicity, endosomal escape and gene silencing.The siRNA-liposomes were internalized into cancer cells within 5 min and then released siRNAs in the cytosol prior to lysosomal degradation upon external temperature elevation. This was confirmed by confocal bioimaging and gene silencing reaching up to 90% and further demonstrated by the protein inhibition of both target genes.The thermoresponsiveness of ammonium bicarbonate containing liposomes enabled the rapid endosomal escape of the particles and resulted in an efficient gene silencing.

Thermoresponsive pegylated bubble liposome nanovectors for efficient siRNA delivery via endosomal escape

KAUST Repository

Alamoudi, Kholod; Martins, Patricia; Croissant, Jonas G.; Patil, Sachin; Omar, Haneen; Khashab, Niveen M.

2017-01-01

Improving the delivery of siRNA into cancer cells via bubble liposomes. Designing a thermoresponsive pegylated liposome through the introduction of ammonium bicarbonate salt into liposomes so as to control their endosomal escape for gene therapy.A sub-200 nm nanovector was fully characterized and examined for cellular uptake, cytotoxicity, endosomal escape and gene silencing.The siRNA-liposomes were internalized into cancer cells within 5 min and then released siRNAs in the cytosol prior to lysosomal degradation upon external temperature elevation. This was confirmed by confocal bioimaging and gene silencing reaching up to 90% and further demonstrated by the protein inhibition of both target genes.The thermoresponsiveness of ammonium bicarbonate containing liposomes enabled the rapid endosomal escape of the particles and resulted in an efficient gene silencing.

Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma

International Nuclear Information System (INIS)

Kresl, John J.; Schild, Steven E.; Henning, George T.; Gunderson, Leonard L.; Donohue, John; Pitot, Henry; Haddock, Michael G.; Nagorney, David

2002-01-01

Purpose: This study was performed to evaluate the outcome of patients with gallbladder cancer who received postoperative concurrent chemotherapy and radiation therapy. Methods and Materials: Curative resection followed by adjuvant combined modality therapy with external beam radiation therapy (EBRT) and chemotherapy was attempted in 21 consecutive gallbladder carcinoma (GBC) patients at the Mayo Clinic from 1985 through 1997. All patients received concurrent 5-fluorouracil during EBRT. EBRT fields encompassed the tumor bed and regional lymph nodes (median dose of 54 Gy in 1.8-2.0-Gy fractions). One patient received 15 Gy intraoperatively after EBRT. A retrospective analysis was performed for the end points of local control, distant failure, and overall survival. Results: After maximal resection, 12 patients had no residual disease on pathologic evaluation, 5 had microscopic residual disease, and 4 had gross residual disease. One patient had Stage I disease, and 20 had Stage III-IV disease. With median follow-up of 5 years (range: 2.6-11.5 years), 5-year survival for the entire cohort was 33%. The 5-year survival rate of patients with Stage I-III disease was 65% vs. 0% for those with Stage IV disease (p 54 Gy (microscopic residual, 3 patients; gross residual, 1 patient; negative but narrow margins, 2 patients) vs. 65% for the 15 who received a lower dose (3, gross residual; 2, microresidual; 10, negative margins). Conclusion: Patients with completely resected (negative margins) GBC followed by adjuvant EBRT plus 5-fluorouracil chemotherapy had a relatively favorable prognosis, with a 5-year survival rate of 64%. These results seem to be superior to historical surgical controls from the Mayo Clinic and other institutions, which report 5-year survival rates of approximately 33% with complete resection alone. Both tumor stage and extent of resection seemed to influence survival and local control. More aggressive measures using current cancer therapies and integration

Optimization on Preparation Conditions of Salidroside Liposome and Its Immunological Activity on PCV-2 in Mice

Directory of Open Access Journals (Sweden)

Yibo Feng

2015-01-01

Full Text Available The aim of this study was to optimize the preparation conditions of salidroside liposome with high encapsulation efficiency (EE and to study the immunological enhancement activity of salidroside liposome as porcine circovirus type 2 virus (PCV-2 vaccine adjuvant. Response surface methodology (RSM was selected to optimize the conditions for the preparation of salidroside liposome using Design-Expert V8.0.6 software. Three kinds of salidroside liposome adjuvants were prepared to study their adjuvant activity. BALB/c mice were immunized with PCV-2 encapsulated in different kinds of salidroside liposome adjuvants. The PCV-2-specific IgG in immunized mice serum was determined with ELISA. The results showed that when the concentration of ammonium sulfate was 0.26 mol·L−1, ethanol volume 6.5 mL, temperature 43°C, ethanol injection rate 3 mL·min−1, and salidroside liposome could be prepared with high encapsulation efficiency of 94.527%. Salidroside liposome as adjuvant could rapidly induce the production of PCV-2-specific IgG and salidroside liposome I adjuvant proved to provide the best effect among the three kinds of salidroside liposome adjuvants.

Biological activity of liposomal vanillin.

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Castan, Leniher; Del Toro, Grisel; Fernández, Adolfo A; González, Manuel; Ortíz, Emilia; Lobo, Daliana

2013-06-01

This article presents a study of vanillin encapsulation inside multilamellar liposomes, with emphasis on the evaluation of antioxidant activity, the hemolytic effect, and the antisickling properties of these products. Egg phosphatidylcholine-cholesterol and egg phosphatidylcholine-cholesterol-1-O-decylglycerol liposomes were prepared by mechanical dispersion, all with vanillin included. Vesicles were characterized by determination of encapsulation efficiency and vanillin retention capacity. Antioxidant activity was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. The hemolytic effect of liposomes was also evaluated by spectrophotometry, as well as the antisickling activity by the Huck test using optical microscopy. Results showed that the lipid composition of liposomes did not significantly affect the encapsulation efficiency. Stable vesicles were obtained with a high retention percentage of vanillin. Liposomes exhibited a high capture of the DPPH radical compared to free vanillin and 1-O-decylglycerol (C10) in solution. Vesicles caused no significant hemolisys in normal erythrocytes, nor in those coming from patients with sickle cell anemia. Vanillin encapsulated in liposomes retained its antisickling activity, with a greater effect for C10-containing vesicles. Our results show that vanillin encapsulation in liposomes is a way to enhance the pharmacologic properties of this molecule using a suitable vehicle.

Antioxidant properties of biohybrids based on liposomes and sage silver nanoparticles.

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Barbinta-Patrascu, Marcela Elisabeta; Bunghez, Ioana-Raluca; Iordache, Stefan Marian; Badea, Nicoleta; Fierascu, Radu-Claudiu; Ion, Rodica Mariana

2013-03-01

This paper is aimed to describe a simple and rapid eco-friendly bottom-up approach for the preparation of antioxidant silver bionanostructures using a leaf extract from sage (Salvia officinalis L.). The bioreduction property of sage in the synthesis of silver nanoparticles was investigated by UV-VIS and Attenuated Total Reflectance Fourier Transform Infrared spectroscopy. During their preparation, the particle size analysis was performed by using Dynamic Light Scattering technique. Ultrasonic irradiation was used to obtain sage silver nanoparticles. The morphology (size and shape) of the herbal silver nanoparticles was evaluated by Scanning Electron Microscopy that revealed the formation of spherical phytonanoparticles with size less than 80 nm. In order to increase their stability and their biocompatibility, the sage silver nanoparticles were introduced in two types of liposomes: soybean lecithin- and Chla-DPPC-lipid vesicles which were prepared by thin film hydration method. X-Ray Fluorescence analysis confirmed the silver presence in liposomes/sage-AgNPs biohybrids. The stability of liposomes/herbal AgNPs bioconstructs was checked by zeta potential measurements. The most stable biohybrids: Chla-DPPC/sage-AgNPs with zeta potential value of -34.2 mV, were characterized by Atomic Force Microscopy revealing the spherical and quasi-spherical shaped profiles of these nanobiohybrids with size less than 96 nm. The antioxidant activity of the silver bionanostructures was evaluated using chemiluminescence assay. The developed eco-friendly silver phytonanostructures based on lipid membranes, nanosilver and sage extract, manifest strong antioxidant properties (between 86.5% and 98.6%).

High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile

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Mukthavaram R

2013-10-01

Full Text Available Rajesh Mukthavaram,1 Pengfei Jiang,1 Rohit Saklecha,1 Dmitri Simberg,3,4 Ila Sri Bharati,1 Natsuko Nomura,1 Ying Chao,1 Sandra Pastorino,1 Sandeep C Pingle,1 Valentina Fogal,1 Wolf Wrasidlo,1,2 Milan Makale,1,2 Santosh Kesari1,21Translational Neuro-Oncology Laboratories, 2Department of Neurosciences, 3Solid Tumor Therapeutics Program, Moores Cancer Center, UC San Diego, La Jolla, CA, 4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, CO, USAAbstract: Staurosporine (STS is a potent pan-kinase inhibitor with marked activity against several chemotherapy-resistant tumor types in vitro. The translational progress of this compound has been hindered by poor pharmacokinetics and toxicity. We sought to determine whether liposomal encapsulation of STS would enhance antitumor efficacy and reduce toxicity, thereby supporting the feasibility of further preclinical development. We developed a novel reverse pH gradient liposomal loading method for STS, with an optimal buffer type and drug-to-lipid ratio. Our approach produced 70% loading efficiency with good retention, and we provide, for the first time, an assessment of the in vivo antitumor activity of STS. A low intravenous dose (0.8 mg/kg inhibited U87 tumors in a murine flank model. Biodistribution showed preferential tumor accumulation, and body weight data, a sensitive index of STS toxicity, was unaffected by liposomal STS, but did decline with the free compound. In vitro experiments revealed that liposomal STS blocked Akt phosphorylation, induced poly(ADP-ribose polymerase cleavage, and produced cell death via apoptosis. This study provides a basis to explore further the feasibility of liposomally encapsulated STS, and potentially related compounds for the management of resistant solid tumors.Keywords: liposomes, staurosporine, glioblastoma, biodistribution, efficacy

Stimulus-responsive liposomes as smart nanoplatforms for drug delivery applications.

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Zangabad, Parham Sahandi; Mirkiani, Soroush; Shahsavari, Shayan; Masoudi, Behrad; Masroor, Maryam; Hamed, Hamid; Jafari, Zahra; Taghipour, Yasamin Davatgaran; Hashemi, Hura; Karimi, Mahdi; Hamblin, Michael R

2018-02-01

Liposomes are known to be promising nanoparticles (NPs) for drug delivery applications. Among different types of self-assembled NPs, liposomes stand out for their non-toxic nature, and their possession of dual hydrophilic-hydrophobic domains. Advantages of liposomes include the ability to solubilize hydrophobic drugs, the ability to incorporate different hydrophilic and lipophilic drugs at the same time, lessening the exposure of host organs to potentially toxic drugs and allowing modification of the surface by a variety of different chemical groups. This modification of the surface, or of the individual constituents, may be used to achieve two important goals. Firstly, ligands for active targeting can be attached that are recognized by cognate receptors over-expressed on the target cells of tissues. Secondly, modification can be used to impart a stimulus-responsive or "smart" character to the liposomes, whereby the cargo is released on demand only when certain internal stimuli (pH, reducing agents, specific enzymes) or external stimuli (light, magnetic field or ultrasound) are present. Here, we review the field of smart liposomes for drug delivery applications.

Evaluation of a combination tumor treatment using thermo-triggered liposomal drug delivery and carbon ion irradiation.

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Kokuryo, Daisuke; Aoki, Ichio; Yuba, Eiji; Kono, Kenji; Aoshima, Sadahito; Kershaw, Jeff; Saga, Tsuneo

2017-07-01

The combination of radiotherapy with chemotherapy is one of the most promising strategies for cancer treatment. Here, a novel combination strategy utilizing carbon ion irradiation as a high-linear energy transfer (LET) radiotherapy and a thermo-triggered nanodevice is proposed, and drug accumulation in the tumor and treatment effects are evaluated using magnetic resonance imaging relaxometry and immunohistology (Ki-67, n = 15). The thermo-triggered liposomal anticancer nanodevice was administered into colon-26 tumor-grafted mice, and drug accumulation and efficacy was compared for 6 groups (n = 32) that received or did not receive the radiotherapy and thermo trigger. In vivo quantitative R 1 maps visually demonstrated that the multimodal thermosensitive polymer-modified liposomes (MTPLs) can accumulate in the tumor tissue regardless of whether the region was irradiated by carbon ions or not. The tumor volume after combination treatment with carbon ion irradiation and MTPLs with thermo-triggering was significantly smaller than all the control groups at 8 days after treatment. The proposed strategy of combining high-LET irradiation and the nanodevice provides an effective approach for minimally invasive cancer treatment. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Liposome kinetics in infarcted canine myocardium

International Nuclear Information System (INIS)

Caride, V.J.; Twickler, J.; Zaret, B.L.

1984-01-01

To study the mechanisms and kinetics of liposome deposition in the region of the experimental myocardial infarction, the myocardial distribution of positive and negative liposomes was determined as a function of regional myocardial blood flow and time after administration. The study was performed in dogs at 1 and 24 h following experimental myocardial infarction. Twenty-four hours after coronary artery occlusion, the initial myocardial distribution of positive and negative liposomes (2 min) is directly proportional to regional myocardial blood flow. With time, there is reduction of the radiotracer associated with negative liposomes from all myocardial regions (p less than 0.01). In contrast, in areas of moderate and severe blood flow reduction, there is progressive accumulation of tracers entrapped or incorporated in positive liposomes. This increment becomes significant in 120 min (p less than 0.005). Similar findings are observed in studies performed 1 h after coronary artery occlusion. Dual-label liposomes [( 3 H]cholesterol and [99mTc]diethylenetriamine pentaacetic acid) were used to study the integrity of liposomes in normal and ischemic myocardium. Significant dissociation of the aqueous and lipid labels of positive liposomes is observed 1 h following coronary artery occlusion. In the 24-h myocardial infarction model, dissociation of the aqueous and lipid labels in ischemic myocardium is also observed. This phenomenon is more pronounced with positive than with negative liposomes (p less than 0.02)

Kinetic Targeting of pegylated liposomal Doxorubicin: a new Approach to Reduce Toxicity during Chemotherapy (CARL-trial

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Jansen Martin

2011-08-01

Full Text Available Abstract Background The therapeutic success of chemotherapeutic agents is often limited by severe adverse effects. To reduce toxicity of these drugs, nanoscale particle-based drug delivery systems (DDS are used. DDS accumulate to some extent in tumor tissues, but only a very small portion of a given dose reaches this target. Accumulation of DDS in tumor tissues is supposed to be much faster than in certain other tissues in which side effects occur ("Kinetic Targeting". Once saturation in tumor tissue is achieved, most of the administered DDS still circulate in the plasma. The extracorporeal elimination of these circulating nanoparticles would probably reduce toxicity. Methods For the CARL-trial (Controlled Application and Removal of Liposomal chemotherapeutics, pegylated liposomal doxorubicin (PLD was used as chemotherapeutic agent and double filtration plasmapheresis (DFPP was performed for extracorporeal elimination of liposomes. PLD was given as 40 mg/m2 every 3 weeks in combination with vinorelbine 2 × 25 mg/m2 (neoadjuvant treatment of breast cancer, 12 patients, or as 40 mg/m2 every 4 weeks (recurrent ovarian cancer, 3 patients. Primary endpoints were the efficiency and safety profile of DFPP, and secondary endpoints were side effects and tumor response. Results DFPP eliminated ~62% of circulating PLD, corresponding to ~45% of the total dose (n = 57 cycles. AUC of doxorubicin was reduced by 50%. No leakage of doxorubicin was detected during elimination, and no relevant DFPP-related side effects occurred. Reduction in tumor size > 30% occurred in 10/12 (neoadjuvant and in 1/3 patients (recurrent. Only five grade 2 events and one grade 3 event (mucositis, neutropenia or leucopenia and a single palmar-plantar erythrodysesthesia grade 2 were reported. Conclusion Extracorporeal elimination of PLD by DFPP is safe and efficient. CARL can diminish the main dose-limiting side effects of PLD, and probably many different DDS alike. Trial

Liposome fusion and lipid exchange on ultraviolet irradiation of liposomes containing a photochromic phospholipid

International Nuclear Information System (INIS)

Morgan, C.G.; Sandhu, S.S.; Mitchell, A.C.

1995-01-01

A photochromic phospholipid, 1,2-bis[4-n-butylphenylazo)phenylbutyroyl]phosphatidylcholine (Bis-Azo PC) has been incorporated inot liposomes of gel- and liquid-crystalline-phase phospholipids. Liposomes of gel-phase phospholipid are stable in the presence of the trans photostationary state Bis-Az0 PC and can encapsulate fluorescent marker dye. On photoisomerization to the cis photostationary state, trapped marker is rapidly released. Liposomes containing Bis-Azo PC can rapidly fuse together after UV isomerization, this process continuing in the dark. Exposure to white light causes reversion of Bis-Azo PC to the trans form and halts dye leakage and vesicle fusion. Both unilamellar and multilamellar liposomes are able to fuse together on UV exposure. On UV photolysis, liposomes containing Bis-Azo PC do not fuse with a large excess of unlabeled liposomes, but transfer of Bis-Azo PC can be demonstrated spectrophotometrically. Vesicles of pure gel-phase lipid containing trapped marker dye but initially no Bis-Azo PC become leaky as a result of this lipid transfer. Liposomes composed of liquid-crystalline-phase phosphatidylcholine-containing Bis-Azo PC neither leak trapped marker nor fuse together on photolysis, nor do liquid-crystalline-phase liposomes, fuse with gel-phase liposomes under these conditions. (Author)

The OsO(3)F(+) and mu-F(OsO(3)F)(2)(+) cations: their syntheses and study by Raman and (19)F NMR spectroscopy and electron structure calculations and X-ray crystal structures of [OsO(3)F][PnF(6)] (Pn = As, Sb), [OsO(3)F][HF](2)[AsF(6)], [OsO(3)F][HF][SbF(6)], and [OsO(3)F][Sb(3)F(16)].

Science.gov (United States)

Gerken, Michael; Dixon, David A; Schrobilgen, Gary J

2002-01-28

The fluoride ion donor properties of OsO(3)F(2) have been investigated. The salts [OsO(3)F][AsF(6)], [OsO(3)F][HF](2)[AsF(6)], mu-F(OsO(3)F)(2)[AsF(6)], [OsO(3)F][HF](2)[SbF(6)], and [OsO(3)F][HF][SbF(6)] have been prepared by reaction of OsO(3)F(2) with AsF(5) and SbF(5) in HF solvent and have been characterized in the solid state by Raman spectroscopy. The single-crystal X-ray diffraction studies of [OsO(3)F][AsF(6)] (P2(1)/n, a = 7.0001(11) A, c = 8.8629(13) A, beta = 92.270(7) degrees, Z = 4, and R(1) = 0.0401 at -126 degrees C), [OsO(3)F][SbF(6)] (P2(1)/c, a = 5.4772(14) A, b = 10.115(3) A, c = 12.234(3) A, beta = 99.321(5) degrees, Z = 4, and R(1) = 0.0325 at -173 degrees C), [OsO(3)F][HF](2)[AsF(6)] (P2(1)/n, a = 5.1491(9) A, b = 8.129(2) A, c = 19.636(7) A, beta = 95.099(7) degrees, Z = 4, and R(1) = 0.0348 at -117 degrees C), and [OsO(3)F][HF][SbF(6)] (Pc, a = 5.244(4) A, b = 9.646(6) A, c = 15.269(10) A, beta = 97.154(13) degrees, Z = 4, and R(1) = 0.0558 at -133 degrees C) have shown that the OsO(3)F(+) cations exhibit strong contacts to the anions and HF solvent molecules giving rise to cyclic, dimeric structures in which the osmium atoms have coordination numbers of 6. The reaction of OsO(3)F(2) with neat SbF(5) yielded [OsO(3)F][Sb(3)F(16)], which has been characterized by (19)F NMR spectroscopy in SbF(5) and SO(2)ClF solvents and by Raman spectroscopy and single-crystal X-ray diffraction in the solid state (P4(1)m, a = 10.076(6) A, c = 7.585(8) A, Z = 2, and R(1) = 0.0858 at -113 degrees C). The weak fluoride ion basicity of the Sb(3)F(16)(-) anion resulted in an OsO(3)F(+) cation (C(3)(v) point symmetry) that is well isolated from the anion and in which the osmium is four-coordinate. The geometrical parameters and vibrational frequencies of OsO(3)F(+), ReO(3)F, mu-F(OsO(3)F)(2)(+), (FO(3)Os--FPnF(5))(2), and (FO(3)Os--(HF)(2)--FPnF(5))(2) (Pn = As, Sb) have been calculated using density functional theory methods.

{sup 111}In-anti-F4/80-A3-1 antibody: a novel tracer to image macrophages

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Terry, Samantha Y.A. [Radboud University Medical Center, Department of Radiology and Nuclear Medicine, Nijmegen (Netherlands); King' s College London, St Thomas' Hospital, Department of Imaging Chemistry and Biology, London (United Kingdom); Boerman, Otto C.; Gerrits, Danny; Franssen, Gerben M.; Oyen, Wim J.G. [Radboud University Medical Center, Department of Radiology and Nuclear Medicine, Nijmegen (Netherlands); Metselaar, Josbert M. [University of Twente, Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, Enschede (Netherlands); Lehmann, Steffi; Gerdes, Christian A. [Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Zurich (Switzerland); Abiraj, Keelara [Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development (pRED), Basel (Switzerland)

2015-08-15

Here, the expression of F4/80 on the cell surface of murine macrophages was exploited to develop a novel imaging tracer that could visualize macrophages in vivo. The immunoreactive fraction and IC{sub 50} of anti-F4/80-A3-1, conjugated with diethylenetriaminepentaacetic acid (DTPA) and radiolabelled with {sup 111}In, were determined in vitro using murine bone marrow-derived macrophages. In vivo biodistribution studies were performed with {sup 111}In-anti-F4/80-A3-1 and isotype-matched control antibody {sup 111}In-rat IgG2b at 24 and 72 h post-injection (p.i.) in SCID/Beige mice bearing orthotopic MDA-MB-231 xenografts. In some studies mice were also treated with liposomal clodronate. Macrophage content in tissues was determined immunohistochemically. Micro-single photon emission computed tomography (SPECT)/CT images were also acquired. In vitro binding assays showed that {sup 111}In-anti-F4/80-A3-1 specifically binds F4/80 receptor-positive macrophages. The immunoreactivity of anti-F4/80-A3-1 was 75 % and IC{sub 50} was 0.58 nM. In vivo, injection of 10 or 100 μg {sup 111}In-anti-F4/80-A3-1 resulted in splenic uptake of 78 %ID/g and 31 %ID/g, respectively, and tumour uptake of 1.38 %ID/g and 4.08 %ID/g, respectively (72 h p.i.). Liposomal clodronate treatment reduced splenic uptake of 10 μg {sup 111}In-anti-F4/80-A3-1 from 248 %ID/g to 114 %ID/g and reduced {sup 111}In-anti-F4/80-A3-1 uptake in the liver and femur (24 h p.i.). Tracer retention in the blood and tumour uptake increased (24 h p.i.). Tumour uptake of {sup 111}In-anti-F4/80-A3-1 was visualized by microSPECT/CT. Macrophage density in the spleen and liver decreased in mice treated with liposomal clodronate. Uptake of {sup 111}In-rat IgG2b was lower in the spleen, liver and femur when compared to {sup 111}In-anti-F4/80-A3-1. Radiolabelled anti-F4/80-A3-1 antibodies specifically localize in tissues infiltrated by macrophages in mice and can be used to visualize tumours. The liver and spleen act as antigen

Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2–3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells

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Juang V

2016-11-01

Full Text Available Vivian Juang,1 Hsin-Pin Lee,2 Anya Maan-Yuh Lin,1,3 Yu-Li Lo1 1Department and Institute of Pharmacology, National Yang-Ming University, 2Department of Biological Sciences and Technology, National University of Tainan, 3Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China Abstract: Antimicrobial peptides (AMPs have been recently evaluated as a new generation of adjuvants in cancer chemotherapy. In this study, we designed PEGylated liposomes encapsulating epirubicin as an antineoplastic agent and tilapia hepcidin 2–3, an AMP, as a multidrug resistance (MDR transporter suppressor and an apoptosis/autophagy modulator in human cervical cancer HeLa cells. Cotreatment of HeLa cells with PEGylated liposomal formulation of epirubicin and hepcidin 2–3 significantly increased the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or hepcidin 2–3 were found to noticeably escalate the intracellular H2O2 and O2- levels of cancer cells. Furthermore, these treatments considerably reduced the mRNA expressions of MDR protein 1, MDR-associated protein (MRP 1, and MRP2. The addition of hepcidin 2–3 in liposomes was shown to markedly enhance the intracellular epirubicin uptake and mainly localized into the nucleus. Moreover, this formulation was also found to trigger apoptosis and autophagy in HeLa cells, as validated by significant increases in the expressions of cleaved poly ADP ribose polymerase, caspase-3, caspase-9, and light chain 3 (LC3-II, as well as a decrease in mitochondrial membrane potential. The apoptosis induction was also confirmed by the rise in sub-G1 phase of cell cycle assay and apoptosis percentage of annexin V/propidium iodide assay. We found that liposomal epirubicin and hepcidin 2–3 augmented the accumulation of GFP-LC3 puncta as amplified by chloroquine, implying the involvement of autophagy. Interestingly, the partial inhibition of necroptosis and the epithelial�

Preparation, characterization, and efficient transfection of cationic liposomes and nanomagnetic cationic liposomes

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Samadikhah HR

2011-10-01

Full Text Available Hamid Reza Samadikhah1,*, Asia Majidi2,*, Maryam Nikkhah2, Saman Hosseinkhani11Department of Biochemistry, 2Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran *These authors contributed equally to this work Purpose: Cationic liposomes (CLs are composed of phospholipid bilayers. One of the most important applications of these particles is in drug and gene delivery. However, using CLs to deliver therapeutic nucleic acids and drugs to target organs has some problems, including low transfection efficiency in vivo. The aim of this study was to develop novel CLs containing magnetite to overcome the deficiencies. Patients and methods: CLs and magnetic cationic liposomes (MCLs were prepared using the freeze-dried empty liposome method. Luciferase-harboring vectors (pGL3 were transferred into liposomes and the transfection efficiencies were determined by luciferase assay. Firefly luciferase is one of most popular reporter genes often used to measure the efficiency of gene transfer in vivo and in vitro. Different formulations of liposomes have been used for delivery of different kinds of gene reporters. Lipoplex (liposome–plasmid DNA complexes formation was monitored by gel retardation assay. Size and charge of lipoplexes were determined using particle size analysis. Chinese hamster ovary cells were transfected by lipoplexes (liposome-pGL3; transfection efficiency and gene expression level was evaluated by luciferase assay. Results: High transfection efficiency of plasmid by CLs and novel nanomagnetic CLs was achieved. Moreover, lipoplexes showed less cytotoxicity than polyethyleneimine and Lipofectamine™. Conclusion: Novel liposome compositions (1,2-dipalmitoyl-sn-glycero-3-phosphocholine [DPPC]/dioctadecyldimethylammonium bromide [DOAB] and DPPC/cholesterol/DOAB with high transfection efficiency can be useful in gene delivery in vitro. MCLs can also be used for targeted gene delivery, due to

Symmetric group: Algebraic formulas for some S/sub f/ 6j symbols and S/sub f/containsS/sub f/1 x S/sub f/2 3jm symbols

International Nuclear Information System (INIS)

Haase, R.W.; Dirl, R.

1986-01-01

Explicit rank-dependent expressions have been obtained for some symmetric group (S/sub f/) 6j symbols and some S/sub f/containsS/sub f/ 1 x S/sub f/ 2 3jm symbols using Butler's recursion method. A key point in deriving these results is the use of the reduced notation introduced by Murnaghan to label irreps. Various symmetries of the 6j and 3jm symbols have been imposed. These include the complex conjugation, permutation, and transpose conjugation. We incorporate a new symmetry that arises from the occurrence of the two isomorphic direct product groups S/sub f/ 1 x S/sub f/ 2 and S/sub f/ 2 x S/sub f/ 1 as subgroups of S/sub f/. In relation to the tables of 6j and 3jm symbols presented, a discussion is given of the symmetric group-unitary group duality

Phosphatidylserine-Liposomes Promote Tolerogenic Features on Dendritic Cells in Human Type 1 Diabetes by Apoptotic Mimicry

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Silvia Rodriguez-Fernandez

2018-02-01

Full Text Available Type 1 diabetes (T1D is a metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. With its incidence increasing worldwide, to find a safe approach to permanently cease autoimmunity and allow β-cell recovery has become vital. Relying on the inherent ability of apoptotic cells to induce immunological tolerance, we demonstrated that liposomes mimicking apoptotic β-cells arrested autoimmunity to β-cells and prevented experimental T1D through tolerogenic dendritic cell (DC generation. These liposomes contained phosphatidylserine (PS—the main signal of the apoptotic cell membrane—and β-cell autoantigens. To move toward a clinical application, PS-liposomes with optimum size and composition for phagocytosis were loaded with human insulin peptides and tested on DCs from patients with T1D and control age-related subjects. PS accelerated phagocytosis of liposomes with a dynamic typical of apoptotic cell clearance, preserving DCs viability. After PS-liposomes phagocytosis, the expression pattern of molecules involved in efferocytosis, antigen presentation, immunoregulation, and activation in DCs concurred with a tolerogenic functionality, both in patients and control subjects. Furthermore, DCs exposed to PS-liposomes displayed decreased ability to stimulate autologous T cell proliferation. Moreover, transcriptional changes in DCs from patients with T1D after PS-liposomes phagocytosis pointed to an immunoregulatory prolife. Bioinformatics analysis showed 233 differentially expressed genes. Genes involved in antigen presentation were downregulated, whereas genes pertaining to tolerogenic/anti-inflammatory pathways were mostly upregulated. In conclusion, PS-liposomes phagocytosis mimics efferocytosis and leads to phenotypic and functional changes in human DCs, which are accountable for tolerance induction. The herein reported results reinforce the potential of this novel immunotherapy to re-establish immunological

Efficacy of Liposomal Bupivacaine Infiltration on the Management of Total Knee Arthroplasty.

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Sakamoto, Bryan; Keiser, Shelly; Meldrum, Russell; Harker, Gene; Freese, Andrew

2017-01-01

Liposomal bupivacaine is a novel extended-duration anesthetic that has recently been used for local infiltration in total knee arthroplasty (TKA). Athough liposomal bupivacaine is widely used, it is unknown if the benefits justify the cost in the veteran population at our institution. To evaluate a change in practice: the effect of local infiltration of liposomal bupivacaine on perioperative outcomes in patients undergoing primary TKA. A retrospective cohort study was conducted among patients who underwent primary TKA at a Veterans Affairs Medical Center before (March 3, 2013-March 2, 2014) and after (March 3, 2014-March 2, 2015) the implementation of liposomal bupivacaine for local infiltration in TKA. Drug utilization evaluation of liposomal bupivacaine for local infiltration in TKA. Use of opioids after discharge from the postanesthesia care unit. Among 199 patients, those who received liposomal bupivacaine after primary TKA (mean [SD] age, 65.3 [6.9] years; 93 males and 5 females) had a reduced median opioid use in the first 24 hours after surgery compared with those who did not receive liposomal bupivacaine (mean [SD] age, 64.9 [8.4] years; 95 males and 6 females; [intravenous morphine equivalents, 12.50 vs 22.50 mg; P = .001]). The use of patient-controlled analgesia was also reduced among patients who received liposomal bupivacaine vs those who did not (49 vs 91; P bupivacaine vs those who did not (4 vs 20; P = .001). The number of patients in the postanesthesia care unit with no pain was improved among those who received liposomal bupivacaine vs those who did not (44 vs 19; P bupivacaine vs those who did not (4.0 [0.0-6.6] vs 5.5 [3.0-7.5]; P = .001), patients who received liposomal bupivacaine had greater median (interquartile range) pain scores 48 hours (5.5 [4.0-7.0] vs 5.0 [3.0-6.0]; P = .01), 72 hours (5.0 [4.0-6.0] vs 4.0 [2.0-6.0]; P = .002), and 96 hours (5.0 [3.0-6.5] vs 4.0 [1.0-5.0]; P = .003) after surgery than those

Anomalous electron-attachment properties of perfluoropropylene (1-C3F6) and their effect on the breakdown strength of this gas

International Nuclear Information System (INIS)

Hunter, S.R.; Christophorou, L.G.; McCorkle, D.L.; Sauers, I.; Ellis, H.W.; James, D.R.

1982-01-01

Electron attachment to perfluoropropylene (1-C 3 F 6 ) in 1-C 3 F 6 /buffer gas mixtures has been found to be anomalously dependent on both the 1-C 3 F 6 and buffer gas pressures, as well as on the gas temperature. We have found also that the uniform field breakdown strength of pure 1-C 3 F 6 is dependent on gas pressure but not on the gas temperature. A mass spectrometer study of the negative ions formed in a moderately high pressure corona discharge has been made, and the principal negative ions formed by electron attachment to 1-C 3 F 6 have been identified. Based on these studies, a reaction scheme for electron attachment to 1-C 3 F 6 is proposed which results in stable negative ion clusters but does not involve pre-existing dimers. Further, we propose that the observed pressure dependence in the breakdown strength of this gas is due to the large pressure dependence of the electron attachment process we observed

Liposome-Based Delivery Systems in Plant Polysaccharides

International Nuclear Information System (INIS)

Meiwan, C.; Yitao, W.; Yanfang, Z.; Xinsheng, P.; Jingjing, H.; Ping, Z.

2012-01-01

Plant polysaccharides consist of many monosaccharide by α or β glycosidic bond which can be extracted by the water, alcohol, lipophile liquid from a variety of plants including Cordyceps sinensis, astragalus, and mushrooms. Recently, many evidences illustrate that natural plant polysaccharides possess various biological activities including strengthening immunity, lowering blood sugar, regulating lipid metabolism, anti oxidation, anti aging, and antitumour. Plant polysaccharides have been widely used in the medical field due to their special features and low toxicity. As an important drug delivery system, liposomes can not only encapsulate small-molecule compound but also big-molecule drug; therefore, they present great promise for the application of plant polysaccharides with unique physical and chemical properties and make remarkable successes. This paper summarized the current progress in plant polysaccharides liposomes, gave an overview on their experiment design method, preparation, and formulation, characterization and quality control, as well as in vivo and in vitro studies. Moreover, the potential application of plant polysaccharides liposomes was prospected as well.

Biomolecular Interactions of Tannin Isolated from Oenothera gigas with Liposomes.

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Sekowski, Szymon; Ionov, Maksim; Dubis, Alina; Mavlyanov, Saidmukhtar; Bryszewska, Maria; Zamaraeva, Maria

2016-04-01

We have examined the interaction between hydrolysable tannin 1-O-galloyl-4,6-hexahydroxydiphenoyl-β-D-glucose (OGβDG) with neutral liposomes as a model of cell membranes composed of three lipids: lecithin, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) at different mass ratios. OGβDG in the concentration range 0.5-15 µg/ml (0.4-12 µM) strongly interacts with liposomal membranes by changing their structure, surface charge and fluidity. Used OGβDG molecules decrease and increase the rigidity of hydrophilic surface and hydrophobic parts of liposomes, respectively. At higher concentrations of tannin (>15 µM), liposomes are aggregated. Fourier Transform Infra-Red (FTIR) analysis showed that mainly -OH groups from OGβDG and also PO(2-) groups from phospholipids are responsible for the interaction. Obtained data indicate the importance of membrane lipid composition in interactions between tannins and cells.

Synthesis and validation of novel cholesterol-based fluorescent lipids designed to observe the cellular trafficking of cationic liposomes.

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Kim, Bieong-Kil; Seu, Young-Bae; Choi, Jong-Soo; Park, Jong-Won; Doh, Kyung-Oh

2015-09-15

Cholesterol-based fluorescent lipids with ether linker were synthesized using NBD (Chol-E-NBD) or Rhodamine B (Chol-E-Rh), and the usefulnesses as fluorescent probes for tracing cholesterol-based liposomes were validated. The fluorescent intensities of liposomes containing these modified lipids were measured and observed under a microscope. Neither compound interfered with the expression of GFP plasmid, and live cell images were obtained without interferences. Changes in the fluorescent intensity of liposomes containing Chol-E-NBD were followed by flow cytometry for up to 24h. These fluorescent lipids could be useful probes for trafficking of cationic liposome-mediated gene delivery. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Effects of Lyophilization on the Physico-Chemical Stability of Sirolimus Liposomes

Directory of Open Access Journals (Sweden)

Parvin Zakeri-Milani

2013-02-01

Full Text Available Purpose: The major limitation in the widespread use of liposome drug delivery system is its instability. Lyophilization is a promising approach to ensure the long-term stability of liposomes. The aim of this study was to prepare sirolimus-loaded liposomes, study their stability and investigate the effect of lyophilization either in the presence or in the absence of lyoprotectant on liposome properties. Methods: Two types of multi-lamellar liposomes, conventional and fusogenic, containing sirolimus were prepared by modified thin film hydration method with different ratio of dipalmitoylphosphatidylcholine (DPPC, cholesterol and dioleoylphosphoethanolamine (DOPE, and were lyophilized with or without dextrose as lyoprotectant. Chemical stability investigation was performed at 4°C and 25°C until 6 months using a validated HPLC method. Physical stability was studied with determination of particle size (PS and encapsulation efficiency (EE % of formulations through 6 months. Results: Chemical stability test at 4°C and 25°C until 6 months showed that drug content of liposomes decreased 8.4% and 20.2% respectively. Initial mean EE % and PS were 72.8 % and 582 nm respectively. After 6 months mean EE % for suspended form, lyophilized without lyoprotectant and lyophilized with lyoprotectant were 54.8 %, 62.3% and 67.1 % at 4°C and 48.2%, 60.4 % and 66.8 % at 25°C respectively. Corresponding data for mean PS were 8229 nm, 2397 nm and 688nm at 4°C and 9362 nm, 1944 nm and 737 nm at 25°C respectively. Conclusion: It is concluded that lyophilization with and without dextrose could increase shelf life of liposome and dextrose has lyoprotectant effect that stabilized liposomes in the lyophilization process.

Cyclisation versus 1,1-Carboboration: Reactions of B(C6F5)3 with Propargyl Amides.

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Melen, Rebecca L; Hansmann, Max M; Lough, Alan J; Hashmi, A Stephen K; Stephan, Douglas W

2013-09-02

A series of propargyl amides were prepared and their reactions with the Lewis acidic compound B(C6F5)3 were investigated. These reactions were shown to afford novel heterocycles under mild conditions. The reaction of a variety of N-substituted propargyl amides with B(C6F5)3 led to an intramolecular oxo-boration cyclisation reaction, which afforded the 5-alkylidene-4,5-dihydrooxazolium borate species. Secondary propargyl amides gave oxazoles in B(C6F5)3 mediated (catalytic) cyclisation reactions. In the special case of disubstitution adjacent to the nitrogen atom, 1,1-carboboration is favoured as a result of the increased steric hindrance (1,3-allylic strain) in the 5-alkylidene-4,5-dihydrooxazolium borate species. Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Safety and feasibility of fasting in combination with platinum-based chemotherapy

International Nuclear Information System (INIS)

Dorff, Tanya B.; Groshen, Susan; Garcia, Agustin; Shah, Manali; Tsao-Wei, Denice; Pham, Huyen; Cheng, Chia-Wei; Brandhorst, Sebastian; Cohen, Pinchas; Wei, Min; Longo, Valter; Quinn, David I.

2016-01-01

Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients. 3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state. The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period. Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An onging randomized trial is studying the effect of 72 h of fasting. Clinicaltrials.gov: NCT00936364, registered propectively on July 9, 2009. The online version of this article (doi:10.1186/s12885-016-2370-6) contains supplementary material, which is available to authorized users

HYPERDIRE. HYPERgeometric functions DIfferential REduction. MATHEMATICA based packages for differential reduction of generalized hypergeometric functions pFp-1, F1, F2, F3, F4

International Nuclear Information System (INIS)

Bytev, Vladimir V.; Kalmykov, Mikhail Yu.; Kniehl, Bernd A.

2013-05-01

HYPERDIRE is a project devoted to the creation of a set of Mathematica based programs for the differential reduction of hypergeometric functions. The current version includes two parts: one, pfq, is relevant for manipulations of hypergeometric functions p+1 F p , and the second one, AppellF1F4, for manipulations with Appell hypergeometric functions F 1 , F 2 , F 3 , F 4 of two variables.

Activity-Based Protein Profiling of Rhomboid Proteases in Liposomes

Czech Academy of Sciences Publication Activity Database

Wolf, E. V.; Seybold, M.; Hadravová, Romana; Stříšovský, Kvido; Verhelst, S. H. L.

2015-01-01

Roč. 16, č. 11 (2015), s. 1616-1621 ISSN 1439-4227 R&D Projects: GA MŠk(CZ) LK11206; GA MŠk LO1302 Institutional support: RVO:61388963 Keywords : activity-based protein profiling * chemical probes * inhibitors * intramembrane proteases * liposomes Subject RIV: CE - Biochemistry Impact factor: 2.850, year: 2015

Development and pharmacokinetic of antimony encapsulated in liposomes of phosphatidylserine using radioisotopes in experimental leishmaniasis

International Nuclear Information System (INIS)

Borborema, Samanta Etel Treiger

2010-01-01

Leishmaniasis are a complex of parasitic diseases caused by intra macrophage protozoa of the genus Leishmania, and is fatal if left untreated. Pentavalent antimonials, though toxic and their mechanism of action being unclear, remain the first-line drugs for treatment. Effective therapy could be achieved by delivering antileishmanial drugs to these sites of infection. Liposomes are phospholipid vesicles that promote improvement in the efficacy and action of drugs in target cell. Liposomes are taken up by the cells of mononuclear phagocytic system (MPS). The purpose of this study was to develop a preparation of meglumine antimonate encapsulated in liposomes of phosphatidylserine and to study its pharmacokinetic in healthy mice to establish its metabolism and distribution. Quantitative analysis of antimony from liposomes demonstrated that Neutron Activation Analysis was the most sensitive technique with almost 100 % of accuracy. All liposome formulations presented a mean diameter size of 150 nm. The determination of IC 50 in infected macrophage showed that liposome formulations were between 10 - 63 fold more effective than the free drug, indicating higher selectivity index. By fluorescence microscopy, an increased uptake of fluorescent-liposomes was seen in infected macrophages during short times of incubation compared with non-infected macrophages. Biodistribution studies showed that meglumine antimonate irradiated encapsulated in liposomes of phosphatidylserine promoted a targeting of antimony for MPS tissues and maintained high doses in organs for a prolonged period. In conclusion, these data suggest that meglumine antimonate encapsulated in liposomes showed higher effectiveness than the non-liposomal drug against Leishmania infection. The development of liposome formulations should be a new alternative for the chemotherapy of infection diseases, especially Leishmaniasis, as they are used to sustain and target pharmaceuticals to the local of infection. (author)

Induction chemotherapy in acute myeloid leukaemia: origins and emerging directions.

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Upadhyay, Vivek A; Fathi, Amir T

2018-03-01

This review summarizes the hallmark developments in induction chemotherapy for acute myeloid leukaemia and further describes future directions in its evolution. We describe the origin of induction chemotherapy. We also describe notable modifications and adjustments to 7+3 induction chemotherapy since its development. Finally, we describe new efforts to modify and add new agents to induction therapy, including '7+3 Plus' combinations. Induction chemotherapy remains the standard of care for the majority of patients with acute myeloid leukaemia. However, its success is limited in a subset of patients by toxicity, failure to achieve remission and potential for subsequent relapse. Novel agents such as mutant fms like tyrosine kinase 3 inhibitors, mutant isocitrate dehydrogenase inhibitors, CD33-antibody drug conjugates and liposomal formulations have demonstrated significant potential as modifications to traditional induction chemotherapy.

¹¹¹In-anti-F4/80-A3-1 antibody: a novel tracer to image macrophages.

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Terry, Samantha Y A; Boerman, Otto C; Gerrits, Danny; Franssen, Gerben M; Metselaar, Josbert M; Lehmann, Steffi; Oyen, Wim J G; Gerdes, Christian A; Abiraj, Keelara

2015-08-01

Here, the expression of F4/80 on the cell surface of murine macrophages was exploited to develop a novel imaging tracer that could visualize macrophages in vivo. The immunoreactive fraction and IC50 of anti-F4/80-A3-1, conjugated with diethylenetriaminepentaacetic acid (DTPA) and radiolabelled with (111)In, were determined in vitro using murine bone marrow-derived macrophages. In vivo biodistribution studies were performed with (111)In-anti-F4/80-A3-1 and isotype-matched control antibody (111)In-rat IgG2b at 24 and 72 h post-injection (p.i.) in SCID/Beige mice bearing orthotopic MDA-MB-231 xenografts. In some studies mice were also treated with liposomal clodronate. Macrophage content in tissues was determined immunohistochemically. Micro-single photon emission computed tomography (SPECT)/CT images were also acquired. In vitro binding assays showed that (111)In-anti-F4/80-A3-1 specifically binds F4/80 receptor-positive macrophages. The immunoreactivity of anti-F4/80-A3-1 was 75 % and IC50 was 0.58 nM. In vivo, injection of 10 or 100 μg (111)In-anti-F4/80-A3-1 resulted in splenic uptake of 78 %ID/g and 31 %ID/g, respectively, and tumour uptake of 1.38 %ID/g and 4.08 %ID/g, respectively (72 h p.i.). Liposomal clodronate treatment reduced splenic uptake of 10 μg (111)In-anti-F4/80-A3-1 from 248 %ID/g to 114 %ID/g and reduced (111)In-anti-F4/80-A3-1 uptake in the liver and femur (24 h p.i.). Tracer retention in the blood and tumour uptake increased (24 h p.i.). Tumour uptake of (111)In-anti-F4/80-A3-1 was visualized by microSPECT/CT. Macrophage density in the spleen and liver decreased in mice treated with liposomal clodronate. Uptake of (111)In-rat IgG2b was lower in the spleen, liver and femur when compared to (111)In-anti-F4/80-A3-1. Radiolabelled anti-F4/80-A3-1 antibodies specifically localize in tissues infiltrated by macrophages in mice and can be used to visualize tumours. The liver and spleen act as antigen sink organs for macrophage-specific tracers.

Comparison of antiemetic effects of granisetron and palonosetron in patients receiving bendamustine-based chemotherapy.

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Uchida, M; Nakamura, T; Makihara, Y; Suetsugu, K; Ikesue, H; Mori, Y; Kato, K; Shiratsuchi, M; Hosohata, K; Miyamoto, T; Akashi, K

2018-05-01

The antiemetic effects and safety of granisetron and palonosetron against chemotherapy-induced nausea and vomiting (CINV) were retrospectively evaluated in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy. A total of 61 patients were eligible for this study. Before starting the bendamustine-based chemotherapy, granisetron or palonosetron were intravenously administered with or without aprepitant and/or dexamethasone. The proportions of patients with complete control (CC) during the overall (during the 6 days after the start of the chemotherapy), acute (up to 2 days), and delayed (3 to 6 days) phases were assessed. CC was defined as complete response with only grade 0-1 nausea, no vomiting, and no use of antiemetic rescue medication. Granisetron or palonosetron alone were administered to 9 and 19 patients, respectively. Aprepitant and/or dexamethasone were combined with granisetron and palonosetron in 28 and 5 patients, respectively. Acute CINV was completely controlled in all patients. Both granisetron monotherapy and palonosetron combination therapy could provide good control of delayed CINV, although the CC rates during the delayed and overall phases were not significantly different among mono- and combination therapy of the antiemetics. There was no significant difference in the frequencies of adverse drug events between the granisetron and palonosetron treatment groups. The present study showed that the antiemetic efficacy and safety of granisetron-based therapy were non-inferior to those of palonosetron-based therapy. Taken together with treatment costs, granisetron monotherapy would be adequate to prevent CINV in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy.

Preparation, characterization, and in vitro release study of albendazole-encapsulated nanosize liposomes

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Panwar, Preety; Pandey, Bhumika; Lakhera, P C; Singh, K P

2010-01-01

The purpose of the present study was to formulate effective and controlled release albendazole liposomal formulations. Albendazole, a hydrophobic drug used for the treatment of hydatid cysts, was encapsulated in nanosize liposomes. Rapid evaporation method was used for the preparation of albendazole-encapsulated conventional and PEGylated liposomes consisting of egg phosphatidylcholine (PC) and cholesterol (CH) in the molar ratios of (6:4) and PC:CH: polyethylene glycol (PEG) (5:4:1), respectively. In this study, PEGylated and conventional liposomes containing albendazole were prepared and their characteristics, such as particle size, encapsulation efficiency, and in vitro drug release were investigated. The drug encapsulation efficiency of PEGylated and conventional liposomes was 81% and 72%, respectively. The biophysical characterization of both conventional and PEG-coated liposomes were done by transmission electron microscopy and UV-vis spectrophotometry. Efforts were made to study in vitro release of albendazole. The drug release rate showed decrease in albendazole release in descending order: free albendazole, albendazole-loaded conventional liposomes, and least with albendazole-loaded PEG-liposomes. Biologically relevant vesicles were prepared and in vitro release of liposome-entrapped albendazole was determined. PMID:20309396

Spin-labelling study of interactions of ovalbumin with multilamellar liposomes and specific anti-ovalbumin antibodies.

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Brgles, Marija; Mirosavljević, Krunoslav; Noethig-Laslo, Vesna; Frkanec, Ruza; Tomasić, Jelka

2007-03-10

Ovalbumin (OVA) has been used continuously as the model antigen in numerous studies of immune reactions and antigen processing, very often encapsulated into liposomes. The purpose of this work was to study the possible interactions of spin-labelled OVA and lipids in liposomal membranes using electron spin resonance (ESR) spectroscopy. OVA was covalently spin-labelled with 4-maleimido-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO-maleimide), characterized and encapsulated into multilamellar, negatively charged liposomes. ESR spectra of this liposomal preparation gave evidence for the interaction of OVA with the lipid bilayers. Such an interaction was also evidenced by the ESR spectra of liposomal preparation containing OVA, where liposomes were spin-labelled with n-doxyl stearic acids. The spin-labelled OVA retains its property to bind specific anti-OVA antibodies, as shown by ESR spectroscopy, but also in ELISA for specific anti-OVA IgG.

Membrane Microdomain Structures of Liposomes and Their Contribution to the Cellular Uptake Efficiency into HeLa Cells.

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Onuki, Yoshinori; Obata, Yasuko; Kawano, Kumi; Sano, Hiromu; Matsumoto, Reina; Hayashi, Yoshihiro; Takayama, Kozo

2016-02-01

The purpose of this study is to obtain a comprehensive relationship between membrane microdomain structures of liposomes and their cellular uptake efficiency. Model liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/cholesterol (Ch) were prepared with various lipid compositions. To detect distinct membrane microdomains in the liposomes, fluorescence-quenching assays were performed at temperatures ranging from 25 to 60 °C using 1,6-diphenyl-1,3,5-hexatriene-labeled liposomes and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl. From the data analysis using the response surface method, we gained a better understanding of the conditions for forming distinct domains (Lo, Ld, and gel phase membranes) as a function of lipid composition. We further performed self-organizing maps (SOM) clustering to simplify the complicated behavior of the domain formation to obtain its essence. As a result, DPPC/DOPC/Ch liposomes in any lipid composition were integrated into five distinct clusters in terms of similarity of the domain structure. In addition, the findings from synchrotron small-angle X-ray scattering analysis offered further insight into the domain structures. As a last phase of this study, an in vitro cellular uptake study using HeLa cells was conducted using SOM clusters' liposomes with/without PEGylation. As a consequence of this study, higher cellular uptake was observed from liposomes having Ch-rich ordered domains.

Herbal liposome for the topical delivery of ketoconazole for the effective treatment of seborrheic dermatitis

Science.gov (United States)

Dave, Vivek; Sharma, Swati; Yadav, Renu Bala; Agarwal, Udita

2017-11-01

The aim of the present study was to develop liposomal gel containing ketoconazole and neem extract for the treatment of seborrheic dermatitis in an effectual means. Azoles derivatives that are commonly used to prevent superficial fungal infections include triazole category like itraconazole. These drugs are available in the form of oral dosage that required a long period of time for treatment. Ketoconazole is available in the form of gel but is not used with any herbal extract. Neem ( Azadirachta indica) leaves show a good anti-bacterial and anti-fungal activity and have great potential as a bioactive compound. The thin film hydration method was used to design an herbal liposomal preparation. The formulation was further subjected to their characterization as particle size, zeta potential, entrapment efficiency, % cumulative drug release, and anti-fungal activity and it was also characterized by the mean of their physicochemical properties such as FTIR, SEM, DSC, TGA, and AFM. The results show that the formulation of liposomes with neem extract F12 were found to be optimum on the basis of entrapment efficiency in the range 88.9 ± 0.7%, with a desired mean particle size distribution of 141.6 nm and zeta potential - 45 mV. The anti-fungal activity of liposomal formulation F12 was carried out against Aspergillus niger and Candida tropicalis by measuring the inhibition zone 8.9 and 10.2 mm, respectively. Stability of optimized formulation was best seen at refrigerated condition. Overall, these results indicated that developed liposomal gel of ketoconazole with neem extract could have great potential for seborrheic dermatitis and showed synergetic effect for the treatment.

Clinical comparative investigation using intensity-modulated radiotherapy combined with concurrent chemotherapy for the local advanced nasopharyngeal carcinoma

International Nuclear Information System (INIS)

Zhao Yingchao; Dai Xiaofang; Wu Gang; Zhao Yanxia; Luo Ming

2009-01-01

Objective: To research the early effects and side-effects of the local advanced nasopharyngeal carcinoma patients using intensity-modulated radiotherapy (IMRT) combined with concurrent chemotherapy. Methods: From January 2005 to January 2007, 60 patients with nasopharyngeal carcinoma of stage m-IV b were received IMRT combined with concurrent chemotherapy in our center. Sixty patients were divided into paclitaxel concurrent group (32 patients) and cisplatin concurrent group (28 patients). The prescribing doses of the primary tumor were 68-72 Gy for each group. The patients of paclitaxel concurrent group received 5-7 times pacitaxel liposome chemotherapy of 30 mg · m -2 ·. The patients of cisplatin concurrent group received 5-7 times cisplatin chemotherapy of 30 mg · m -2 · week -1 . Results: As to the side-effects, the patients of the cisplatin concurrent group got earlier radiodermatitis and radiation-induced mucositis but also got significantly higher rate of radiodermatitis, radiation-induced mucositis, radiation-induced leucopenia and gastrointestinal toxicity, as well as the loss of weight. No significant difference was found on liver and renal functions between two groups.Four patients (12.5%) of the paclitaxel concurrent group were broken-off, which was much better than the cisplatin concurrent group. There was no significant difference on the specific length of break-off time, the 2-year overall survival rate and the 2-year diseaee-free survival rate between two groups. Conclusions: IMRT combined with concurrent chemotherapy of paclitaxel liposome for local advanced nasopharyngeal carcinoma results in less side-effects and better tolerance than IMRT combined with concurrent cisplatin chemotherapy. (authors)

[Long term results of exclusive chemotherapy for glottic squamous cell carcinoma complete clinical responders after induction chemotherapy].

Science.gov (United States)

Vachin, F; Hans, S; Atlan, D; Brasnu, D; Menard, M; Laccourreye, O

2004-06-01

To evaluate the long-term results of exclusive chemotherapy for T1-T3N0M0 glottic squamous cell carcinoma complete clinical responders after induction chemotherapy. Between 1985 and 2000, 69 patients with glottic squamous cell carcinoma complete clinical responders after induction chemotherapy were managed with exclusive chemotherapy at our department. Chemotherapy associated platinum and fluorouracil. This retrospective analysis evaluated actuarial survival, treatment morbidity, oncologic events and laryngeal preservation. Various independent factors were tested for potential correlation with survival and local recurrence. The 5-year Kaplan-Meier actuarial survival, local control, lymph node control estimate were 83,6%, 64,8%, 98,6% respectively. Chemotherapy never resulted in death. The 10-year actuarial metachronous second primary tumors estimate was 32%. The overall laryngeal preservation rate was 98,6%. Altogether our data and the review of the literature suggest that in patients achieving a complete clinical response after and induction based chemotherapy regimen, the completion of an exclusive chemotherapy regimen appears to be a valid alternative to the conventional use of radiotherapy or chemo-radiation protocols.

Recent Trends of Polymer Mediated Liposomal Gene Delivery System

Directory of Open Access Journals (Sweden)

Shyamal Kumar Kundu

2014-01-01

Full Text Available Advancement in the gene delivery system have resulted in clinical successes in gene therapy for patients with several genetic diseases, such as immunodeficiency diseases, X-linked adrenoleukodystrophy (X-ALD blindness, thalassemia, and many more. Among various delivery systems, liposomal mediated gene delivery route is offering great promises for gene therapy. This review is an attempt to depict a portrait about the polymer based liposomal gene delivery systems and their future applications. Herein, we have discussed in detail the characteristics of liposome, importance of polymer for liposome formulation, gene delivery, and future direction of liposome based gene delivery as a whole.

Liposomal curcumin alters chemosensitivity of breast cancer cells to Adriamycin via regulating microRNA expression.

Science.gov (United States)

Zhou, Siying; Li, Jian; Xu, Hanzi; Zhang, Sijie; Chen, Xiu; Chen, Wei; Yang, Sujin; Zhong, Shanliang; Zhao, Jianhua; Tang, Jinhai

2017-07-30

Emerging evidence suggests that curcumin can overcome drug resistance to classical chemotherapies, but poor bioavailability and low absorption have limited its clinical use and the mechanisms remain unclear. Also, Adriamycin (Adr) is one of the most active cytotoxic agents in breast cancer; however, the high resistant rate of Adr leads to a poor prognosis. We utilized encapsulation in liposomes as a strategy to improve the bioavailability of curcumin and demonstrated that liposomal curcumin altered chemosensitivity of Adr-resistant MCF-7 human breast cancer (MCF-7/Adr) by MTT assay. The miRNA and mRNA expression profiles of MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr cells were analyzed by microarray and further confirmed by real-time PCR. We focused on differentially expressed miR-29b-1-5p to explore the involvement of miR-29b-1-5p in the resistance of Adr. Candidate genes of dysregulated miRNAs were identified by prediction algorithms based on gene expression profiles. Networks of KEGG pathways were organized by the selected dysregulated miRNAs. Moreover, protein-protein interaction (PPI) was utilized to map protein interaction networks of curcumin regulated proteins. We first demonstrated liposomal curcumin could rescue part of Adriamycin resistance in breast cancer and further identified 67 differentially expressed microRNAs among MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr. The results showed that lower expressed miR-29b-1-5p decreased the IC50 of MCF-7/Adr cells and higher expressed miR-29b-1-5p, weaken the effects of liposomal curcumin to Adr-resistance. Besides, we found that 20 target genes (mRNAs) of each dysregulated miRNA were not only predicted by prediction algorithms, but also differentially expressed in the microarray. The results showed that MAPK, mTOR, PI3K-Akt, AMPK, TNF, Ras signaling pathways and several target genes such as PPARG, RRM2, SRSF1and EPAS1, may associate with drug resistance of breast cancer cells to Adr. We determined

Mechanism and kinetics of the loss of poorly soluble drugs from liposomal carriers studied by a novel flow field-flow fractionation-based drug release-/transfer-assay.

Science.gov (United States)

Hinna, Askell Hvid; Hupfeld, Stefan; Kuntsche, Judith; Bauer-Brandl, Annette; Brandl, Martin

2016-06-28

process could be adequately described by a single 1st order kinetic model. By varying the donor-to-acceptor lipid mass ratio in the range 1:1 to 1:10, a correlation was established between donor-to-acceptor-lipid mass ratio and transfer kinetics, which is regarded essential for scaling to physiological lipid mass ratios. By applying the assay to a series of structurally related model compounds of different bilayer affinity, transfer and release kinetics were established over the whole expected range of liposome bilayer associated drugs in terms of water solubility and lipophilicity. A very rapid transfer and considerable release from liposomes to the water phase was observed for the more water-soluble compounds Sudan II (clogP 5.45) and Sudan III (clogP 6.83). For the more lipophilic compounds, the rate of transfer from the donor liposomes followed the rank order Sudan IV (fastest)>Oil Red O>Sudan Black>p-THPP (slowest). For an equimolar donor-to-acceptor lipid mass ratio, half-lifes of transfer in the range of 12min (Sudan IV) up to 1.5h (p-THPP) were determined. In essence, the results presented here allow for both, mechanistic insights and predictions of drug loss from liposomal carriers upon exposure to biological sinks, which appear more realistic than the commonly employed in vitro release tests. Copyright © 2016 Elsevier B.V. All rights reserved.

Multimodality imaging demonstrates trafficking of liposomes preferentially to ischemic myocardium

International Nuclear Information System (INIS)

Lipinski, Michael J.; Albelda, M. Teresa; Frias, Juan C.; Anderson, Stasia A.; Luger, Dror; Westman, Peter C.; Escarcega, Ricardo O.; Hellinga, David G.; Waksman, Ron; Arai, Andrew E.; Epstein, Stephen E.

2016-01-01

Introduction: Nanoparticles may serve as a promising means to deliver novel therapeutics to the myocardium following myocardial infarction. We sought to determine whether lipid-based liposomal nanoparticles can be shown through different imaging modalities to specifically target injured myocardium following intravenous injection in an ischemia–reperfusion murine myocardial infarction model. Methods: Mice underwent ischemia–reperfusion surgery and then either received tail-vein injection with gadolinium- and fluorescent-labeled liposomes or no injection (control). The hearts were harvested 24 h later and underwent T1 and T2-weighted ex vivo imaging using a 7 Tesla Bruker magnet. The hearts were then sectioned for immunohistochemistry and optical fluorescent imaging. Results: The mean size of the liposomes was 100 nm. T1-weighted signal intensity was significantly increased in the ischemic vs. the non-ischemic myocardium for mice that received liposomes compared with control. Optical imaging demonstrated significant fluorescence within the infarct area for the liposome group compared with control (163 ± 31% vs. 13 ± 14%, p = 0.001) and fluorescent microscopy confirmed the presence of liposomes within the ischemic myocardium. Conclusions: Liposomes traffic to the heart and preferentially home to regions of myocardial injury, enabling improved diagnosis of myocardial injury and could serve as a vehicle for drug delivery.

Multimodality imaging demonstrates trafficking of liposomes preferentially to ischemic myocardium

Energy Technology Data Exchange (ETDEWEB)

Lipinski, Michael J., E-mail: mjlipinski12@gmail.com [MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (United States); Albelda, M. Teresa [GIBI2" 3" 0, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia (Spain); Frias, Juan C. [Departamento de Ciencias Biomédicas, Universidad CEU Cardenal Herrera, Valencia (Spain); Anderson, Stasia A. [Advanced Cardiovascular Imaging Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (United States); Luger, Dror; Westman, Peter C.; Escarcega, Ricardo O.; Hellinga, David G.; Waksman, Ron [MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (United States); Arai, Andrew E. [Advanced Cardiovascular Imaging Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (United States); Epstein, Stephen E. [MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (United States)

2016-03-15

Introduction: Nanoparticles may serve as a promising means to deliver novel therapeutics to the myocardium following myocardial infarction. We sought to determine whether lipid-based liposomal nanoparticles can be shown through different imaging modalities to specifically target injured myocardium following intravenous injection in an ischemia–reperfusion murine myocardial infarction model. Methods: Mice underwent ischemia–reperfusion surgery and then either received tail-vein injection with gadolinium- and fluorescent-labeled liposomes or no injection (control). The hearts were harvested 24 h later and underwent T1 and T2-weighted ex vivo imaging using a 7 Tesla Bruker magnet. The hearts were then sectioned for immunohistochemistry and optical fluorescent imaging. Results: The mean size of the liposomes was 100 nm. T1-weighted signal intensity was significantly increased in the ischemic vs. the non-ischemic myocardium for mice that received liposomes compared with control. Optical imaging demonstrated significant fluorescence within the infarct area for the liposome group compared with control (163 ± 31% vs. 13 ± 14%, p = 0.001) and fluorescent microscopy confirmed the presence of liposomes within the ischemic myocardium. Conclusions: Liposomes traffic to the heart and preferentially home to regions of myocardial injury, enabling improved diagnosis of myocardial injury and could serve as a vehicle for drug delivery.

Transcutaneous drug delivery by liposomes using fractional laser technology.

Science.gov (United States)

Fujimoto, Takahiro; Wang, Jian; Baba, Kazuki; Oki, Yuka; Hiruta, Yuki; Ito, Masayuki; Ito, Shinobu; Kanazawa, Hideko

2017-07-01

Transdermal delivery of hydrophilic peptides remains a challenge due to their poor cellular uptake and transdermal penetration. We hypothesize that combination of a CO 2 fractional laser to enhance percutaneous absorption and liposomes as transdermal carriers would improve skin penetration of hydrophilic drugs. NA. Liposomes were prepared using membrane fusion lipid dioleoylphosphatidylethanolamine, and used to deliver 5-carboxyfluorescein (CF) and fluorescein isothiocyanate-conjugated ovalbumin (OVA-FITC) as model hydrophilic peptide drugs. Liposome size was estimated by dynamic light scattering. Liposome uptake into murine macrophage cells and penetration or permeation into Yucatan micropig skin after irradiation by CO 2 fractional laser at varying energy levels (laser power and exposure duration) were investigated using Franz cell and fluorescence microscopy. Oxidative damage to the irradiated mouse skin was assessed by electron spin resonance. Size of CF and OVA-FITC encapsulated liposomes was 324 ± 75 nm. Cellular uptake of OVA-FITC delivered by liposomes was 10-fold higher (1,370 relative fluorescence units, RFU) than delivered in solution form (130 RFU). Fractional laser irradiation increased skin permeation rate of CF liposomes (0-10%) and OVA-FITC liposomes (4-40%) in a dose-dependent manner. Although peeling off the stratum corneum facilitated CF liposome penetration at low energy levels (2.69-3.29 J/cm 2 ; 10-20 W for 500 μs), drug permeation was similar (7-8%) in peeled or untreated skin at higher laser energy levels (6.06 J/cm 2 ; 20 W for 1,500 μs). FITC penetrated deeper in the skin after laser irradiation. However, OH, O2-, and VC reactive oxygen species were generated upon irradiation of the skin with a fractional CO 2 laser. Increasing laser power and irradiation, time increased liposome uptake by cells and penetration of peptide drugs across the skin in a dose-dependent manner. High-energy CO 2 fractional laser overcomes the

Is neoadjuvant chemotherapy prior to radio-chemotherapy beneficial in T4 anal carcinoma?

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Moureau-Zabotto, L; Viret, F; Giovaninni, M; Lelong, B; Bories, E; Delpero, J R; Pesenti, C; Caillol, F; de Chaisemartin, C; Minsat, M; Monges, G; Sarran, A; Resbeut, M

2011-07-01

This study retrospectively describes the outcome of a series of 38 patients (pts) with T4 anal carcinoma exclusively treated by radio and chemotherapy. From 1992 to 2007, 38 pts with UST4-N0-2-M0 anal carcinoma were treated with exclusive radiotherapy and chemotherapy. All patients received external beam radiotherapy (EBRT) (median dose 45 Gy) with a concomitant chemotherapy (5-fluorouracil-cisplatin). Eleven patients received neo-adjuvant chemotherapy (5-fluorouracil-cisplatin). After 2-8 weeks, a 15-20 Gy boost was delivered either with EBRT (20 pts) or interstitial (192)Ir brachytherapy (18 pts). Mean follow-up was 66 months. After chemoradiation therapy (CRT), 13 pts (34%) had a complete response, 23 pts (60%) a response >50% (2 pts were not evaluated). The 5-year-disease-free survival was 79.2 ± 6.5%, and the 5-year overall survival was 83.9 ± 6%. Eight patients developed tumor progression (mean delay 8.8 months), six of them requiring a salvage surgery with definitive colostomy for local relapse. Late severe complication requiring colostomy was observed in 2 pts. The 5-year-colostomy-free survival was 78 ± 6.9%. Patients who received primary chemotherapy had a statistically significant better 5-year colostomy-free survival (100% vs. 38 ± 16.4%, P = 0.0006). T4 anal carcinoma can be treated with a curative intent using a sphincter-sparing approach of CRT, and neo-adjuvant chemotherapy should be considered prior to radiotherapy. Copyright © 2011 Wiley-Liss, Inc.

Moessbauer study of LaFeAsO and F-doped superconductors in external magnetic fields

International Nuclear Information System (INIS)

Kitao, S; Kobayashi, Y; Higashitaniguchi, S; Kurokuzu, M; Saito, M; Seto, M; Mitsui, T; Kamihara, Y; Hirano, M; Hosono, H

2010-01-01

The iron-based F-doped superconductors LaFeAsO 1-x F x with a transition temperature of 24 K (for x = 0.07) and 26 K (x = 0.11) and its parent material LaFeAsO were studied using 57 Fe Moessbauer spectroscopy. Further investigation was carried out by applying external magnetic fields. F-doped superconductors showed a singlet pattern with no magnetic splitting throughout the temperature range from 4.2 to 298 K. On the other hand, magnetically-split spectra were observed in the parent LaFeAsO below the Neel temperature of about 140 K. The internal magnetic field reached 5.3 T at 4.2 K. The external magnetic fields up to 14 T were applied to the singlet phases, F-doped superconductors and the parent LaFeAsO above the Neel temperature. The induced magnetically-split spectra showed the internal magnetic fields with the comparable value to the applied fields. This fact confirmed that these singlet phases have the paramagnetic feature. The magnetic fields were also applied to the magnetically-ordered phase of LaFeAsO below the Neel temperature. The evolution of the spectra depending on the external magnetic fields was clearly explained by a model with two sublattice spins of the powdered antiferromagnet. This fact confirmed the magnetically-ordered phase is an antiferromagnet. The spin-flop field was also estimated by the model as about 26 T.

Liposome-encapsulated EF24-HPβCD inclusion complex: a preformulation study and biodistribution in a rat model

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Agashe, H.; Lagisetty, P.; Sahoo, K.; Bourne, D.; Grady, B.; Awasthi, V.

2011-06-01

3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24) is an anti-proliferative diphenyldifluoroketone analog of curcumin with more potent activity. The authors describe a liposome preparation of EF24 using a "drug-in-CD-in liposome" approach. An aqueous solution of EF24 and hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex (IC) was used to prepare EF24 liposomes. The liposome size was reduced by a combination of multiple freeze-thaw cycles. Co-encapsulation of glutathione inside the liposomes conferred them with the capability of labeling with imageable radionuclide Tc-99m. Phase solubility analysis of EF24-HPβCD mixture provided k 1:1 value of 9.9 M-1. The enhanced aqueous solubility of EF24 (from 1.64 to 13.8 mg/mL) due to the presence of HPβCD helped in the liposome preparation. About 19% of the EF24 IC was encapsulated inside the liposomes (320.5 ± 2.6 nm) by dehydration-rehydration technique. With extrusion technique, the size of 177 ± 6.5 nm was obtained without any effect on encapsulation efficiency. The EF24-liposomes were evaluated for anti-proliferative activity in lung adenocarcinoma H441 and prostate cancer PC-3 cells. The EF24-liposomes demonstrated anti-proliferative activity superior to that of plain EF24 at 10 μM dose. When injected in rats, the Tc-99m-labeled EF24-liposomes cleared from blood with an α- t 1/2 of 21.4 min and β- t 1/2 of 397 min. Tissue radioactivity counting upon necropsy showed that the majority of clearance was due to the uptake in liver and spleen. The results suggest that using "drug-in-CD-in liposome" approach is a feasible strategy to formulate an effective parenteral preparation of EF24. In vitro studies show that the liposomal EF24 remains anti-proliferative, while presenting an opportunity to image its biodistribution.

Sustained release of intravitreal flurbiprofen from a novel drug-in-liposome-in-hydrogel formulation.

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Pachis, K; Blazaki, S; Tzatzarakis, M; Klepetsanis, P; Naoumidi, E; Tsilimbaris, M; Antimisiaris, S G

2017-11-15

A novel Flurbiprofen (FLB)-in-liposome-in-hydrogel formulation was developed, as a method to sustain the release and increase the ocular bioavailability of FLB following intravitreal injection. For this, FLB loading into liposomes was optimized and liposomes were entrapped in thermosensitive hydrogels consisted of Pluronic F-127 (P). FLB solution, liposomes, and FLB dissolved in hydrogel were also used as control formulations. Actively loaded liposomes were found to be optimal for high FLB loading and small size, while in vitro studies revealed that P concentration of 18% (w/v) was best to retain the integrity of the hydrogel-dispersed liposome, compared to a 20% concentration. The in vitro release of FLB was significantly sustained when FLB-liposomes were dispersed in the hydrogel compared to hydrogel dissolved FLB, as well as the other control formulations. In vivo studies were carried out in pigmented rabbits which were injected through a 27G needle with 1mg/mL FLB in the different formulation-types. Ophthalmic examinations after intravitreal injection of all FLB formulations, revealed no evidence of inflammation, hemorrhage, uveitis or endophthalmitis. Pharmacokinetic analysis results confirm that the hybrid drug delivery system increases the bioavailability (by 1.9 times compared to solution), and extends the presence of the drug in the vitreous cavity, while liposome and hydrogel formulations demonstrate intermediate performance. Furthermore the hybrid system increases MRT of FLB in aqueous humor and retina/choroid tissues, compared to all the control formulations. Currently the potential therapeutic advances of FLB sustained release formulations for IVT administration are being evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

Predictive value of BRCA1/2 mRNA expression for response to neoadjuvant chemotherapy in BRCA-negative breast cancers.

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Xu, Ye; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

2018-01-01

It is well known that BRCA1 and BRCA2 play a central role in DNA repair, but the relationship between BRCA1 and BRCA2 mRNA expression and response to neoadjuvant chemotherapy in sporadic breast cancer patients has not been well established. Here, we investigate the association between BRCA1 or BRCA2 mRNA expression levels and pathological response in 674 BRCA1/2 mutation-negative breast cancer patients who received neoadjuvant chemotherapy. BRCA1 and BRCA2 mRNA expression were assessed using quantitative real-time polymerase chain reaction in core biopsy breast cancer tissue obtained prior to the initiation of neoadjuvant chemotherapy. A total 129 patients (19.1%) achieved pathological complete response (pCR) after neoadjuvant chemotherapy. Among patients treated with anthracycline-based chemotherapy (n = 531), BRCA1 mRNA low expression patients had a significantly higher pCR rate than intermediate or high BRCA1 mRNA expression groups (24.6% vs 16.8% or 14.0%, P = .031) and retained borderline significance (OR = 1.54, 95% CI = 0.93-2.56, P = .094) in multivariate analysis. Among the 129 patients who received a taxane-based regimen, pCR rate showed no differences in BRCA1 low, intermediate, and high mRNA level subgroups (19.6%, 26.8% and 21.4%, respectively; P = .71). BRCA2 mRNA level was not associated with pCR rate in the anthracyline-based treated subgroup (P = .60) or the taxane-based regimen subgroup (P = .82). Taken together, our findings suggested that BRCA1 mRNA expression could be used as a predictive marker in BRCA1/2 mutation-negative breast cancer patients who received neoadjuvant anthracycline-based treatment. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Assessment of the Radiation-Equivalent of Chemotherapy Contributions in 1-Phase Radio-chemotherapy Treatment of Muscle-Invasive Bladder Cancer

International Nuclear Information System (INIS)

Plataniotis, George A.; Dale, Roger G.

2014-01-01

Purpose: To estimate the radiation equivalent of the chemotherapy contribution to observed complete response rates in published results of 1-phase radio-chemotherapy of muscle-invasive bladder cancer. Methods and Materials: A standard logistic dose–response curve was fitted to data from radiation therapy-alone trials and then used as the platform from which to quantify the chemotherapy contribution in 1-phase radio-chemotherapy trials. Two possible mechanisms of chemotherapy effect were assumed (1) a fixed radiation-independent contribution to local control; or (2) a fixed degree of chemotherapy-induced radiosensitization. A combination of both mechanisms was also considered. Results: The respective best-fit values of the independent chemotherapy-induced complete response (CCR) and radiosensitization (s) coefficients were 0.40 (95% confidence interval −0.07 to 0.87) and 1.30 (95% confidence interval 0.86-1.70). Independent chemotherapy effect was slightly favored by the analysis, and the derived CCR value was consistent with reports of pathologic complete response rates seen in neoadjuvant chemotherapy-alone treatments of muscle-invasive bladder cancer. The radiation equivalent of the CCR was 36.3 Gy. Conclusion: Although the data points in the analyzed radio-chemotherapy studies are widely dispersed (largely on account of the diverse range of chemotherapy schedules used), it is nonetheless possible to fit plausible-looking response curves. The methodology used here is based on a standard technique for analyzing dose-response in radiation therapy-alone studies and is capable of application to other mixed-modality treatment combinations involving radiation therapy

[A Case of Advanced Rectal Cancer Resected Successfully after Induction Chemotherapy with Modified FOLFOX6 plus Panitumumab].

Science.gov (United States)

Yukawa, Yoshimi; Uchima, Yasutake; Kawamura, Minori; Takeda, Osami; Hanno, Hajime; Takayanagi, Shigenori; Hirooka, Tomoomi; Dozaiku, Toshio; Hirooka, Takashi; Aomatsu, Naoki; Hirakawa, Toshiki; Iwauchi, Takehiko; Nishii, Takafumi; Morimoto, Junya; Nakazawa, Kazunori; Takeuchi, Kazuhiro

2016-05-01

We report a case of advanced colon cancer that was effectively treated with mFOLFOX6 plus panitumumab combination chemotherapy. The patient was a 54-year-old man who had type 2 colon cancer of the rectum. An abdominal CT scan demonstrated rectal cancer with bulky lymph node metastasis and 1 hepatic node (rectal cancer SI [bladder retroperitoneum], N2M0H1P0, cStage IV). He was treated with mFOLFOX6 plus panitumumab as neoadjuvant chemotherapy. After 4 courses of chemotherapy, CT revealed that the primary lesion and regional metastatic lymph nodes had reduced in size (rectal cancer A, N1H1P0M0, cStage IV). Anterior rectal resection with D3 nodal dissection and left lateral segmentectomy of the liver was performed. The histological diagnosis was tubular adenocarcinoma (tub2-1), int, INF a, pMP, ly0, v0, pDM0, pPM0, R0. He was treated with 4 courses of mFOLFOX6 after surgery. The patient has been in good health without a recurrence for 2 years and 5 months after surgery. This case suggests that induction chemotherapy with mFOLFOX6 plus panitumumab is a potentially effective regimen for advanced colon cancer.

Liposomal membrane disruption by means of miniaturized dielectric-barrier discharge in air: liposome characterization

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Svarnas, P.; Asimakoulas, L.; Katsafadou, M.; Pachis, K.; Kostazos, N.; Antimisiaris, S. G.

2017-08-01

The increasing interest of the plasma community in the application of atmospheric-pressure cold plasmas to bio-specimen treatment has led to the creation of the emerging field of plasma biomedicine. Accordingly, plasma setups based on dielectric-barrier discharges have already been widely tested for the inactivation of various cells. Most of these systems refer to the plasma jet concept where noble gases penetrate atmospheric air and are subjected to the influence of high electric fields, thus forming guided streamers. Following the original works of our group where liposomal membranes were proposed as models for studying the interaction between plasma jets and cells, we present herein a study on liposomal membrane disruption by means of miniaturized dielectric-barrier discharge running in atmospheric air. Liposomal membranes of various lipid compositions, lamellarities, and sizes are treated at different times. It is shown that the dielectric-barrier discharge of low mean power leads to efficient liposomal membrane disruption. The latter is achieved in a controllable manner and depends on liposome properties. Additionally, it is clearly demonstrated that liposomal membrane disruption takes place even after plasma extinction, i.e. during post-treatment, resembling thus an ‘apoptosis’ effect, which is well known today mainly for cell membranes. Thus, the adoption of the present concept would be beneficial for tailoring studies on plasma-treated cell-mimics. Finally, the liposome treatment is discussed with respect to possible physicochemical mechanisms and potential discharge modification due to the various compositions of the liquid electrode.

Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided versus empirical chemotherapy in unresectable non-small cell lung cancer.

Science.gov (United States)

Moon, Yong Wha; Sohn, Joo Hyuk; Kim, Yong Tai; Chang, Hyun; Jeong, Jae Heon; Lee, Young Joo; Chang, Joon; Kim, Se Kyu; Jung, Minkyu; Hong, Soojung; Choi, Sung Ho; Kim, Joo-Hang

2009-10-01

We retrospectively compared adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided and empirical chemotherapies for unresectable non-small cell lung cancer (NSCLC) in this case-control study. Unresectable NSCLC patients receiving ATP-CRA-guided platinum-based doublets as first-line therapy were enrolled as cases (n=27; 14 platinum-sensitive and 13 platinum-resistant patients). Performance status, stage, and chemotherapeutic regimen-matched patients receiving empirical chemotherapy were selected from the retrospective database as controls (n=93) in a case to control ratio of approximately 1:3. Response rate and survival (progression-free; overall) in both groups were not significantly different. However, the platinum-sensitive subgroup by ATP-CRA showed a higher response rate than the empirical group (71 versus 38%; p=0.023) with a trend toward longer progression-free survival (8.7 versus 4.8 months for platinum-sensitive versus empirical; p=0.223) and overall survival (not reached versus 12.6 months for platinum-sensitive versus empirical for p=0.134). ATP-CRA may be helpful in selecting platinum-responsive patients in unresectable NSCLC. We consider that nonplatinum doublets in platinum-resistant patients by ATP-CRA may be a more adapted approach than platinum-based doublets in future clinical trials.

Effect of External Use of Sesame Oil in the Prevention of Chemotherapy-Induced Phlebitis

Science.gov (United States)

Nekuzad, Nilufar; Ashke Torab, Tahereh; Mojab, Faraz; Alavi-Majd, Hamid; Azadeh, Payam; Ehtejab, Gholamreza

2012-01-01

Intravenous chemotherapy is an important mean for the treatment of cancers. Infusion phlebitis (Ph) is a common and acute complication of chemotherapy. The frequency of Ph is about 70% in patients undergoing chemotherapeutic management. It can induce the pain, increase the risk of thrombophlebitis, lead to incomplete follow-up, and thereby, affect the patient’s health status. Respecting the great importance of these issues, it is essential to prevent Ph. This study conducted to determine the effect of external use of Sesame Oil (SO) in the prevention of Ph. Sixty patients with colon or rectum cancer, who admitted for chemotherapeutic management, enrolled in clinical trial and were randomly divided into two equal groups: Control and Intervention. Ten drops of SO was applied twice a day for 14 days externally in intervention group, whereas the control group received nothing. Incidence and grade of Ph was measured in both groups. Data was analyzed through independent t-test, Χ2, Fisher’s exact test, Mann-Whitney, and Lagrange survival using SPSS 16. The incidence of Ph was 10% and 80% in intervention group and control group, respectively.There was a significant difference between two groups (p < 0.05). Ph was 8 times more frequent in control group (R R = 8; AR R = 70%). In addition, there was statistically significant difference between the grade and incidence of Ph with SO and control group (p < 0.05). According to these results, it seems that external use of SO is effective, safe and well-tolerated for prophylaxis from Ph. Therefore, it can be suggested as a selected prevention method for reducing the complication. PMID:24250538

Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers

Directory of Open Access Journals (Sweden)

Tongtong Zhang

2018-05-01

Full Text Available Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler (LCD for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 μm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency. Key words: Curcumin, Dry powder inhaler, Liposome, Primary lung cancer, Pulmonary delivery

Engineering of an Inhalable DDA/TDB Liposomal Adjuvant

DEFF Research Database (Denmark)

Ingvarsson, Pall Thor; Yang, Mingshi; Mulvad, Helle

2013-01-01

The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB).......The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB)....

In vivo and in vitro evaluation of octyl methoxycinnamate liposomes

Directory of Open Access Journals (Sweden)

de Carvalho Varjão Mota A

2013-12-01

the HET-CAM test, indicating good histocompatibility. The formulation containing liposome/OMC had a higher in vivo solar photoprotection factor, but did not show increased water resistance. Inclusion in liposomes was able to slow down the release of OMC from the formulation, with a lower steady-state flux (3.9 ± 0.33 µg/cm2/hour compared with the conventional formulation (6.3 ± 1.21 µg/cm2/hour. The stripping method showed increased uptake of OMC in the stratum corneum, giving an amount of 22.64 ± 7.55 µg/cm2 of OMC, which was higher than the amount found for the conventional formulation (14.57 ± 2.30 µg/cm2.Conclusion: These results indicate that liposomes are superior carriers for OMC, and confer greater safety and efficacy to sunscreen formulations.Keywords: sunscreen, liposome, tape stripping, technetium-99-m, lipase

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

DEFF Research Database (Denmark)

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

2011-01-01

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

Enzymatic degradation of polymer covered SOPC-liposomes in relation to drug delivery

DEFF Research Database (Denmark)

Davidsen, Jesper; Vermehren, C.; Frøkjær, S.

2001-01-01

Polyethylenoxide (PEG) covered liposomes are used as lipid-based drug-delivery systems. In comparison to conventional liposomes the polymer-covered liposomes display a long circulation half-life in the blood stream. We investigate the influence of polyethyleneoxide-distearoylphosphatidylethanolam......Polyethylenoxide (PEG) covered liposomes are used as lipid-based drug-delivery systems. In comparison to conventional liposomes the polymer-covered liposomes display a long circulation half-life in the blood stream. We investigate the influence of polyethyleneoxide...

Amperometric glucose biosensor based on layer-by-layer films of microperoxidase-11 and liposome-encapsulated glucose oxidase.

Science.gov (United States)

Graça, J S; de Oliveira, R F; de Moraes, M L; Ferreira, M

2014-04-01

An important step in several bioanalytical applications is the immobilization of biomolecules. Accordingly, this procedure must be carefully chosen to preserve their biological structure and fully explore their properties. For this purpose, we combined the versatility of the layer-by-layer (LbL) method for the immobilization of biomolecules with the protective behavior of liposome-encapsulated systems to fabricate a novel amperometric glucose biosensor. To obtain the biosensing unit, an LbL film of the H2O2 catalyst polypeptide microperoxidase-11 (MP-11) was assembled onto an indium-tin oxide (ITO) electrode followed by the deposition of a liposome-encapsulated glucose oxidase (GOx) layer. The biosensor response toward glucose detection showed a sensitivity of 0.91±0.09 (μA/cm2)/mM and a limit of detection (LOD) of 8.6±1.1 μM, demonstrating an improved performance compared to similar biosensors with a single phospholipid-liposome or even containing a non-encapsulated GOx layer. Finally, glucose detection was also performed in a zero-lactose milk sample to demonstrate the potential of the biosensor for food analysis. Copyright © 2014 Elsevier B.V. All rights reserved.

Differential scanning calorimetry study on the binding of nucleic acids to dimyristoylphosphatidylcholine-sphingosine liposomes.

Science.gov (United States)

Kõiv, A; Mustonen, P; Kinnunen, P K

1994-03-31

Binding of DNA and RNA to sphingosine-containing dimyristoylphosphatidylcholine (DMPC) liposomes was characterized by differential scanning calorimetry. The thermal phase behaviour of neat DMPC liposomes was unaffected by the presence of the nucleic acids. However, significant alterations in the melting profiles of the DMPC/sphingosine composite membranes were produced by DNA and RNA, thus revealing their binding to the liposomes. For example, for 79:21 (molar ratio) DMPC/sphingosine liposomes a single endotherm at 29.1 degrees C with an enthalpy of 6.3 kcal/mol lipid was observed. In the presence of DNA at the nucleotide/sphingosine ratio of 0.6 this endotherm separated into three distinct peaks at 28.0, 31.4 and 35.1 degrees C, together with an approximately 22% reduction in the total enthalpy. Further increase in DNA concentration up to 1.5 nucleotides per sphingosine led to complete loss of the original heat absorption peak of the DMPC/sphingosine liposomes, while an endotherm at 34.3 degrees C with delta H of 2.7 kcal/mol developed. By visual inspection, rapid and extensive aggregation of the liposomes due to DNA was evident. Evidence for DNA-induced phase separation was also provided by compression isotherms of sphingosine containing DMPC monolayers recorded over an aqueous buffer both in the presence and absence of DNA. The effects of RNA on the thermal phase behaviour of the composite liposomes were qualitatively similar to those described above for DNA. Notably, the presence of eggPA abolished the nucleic acid induced heat capacity changes for DMPC/sphingosine liposomes probably because of neutralization of the positive charge of sphingosine. The binding of DNA to DMPC/sphingosine liposomes occurred both below and above the lipid phase transition temperature, as shown by fluorescence resonance energy transfer utilizing adriamycin-labelled DNA as a quencher and membrane incorporated pyrene-labelled phospholipid as a donor. However, the apparent binding to

Assessment of pulmonary toxicities in breast cancer patients undergoing treatment with anthracycline and taxane based chemotherapy and radiotherapy- a prospective study

Directory of Open Access Journals (Sweden)

Aramita Saha

2013-12-01

Full Text Available Background: Anthracycline based regiments and/or taxanes and adjuvant radiotherapy; the main modalities of treatment for breast cancers are associated with deterioration of pulmonary functions and progressive pulmonary toxicities. Aim: Assessment of pulmonary toxicities and impact on pulmonary functions mainly in terms of decline of forced vital capacity (FVC and the ratio of forced expiratory volume (FEV in 1 Second and FEV1/FVC ratio with different treatment times and follow ups in carcinoma breast patients receiving anthracycline and/or taxane based chemotherapy and radiotherapy. Materials and methods: A prospective single institutional cohort study was performed with 58 breast cancer patients between January 2011 to July 2012 who received either anthracycline based (37 patients received 6 cycles FAC= 5 FU, Adriamycin, Cyclophosphamide regime and radiotherapy or anthracycline and taxane based chemotherapy (21 patients received 4cycles AC= Adriamycin, Cyclophosphamide; followed by 4 cycles of T=Taxane and radiotherapy. Assessment of pulmonary symptoms and signs, chest x-ray and pulmonary function tests were performed at baseline, midcycle, at end of chemotherapy, at end radiotherapy, at 1 and 6 months follow ups and compared. By means of a two-way analysis of variance (ANOVA model, the course of lung parameters across the time points was compared. Results and Conclusion: Analysis of mean forced vital capacities at different points of study times showed definitive declining pattern, which is at statistically significant level at the end of 6th month of follow up (p=0.032 .The FEV1/FVC ratio (in percentage also revealed a definite decreasing pattern over different treatment times and at statistically significant level at 6th month follow up with p value 0.003. Separate analysis of mean FEV1/FVC ratios over time in anthracycline based chemotherapy and radiotherapy group as well as anthracycline and taxane based chemotherapy and radiotherapy group

Engineering liposomal nanoparticles for targeted gene therapy.

Science.gov (United States)

Zylberberg, C; Gaskill, K; Pasley, S; Matosevic, S

2017-08-01

Recent mechanistic studies have attempted to deepen our understanding of the process by which liposome-mediated delivery of genetic material occurs. Understanding the interactions between lipid nanoparticles and cells is still largely elusive. Liposome-mediated delivery of genetic material faces systemic obstacles alongside entry into the cell, endosomal escape, lysosomal degradation and nuclear uptake. Rational design approaches for targeted delivery have been developed to reduce off-target effects and enhance transfection. These strategies, which have included the modification of lipid nanoparticles with target-specific ligands to enhance intracellular uptake, have shown significant promise at the proof-of-concept stage. Control of physical and chemical specifications of liposome composition, which includes lipid-to-DNA charge, size, presence of ester bonds, chain length and nature of ligand complexation, is integral to the performance of targeted liposomes as genetic delivery agents. Clinical advances are expected to rely on such systems in the therapeutic application of liposome nanoparticle-based gene therapy. Here, we discuss the latest breakthroughs in the development of targeted liposome-based agents for the delivery of genetic material, paying particular attention to new ligand and cationic lipid design as well as recent in vivo advances.

The Treatment of Breast Cancer Using Liposome Technology

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Sarah Brown

2012-01-01

Full Text Available Liposome-based chemotherapeutics used in the treatment of breast cancer can in principle enhance the therapeutic index of otherwise unencapsulated anticancer drugs. This is partially attributed to the fact that encapsulation of cytotoxic agents within liposomes allows for increased concentrations of the drug to be delivered to the tumor site. In addition, the presence of the phospholipid bilayer prevents the encapsulated active form of the drug from being broken down in the body prior to reaching tumor tissue and also serves to minimize exposure of the drug to healthy sensitive tissue. While clinically approved liposome-based chemotherapeutics such as Doxil have proven to be quite effective in the treatment of breast cancer, significant challenges remain involving poor drug transfer between the liposome and cancerous cells. In this review, we discuss the recent advancements made in the development of liposome-based chemotherapeutics with respect to improved drug transfer for use in breast cancer therapy.

Immunohistochemical Expression of CD-10, BCL-6 and MUM-1 Antibodies and Immediate Clinical Response in Patients of Diffuse Large B-Cell Lymphomas after Six Cycles of Chemotherapy

International Nuclear Information System (INIS)

Hassan, U.; Ishtiaq, S.; Hussain, M.

2014-01-01

Objective: To determine the expression of CD-10, BCL-6 and MUM-1 in patients with diffuse large B-cell lymphoma (DLBCL) and its association with immediate clinical response after six cycles of CHOP chemotherapy. Study Design: Analytical study. Place and Duration of Study: Armed Forces Institute of Pathology (AFIP), Rawalpindi in collaboration with Nuclear medicine, Oncology and Radiotherapy Institute (NORI), Islamabad from September 2010 to September 2011. Methodology: CD-10, BCL-6 and MUM-1 antibodies were applied on cases diagnosed as DLBCL. Immediate clinical response was noted after 6 cycles of chemotherapy with the help of oncologist and divided into complete response, partial response, stable disease and relapse/ progression. Patient's age, results of expression of CD-10, BCL-6 and MUM-1 and results of immediate clinical response to chemotherapy were noted. Regarding analysis of prognostic markers (CD-10, BCL-6 and MUM-1), chi-square test was used for immediate clinical response to chemotherapy in DLBCL. Results: CD-10 was positive in 40% cases, BCL-6 in 58.7% cases and MUM-1 was positive in 46.7% cases. About 41.3% of patients showed complete response, 10.6% partial response, 17.3% stable disease and 30.8% showed relapse/progression. CD-10 expression in DLBCL was associated with better immediate clinical response (p = 0.011) whereas MUM-1 expression in DLBCL was associated with poor immediate clinical response (p < 0.0001). However, there was no statistically significant association of BCL-6 with immediate clinical response (p = 0.22). Conclusion: DLBCL shows expression of CD-10, BCL-6 and MUM-1 in nearly fifty percent of the cases. CD-10 is associated with good whereas MUM is associated with poor response. However, there was no association of BCL-6 with immediate clinical response. (author)

Optimization and modeling of the remote loading of luciferin into liposomes.

Science.gov (United States)

Hansen, Anders Højgaard; Lomholt, Michael A; Hansen, Per Lyngs; Mouritsen, Ole G; Arouri, Ahmad

2016-07-11

We carried out a mechanistic study to characterize and optimize the remote loading of luciferin into preformed liposomes of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPC/DPPG) 7:3 mixtures. The influence of the loading agent (acetate, propionate, butyrate), the metal counterion (Na(+), K(+), Ca(+2), Mg(+2)), and the initial extra-liposomal amount of luciferin (nL(add)) on the luciferin Loading Efficiency (LE%) and luciferin-to-lipid weight ratio, i.e., Loading Capacity (LC), in the final formulation was determined. In addition, the effect of the loading process on the colloidal stability and phase behavior of the liposomes was monitored. Based on our experimental results, a theoretical model was developed to describe the course of luciferin remote loading. It was found that the highest luciferin loading was obtained with magnesium acetate. The use of longer aliphatic carboxylates or inorganic proton donors pronouncedly reduced luciferin loading, whereas the effect of the counterion was modest. The remote-loading process barely affected the colloidal stability and drug retention of the liposomes, albeit with moderate luciferin-induced membrane perturbations. The correlation between luciferin loading, expressed as LE% and LC, and nL(add) was established, and under our conditions the maximum LC was attained using an nL(add) of around 2.6μmol. Higher amounts of luciferin tend to pronouncedly perturb the liposome stability and luciferin retention. Our theoretical model furnishes a fair quantitative description of the correlation between nL(add) and luciferin loading, and a membrane permeability coefficient for uncharged luciferin of 1×10(-8)cm/s could be determined. We believe that our study will prove very useful to optimize the remote-loading strategies of moderately polar carboxylic acid drugs in general. Copyright © 2016 Elsevier B.V. All rights reserved.

Treatment response evaluation with 18F-FDG PET/CT and 18F-NaF PET/CT in multiple myeloma patients undergoing high-dose chemotherapy and autologous stem cell transplantation.

Science.gov (United States)

Sachpekidis, Christos; Hillengass, J; Goldschmidt, H; Wagner, B; Haberkorn, U; Kopka, K; Dimitrakopoulou-Strauss, A

2017-01-01

The aim of this study was to assess the combined use of the radiotracers 18 F-FDG and 18 F-NaF in treatment response evaluation of a group of multiple myeloma (MM) patients undergoing high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) by means of static (whole-body) and dynamic PET/CT (dPET/CT). Thirty-four patients with primary, previously untreated MM scheduled for treatment with HDT followed by ASCT were enrolled in the study. All patients underwent PET/CT scanning with 18 F-FDG and 18 F-NaF before and after therapy. Treatment response by means of PET/CT was assessed according to the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria. The evaluation of dPET/CT studies was based on qualitative evaluation, semi-quantitative (SUV) calculation, and quantitative analysis based on two-tissue compartment modelling and a non-compartmental approach leading to the extraction of fractal dimension (FD). An analysis was possible in 29 patients: three with clinical complete response (CR) and 26 with non-CR (13 patients near complete response-nCR, four patients very good partial response-VGPR, nine patients partial response-PR). After treatment, 18 F-FDG PET/CT was negative in 14/29 patients and positive in 15/29 patients, showing a sensitivity of 57.5 % and a specificity of 100 %. According to the EORTC 1999 criteria, 18 F-FDG PET/CT-based treatment response revealed CR in 14 patients ( 18 F-FDG PET/CT CR), PR in 11 patients ( 18 F-FDG PET/CT PR) and progressive disease in four patients ( 18 F-FDG PET/CT PD). In terms of 18 F-NaF PET/CT, 4/29 patients (13.8 %) had a negative baseline scan, thus failed to depict MM. Regarding the patients for which a direct lesion-to-lesion comparison was feasible, 18 F-NaF PET/CT depicted 56 of the 129 18 F-FDG positive lesions (43 %). Follow-up 18 F-NaF PET/CT showed persistence of 81.5 % of the baseline 18 F-NaF positive MM lesions after treatment, despite the fact that 64

Liposome-encapsulated EF24-HP{beta}CD inclusion complex: a preformulation study and biodistribution in a rat model

Energy Technology Data Exchange (ETDEWEB)

Agashe, H; Lagisetty, P; Sahoo, K; Bourne, D [University of Oklahoma Health Sciences Center, Department of Pharmaceutical Sciences (United States); Grady, B [School of Chemical, Biological and Materials Engineering (United States); Awasthi, V [University of Oklahoma Health Sciences Center, Department of Pharmaceutical Sciences (United States)

2011-06-15

3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24) is an anti-proliferative diphenyldifluoroketone analog of curcumin with more potent activity. The authors describe a liposome preparation of EF24 using a 'drug-in-CD-in liposome' approach. An aqueous solution of EF24 and hydroxypropyl-{beta}-cyclodextrin (HP{beta}CD) inclusion complex (IC) was used to prepare EF24 liposomes. The liposome size was reduced by a combination of multiple freeze-thaw cycles. Co-encapsulation of glutathione inside the liposomes conferred them with the capability of labeling with imageable radionuclide Tc-99m. Phase solubility analysis of EF24-HP{beta}CD mixture provided k{sub 1:1} value of 9.9 M{sup -1}. The enhanced aqueous solubility of EF24 (from 1.64 to 13.8 mg/mL) due to the presence of HP{beta}CD helped in the liposome preparation. About 19% of the EF24 IC was encapsulated inside the liposomes (320.5 {+-} 2.6 nm) by dehydration-rehydration technique. With extrusion technique, the size of 177 {+-} 6.5 nm was obtained without any effect on encapsulation efficiency. The EF24-liposomes were evaluated for anti-proliferative activity in lung adenocarcinoma H441 and prostate cancer PC-3 cells. The EF24-liposomes demonstrated anti-proliferative activity superior to that of plain EF24 at 10 {mu}M dose. When injected in rats, the Tc-99m-labeled EF24-liposomes cleared from blood with an {alpha}-t{sub 1/2} of 21.4 min and {beta}-t{sub 1/2} of 397 min. Tissue radioactivity counting upon necropsy showed that the majority of clearance was due to the uptake in liver and spleen. The results suggest that using 'drug-in-CD-in liposome' approach is a feasible strategy to formulate an effective parenteral preparation of EF24. In vitro studies show that the liposomal EF24 remains anti-proliferative, while presenting an opportunity to image its biodistribution.

Liposome-encapsulated EF24-HP{beta}CD inclusion complex: a preformulation study and biodistribution in a rat model

Energy Technology Data Exchange (ETDEWEB)

Agashe, H.; Lagisetty, P.; Sahoo, K.; Bourne, D. [University of Oklahoma Health Sciences Center, Department of Pharmaceutical Sciences (United States); Grady, B. [School of Chemical, Biological and Materials Engineering (United States); Awasthi, V., E-mail: vawasthi@ouhsc.edu [University of Oklahoma Health Sciences Center, Department of Pharmaceutical Sciences (United States)

2011-06-15

3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24) is an anti-proliferative diphenyldifluoroketone analog of curcumin with more potent activity. The authors describe a liposome preparation of EF24 using a 'drug-in-CD-in liposome' approach. An aqueous solution of EF24 and hydroxypropyl-{beta}-cyclodextrin (HP{beta}CD) inclusion complex (IC) was used to prepare EF24 liposomes. The liposome size was reduced by a combination of multiple freeze-thaw cycles. Co-encapsulation of glutathione inside the liposomes conferred them with the capability of labeling with imageable radionuclide Tc-99m. Phase solubility analysis of EF24-HP{beta}CD mixture provided k{sub 1:1} value of 9.9 M{sup -1}. The enhanced aqueous solubility of EF24 (from 1.64 to 13.8 mg/mL) due to the presence of HP{beta}CD helped in the liposome preparation. About 19% of the EF24 IC was encapsulated inside the liposomes (320.5 {+-} 2.6 nm) by dehydration-rehydration technique. With extrusion technique, the size of 177 {+-} 6.5 nm was obtained without any effect on encapsulation efficiency. The EF24-liposomes were evaluated for anti-proliferative activity in lung adenocarcinoma H441 and prostate cancer PC-3 cells. The EF24-liposomes demonstrated anti-proliferative activity superior to that of plain EF24 at 10 {mu}M dose. When injected in rats, the Tc-99m-labeled EF24-liposomes cleared from blood with an {alpha}-t{sub 1/2} of 21.4 min and {beta}-t{sub 1/2} of 397 min. Tissue radioactivity counting upon necropsy showed that the majority of clearance was due to the uptake in liver and spleen. The results suggest that using 'drug-in-CD-in liposome' approach is a feasible strategy to formulate an effective parenteral preparation of EF24. In vitro studies show that the liposomal EF24 remains anti-proliferative, while presenting an opportunity to image its biodistribution.

Liposomal Fasudil, a Rho-Kinase Inhibitor, for Prolonged Pulmonary Preferential Vasodilation in Pulmonary Arterial Hypertension

Science.gov (United States)

Gupta, Vivek; Gupta, Nilesh; Shaik, Imam H.; Mehvar, Reza; McMurtry, Ivan F.; Oka, Masahiko; Nozik-Grayck, Eva; Komatsu, Masanobu; Ahsan, Fakhrul

2013-01-01

Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal fasudil formulations was between 68.1±0.8% and 73.6±2.3%, and the cumulative release at 37°C was 98–99% over a period of 5 days. Compared to intravenous (IV) fasudil, a ~10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols. The t1/2 of IV fasudil was 0.39±0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71±0.72 h. One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6±5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH. PMID:23353807

Novel Nano-Liposome Formulation for Dry Eyes with Components Similar to the Preocular Tear Film

Directory of Open Access Journals (Sweden)

Marta Vicario-de-la-Torre

2018-04-01

Full Text Available Dry eye is commonly treated with artificial tears; however, developing artificial tears similar to natural tears is difficult due to the complex nature of tears. We characterized and evaluated a novel artificial tear formulation with components similar to the lipid and aqueous constituents of natural tears. Nano-liposomes, composed in part of phosphatidylcholine, were dispersed in an aqueous solution of bioadhesive sodium hyaluronate. Liposome size, zeta potential, and physicochemical properties of the fresh and stored (4 °C liposomal formulation were analyzed. In vitro tolerance was tested using human corneal and conjunctival cell lines by exposures of 15 min to 4 h. The tolerance of the liposomal formulation was evaluated in animals (rabbits. The average liposome size was 186.3 ± 7.0 nm, and the zeta potential was negative. The osmolarity of the formulation was 198.6 ± 1.7 mOsm, with a surface tension of 36.5 ± 0.4 mN/m and viscosity of 3.05 ± 0.02 mPa·s. Viability values in the human corneal and conjunctival cell lines were always >80%, even after liposomal formulation storage for 8 weeks. Discomfort and clinical signs after instillation in rabbit eyes were absent. The new formulation, based on phosphatidylcholine-liposomes dispersed in sodium hyaluronate has suitable components and characteristics, including high in vitro cell viability and good in vivo tolerance, to serve as a tear substitute.

Nanotechnology for Cancer Therapy Based on Chemotherapy

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Chen-Yang Zhao

2018-04-01

Full Text Available Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics.

Mild hydrothermal crystal growth of new uranium(IV) fluorides, Na{sub 3.13}Mg{sub 1.43}U{sub 6}F{sub 30} and Na{sub 2.50}Mn{sub 1.75}U{sub 6}F{sub 30}: Structures, optical and magnetic properties

Energy Technology Data Exchange (ETDEWEB)

Yeon, Jeongho; Smith, Mark D. [Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208 (United States); Tapp, Joshua; Möller, Angela [Department of Chemistry and Texas Center for Superconductivity, University of Houston, Houston, TX 77204 (United States); Loye, Hans-Conrad zur, E-mail: zurloye@mailbox.sc.edu [Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208 (United States)

2016-04-15

Two new uranium(IV) fluorides, Na{sub 3.13}Mg{sub 1.43}U{sub 6}F{sub 30} (1) and Na{sub 2.50}Mn{sub 1.75}U{sub 6}F{sub 30} (2), were synthesized through an in situ mild hydrothermal route, and were structurally characterized by single crystal X-ray diffraction. The compounds exhibit complex crystal structures composed of corner- or edge-shared UF{sub 9} and MF{sub 6} (M=Mg, Mn) polyhedra, forming hexagonal channels in the three-dimensional framework, in which ordered or disordered divalent metal and sodium atoms reside. The large hexagonal voids contain the nearly regular M(II)F{sub 6} octahedra and sodium ions, whereas the small hexagonal cavities include M(II) and sodium ions on a mixed-occupied site. Magnetic susceptibility measurements yielded effective magnetic moments of 8.36 and 11.6 µ{sub B} for 1 and 2, respectively, confirming the presence and oxidation states of U(IV) and Mn(II). The large negative Weiss constants indicate the spin gap between a triplet and a singlet state in the U(IV). Magnetization data as a function of applied fields revealed that 2 exhibits paramagnetic behavior due to the nonmagnetic singlet ground state of U(IV) at low temperature. UV–vis diffuse reflectance and X-ray photoelectron spectroscopy data were also analyzed. - Graphical abstract: Two new quaternary U(IV) fluorides, Na{sub 3.13}Mg{sub 1.43}U{sub 6}F{sub 30} and Na{sub 2.50}Mn{sub 1.75}U{sub 6}F{sub 30}, were crystallized via an in situ reduction step of U(VI) to U(IV) under mild hydrothermal conditions. The compounds show complex crystal structures based on the 3-D building block of U{sub 6}F{sub 30}. Magnetic property measurements revealed that the U(IV) exhibits a nonmagnetic singlet ground state at low temperature with a spin gap. - Highlights: • Na{sub 3.13}Mg{sub 1.43}U{sub 6}F{sub 30} and Na{sub 2.50}Mn{sub 1.75}U{sub 6}F{sub 30} have been synthesized and characterized. • The U(IV) fluorides exhibit complex three-dimensional crystal structures. • The

Pharmacokinetic analysis of 111 in-labeled liposomal Doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound.

Directory of Open Access Journals (Sweden)

Feng-Yi Yang

Full Text Available The goal of this study was to evaluate the pharmacokinetics of targeted and untargeted (111In-doxorubicin liposomes after these have been intravenously administrated to tumor-bearing mice in the presence of blood-brain barrier disruption (BBB-D induced by focused ultrasound (FUS. An intracranial brain tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM 8401 cells was developed in this study. (111In-labeled human atherosclerotic plaque-specific peptide-1 (AP-1-conjugated liposomes containing doxorubicin (Lipo-Dox; AP-1 Lipo-Dox were used as a microSPECT probe for radioactivity measurements in the GBM-bearing mice. Compared to the control tumors treated with an injection of (111In-AP-1 Lipo-Dox or (111In-Lipo-Dox, the animals receiving the drugs followed by FUS exhibited enhanced accumulation of the drug in the brain tumors (p<0.05. Combining sonication with drugs significantly increased the tumor-to-normal brain doxorubicin ratio of the target tumors compared to the control tumors. The tumor-to-normal brain ratio was highest after the injection of (111In-AP-1 Lipo-Dox with sonication. The (111In-liposomes micro-SPECT/CT should be able to provide important information about the optimum therapeutic window for the chemotherapy of brain tumors using sonication.

Population and phase dynamics of F=1 spinor condensates in an external magnetic field

International Nuclear Information System (INIS)

Romano, D.R.; Passos, E.J.V. de

2004-01-01

We show that the classical dynamics underlying the mean-field description of homogeneous mixtures of spinor F=1 Bose-Einstein condensates in an external magnetic field is integrable as a consequence of number conservation and axial symmetry in spin space. The population dynamics depends only on the quadratic term of the Zeeman energy and on the strength of the spin-dependent term of the atom-atom interaction. We determine the equilibrium populations as function of the ratio of these two quantities and the miscibility of the hyperfine components in the ground state spinors are thoroughly discussed. Outside the equilibrium, the populations are always a periodic function of time where the periodic motion can be a libration or a rotation. Our studies also indicate the absence of metastability

Rapid Quantification and Validation of Lipid Concentrations within Liposomes

Directory of Open Access Journals (Sweden)

Carla B. Roces

2016-09-01

Full Text Available Quantification of the lipid content in liposomal adjuvants for subunit vaccine formulation is of extreme importance, since this concentration impacts both efficacy and stability. In this paper, we outline a high performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD method that allows for the rapid and simultaneous quantification of lipid concentrations within liposomal systems prepared by three liposomal manufacturing techniques (lipid film hydration, high shear mixing, and microfluidics. The ELSD system was used to quantify four lipids: 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC, cholesterol, dimethyldioctadecylammonium (DDA bromide, and ᴅ-(+-trehalose 6,6′-dibehenate (TDB. The developed method offers rapidity, high sensitivity, direct linearity, and a good consistency on the responses (R2 > 0.993 for the four lipids tested. The corresponding limit of detection (LOD and limit of quantification (LOQ were 0.11 and 0.36 mg/mL (DMPC, 0.02 and 0.80 mg/mL (cholesterol, 0.06 and 0.20 mg/mL (DDA, and 0.05 and 0.16 mg/mL (TDB, respectively. HPLC-ELSD was shown to be a rapid and effective method for the quantification of lipids within liposome formulations without the need for lipid extraction processes.

The accuracy of {sup 18}F-FDG PET/CT in predicting the pathological response to neoadjuvant chemotherapy in patients with breast cancer. A meta-analysis and systematic review

Energy Technology Data Exchange (ETDEWEB)

Tian, Fangfang; Shen, Guohua; Diao, Wei; Jia, Zhiyun [West China Hospital of Sichuan University, Department of Nuclear Medicine, Chengdu, Sichuan (China); Deng, Yunfu [West China Hospital of Sichuan University, Department of Oncology, Chengdu (China)

2017-11-15

The aim of this meta-analysis was to evaluate the accuracy of {sup 18}F-FDG PET/CT in predicting the pathological response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients. PubMed, Embase, the Cochrane Library (Central), and the Web of Science (SCI-Expanded) were systematically searched to identify pertinent studies. The methodologic quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2. The Spearman correlation coefficient was used to explore the existence of a threshold effect. Heterogeneity was assessed by the likelihood ratio I {sup 2} index. The pooled values calculated with a mixed-effects model for the sensitivity, specificity and diagnostic odds ratio with 95% confidence intervals were 81.9% (76.0-86.6%), 79.3% (72.1-85.1%) and 17.35 (10.98-27.42), respectively. {sup 18}F-FDG PET/CT has a moderate accuracy in predicting the pathological response during the early process of NAC in breast cancer patients. To increase the role of {sup 18}F-FDG PET/CT in monitoring the therapy response, future prospective studies are needed to explore how chemotherapy regimens and different subtypes affect the levels of glucose metabolism. (orig.)

Dual drug delivery using "smart" liposomes for triggered release of anticancer agents

Science.gov (United States)

Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K.

2013-07-01

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-α) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG2000-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG2000-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 ± 0.5 °C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 ± 1 °C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI50 = 6.5 μg/ml) than positive control (Adriamycin, GI50 = 9.1 μg/ml) and FR-targeted PEGylated liposomes GI50 (14.7 μg/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called "smart liposomes" which has not only mediated effective targeting to FR-α but also triggered release of drugs upon hyperthermia.

The low-temperature structures of Hgsub(3-delta)SbF6 and Hgsub(3-delta)TaF6

International Nuclear Information System (INIS)

Tun, Z.; Brown, I.D.

1986-01-01

The Hg chains in both Hgsub(3-delta)SbF 6 and Hgsub(3-delta)TaF 6 order below room temperature. Down to about 190 K the ordering results from the interaction between parallel chains. It is short range and is different for the two compounds. Below 190 K both compounds transform to an isostructural long-range-ordered phase which is driven by the interaction between perpendicular chains. The structure of this phase in both compounds has been determined. Hgsub(3-delta)SbF 6 at 173 K, delta=0.134(1), Msub(r)=810.6(2). It is monoclinic but pseudotetragonal with I4 1 /amd, a=7.655(1), c=12.558(1) A, V=735.9(2) A 3 , Z=4, Dsub(x)=7.314(3) Mg m -3 , graphite-monochromated Mo Kα radiation, lambda=0.71069 A, μ=64.8 mm -1 , F(000)=1337.1(3). Hgsub(3-delta)TaF 6 at 150 K is isostructural but has delta=0.142(1), Msub(r)=868.2(2), a=7.634(1), c=12.610(2) A, V=734.9(2) A, Dsub(x)=7.844(3) Mg m -3 , μ=76.4 mm -1 , F(000)=1422.6(3). Comparison of the low-temperature structures with those at room temperature shows that the thermal contraction results from the shortening of interatomic distances associated with the weak bonds, with the result that the MF 6 (M=Sb, Ta) host lattice shrinks more than the Hg chains. Variation of the atomic displacement parameters with temperature indicates that the large librational displacements of the MF 6 ion result from thermal motion rather than static disorder. (orig.)

X-ray photoelectron spectroscopy as detection tool for coordinated or uncoordinated fluorine atoms demonstrated on fluoride systems NaF, K2TaF7, K3TaF8, K2ZrF6, Na7Zr6F31 and K3ZrF7

Science.gov (United States)

Boča, Miroslav; Barborík, Peter; Mičušík, Matej; Omastová, Mária

2012-07-01

While systems K3TaF8 and K3ZrF7 were prepared by modified molten salt method modified wet pathway was used for reproducible preparation of Na7Zr6F31. Its congruently melting character was demonstrated on simultaneous TG/DSC measurements and XRD patterns. X-ray photoelectron spectroscopy was applied for identification of differently bonded fluorine atoms in series of compounds NaF, K2TaF7, K3TaF8, K2ZrF6, Na7Zr6F31 and K3ZrF7. Three different types of fluorine atoms were described qualitatively and quantitatively. Uncoordinated fluorine atoms (F-) provide signals at lowest binding energies, followed by signals from terminally coordinated fluorine atoms (M-F) and then bridging fluorine atoms (M-F-M) at highest energy. Based on XPS F 1s signals assigned to fluorine atoms in compounds with correctly determined structure it was suggested that fluorine atoms in K3ZrF7 have partially bridging character.

Application of 10BSH entrapped transferrin-PEG-liposome to boron neutron-capture therapy (BNCT) for solid tumor

International Nuclear Information System (INIS)

Maruyama, K.; Ishida, O.; Iwatsuru, M.; Yanagie, H.; Eriguchi, M.; Kobayashi, H.

2000-01-01

The successful treatment of cancer by BNCT requires the selective concentration of 10 B within malignant tumor cells. Intracellular targeting ability and cytotoxic effects of 10 B entrapped TF-PEG-liposomes, in which TF is covalently linked to the distal terminal of PEG chains on the external surface of PEG-liposomes, were examined in Colon 26 tumor-bearing mice. TF-PEG-liposomes readily bound to tumor cells in vivo, and were internalized by receptor-mediated endocytosis. 10 B-PEG-liposomes and 10 B-TF-PEG-liposomes showed prolonged residence time in the circulation and low RES uptake in tumor-bearing mice, resulting in enhanced extravasation of the liposomes into the solid tumor tissue and reached high level of 10 B content in tumor. After thermal neutron irradiation of mice injected with 10 B-PEG-liposomes or 10 B-TF-PEG-liposome, tumor growth was suppressed relative to controls. These results suggest that intravenous injection of 10 B TF-PEG-liposome can increase the intracellular retention of 10 B atoms, which were introduced by receptor mediated endocytosis after binding, causing tumor growth suppression in vivo upon thermal neutron irradiation. (author)

Gemcitabine-Based Chemotherapy in Adrenocortical Carcinoma: A Multicenter Study of Efficacy and Predictive Factors.

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Henning, Judith E K; Deutschbein, Timo; Altieri, Barbara; Steinhauer, Sonja; Kircher, Stefan; Sbiera, Silviu; Wild, Vanessa; Schlötelburg, Wiebke; Kroiss, Matthias; Perotti, Paola; Rosenwald, Andreas; Berruti, Alfredo; Fassnacht, Martin; Ronchi, Cristina L

2017-11-01

Adrenocortical carcinoma (ACC) is rare and confers an unfavorable prognosis in advanced stages. Other than combination chemotherapy with cisplatin, etoposide, doxorubicin, and mitotane, the second- and third-line regimens are not well-established. Gemcitabine (GEM)-based chemotherapy was suggested in a phase 2 clinical trial with 28 patients. In other solid tumors, human equilibrative nucleoside transporter type 1 (hENT1) and/or ribonucleotide reductase catalytic subunit M1 (RRM1) expression have been associated with resistance to GEM. To assess the efficacy of GEM-based chemotherapy in ACC in a real-world setting and the predictive role of molecular parameters. Retrospective multicenter study. Referral centers of university hospitals. A total of 145 patients with advanced ACC were treated with GEM-based chemotherapy (132 with concomitant capecitabine). Formalin-fixed paraffin-embedded tumor material was available for 70 patients for immunohistochemistry. The main outcome measures were progression-free survival (PFS) and an objective response to GEM-based chemotherapy. The secondary objective was the predictive role of hENT1 and RRM1. The median PFS for the patient population was 12 weeks (range, 1 to 94). A partial response or stable disease was achieved in 4.9% and 25.0% of cases, with a median duration of 26.8 weeks. Treatment was generally well tolerated, with adverse events of grade 3 or 4 occurring in 11.0% of cases. No substantial effect of hENT1 and/or RRM1 expression was observed in response to GEM-based chemotherapy. GEM-based chemotherapy is a well-tolerated, but modestly active, regimen against advanced ACC. No reliable molecular predictive factors could be identified. Owing to the scarce alternative therapeutic options, GEM-based chemotherapy remains an important option for salvage treatment for advanced ACC. Copyright © 2017 Endocrine Society

Spin Tests of 1/20-Scale Models of the Chance Vought Revised XF6U-1 and F6U-1 Airplanes, TED No. NACA 2390

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Klinar, Walter J.; Berman, Theodore

1948-01-01

An investigation has been conducted in the Langley 20-foot free-spinning tunnel on the 1/20-scale model of the Chance Vought XF6U-1 airplane altered to represent the XF6U-1 airplane as it will be spin-tested in flight, and also altered to represent the F6U-1 airplane as it will be produced for service use. Spin tests were made to determine the effects of control settings and movements at the normal loading. The results show that the spins obtained on the revised XF6U-1 airplane will be oscillatory in roll and yaw and that recoveries by rudder reversal will be rapid. Model test results indicate that the F6U-1 airplane will probably not spin. Inasmuch as the results of this investigation show that the new designs are as good as or better than the original XF6U-1 design in regard to spin recovery, it is felt that the conclusions and recommendations reached for the original design can be applied to the new designs for all loading conditions.

Liposome Technology for Industrial Purposes

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Andreas Wagner

2011-01-01

Full Text Available Liposomes, spherical vesicles consisting of one or more phospholipid bilayers, were first described in the mid 60s by Bangham and coworkers. Since then, liposomes have made their way to the market. Today, numerous lab scale but only a few large-scale techniques are available. However, a lot of these methods have serious limitations in terms of entrapment of sensitive molecules due to their exposure to mechanical and/or chemical stress. This paper summarizes exclusively scalable techniques and focuses on strengths, respectively, limitations in respect to industrial applicability. An additional point of view was taken to regulatory requirements concerning liposomal drug formulations based on FDA and EMEA documents.

Filter-extruded liposomes revisited

DEFF Research Database (Denmark)

Hinna, Askell; Steiniger, Frank; Hupfeld, Stefan

2016-01-01

(pore-size, number of filter passages, and flow-rate), flow field-flow fractionation in conjunction with multi-angle laser light scattering (AF4-MALLS, Wyatt Technology Corp., Santa Barbara, CA) was employed. Liposome size-distributions determined by AF4-MALLS were compared with those of dynamic light...... is suggested to prepare large (300 nm) liposomes with rather narrow size distribution, based on the filter extrusion at defined flow-rates in combination with freeze-/ thaw-cycling and bench-top centrifugation....

Entrapment of ovalbumin into liposomes--factors affecting entrapment efficiency, liposome size, and zeta potential.

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Brgles, Marija; Jurasin, Darija; Sikirić, Maja Dutour; Frkanec, Ruza; Tomasić, Jelka

2008-01-01

Various amounts of Ovalbumin (OVA) were encapsulated into positively and negatively charged multilamellar liposomes, with the aim to investigate the entrapment efficiency in different buffers and to study their effects on the liposome size and zeta potential. Results showed that the entrapment efficiency of OVA in anionic liposomes was the same in 10 mM Phosphate Buffer (PB) as in Phosphate-Buffered Saline (PBS; PB + 0.15 M NaCl). Also, liposome size was approximately 1200 nm for all anionic liposomes incorporating OVA. The entrapment efficiency of OVA in cationic liposomes was highly dependent on ionic strength. The size of cationic liposomes was approximately 1200 nm in PBS, regardless of protein content, but increased with the amount of the incorporated protein in PB. Aggregation of cationic liposomes in PB was observed when the mass of the protein was 2.5 mg or greater. The zeta potential of anionic liposomes was negative and of cationic liposomes positive in the whole range of protein mass tested. These results show how different compositions of lipid and aqueous phases can be used to vary the entrapment efficiency, liposome size, and zeta potential--the factors that are of great importance for the use of liposomes as drug carriers.

Dynamic Morphological Changes Induced By GM1 and Protein Interactions on the Surface of Cell-Sized Liposomes

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Masahiro Takagi

2013-06-01

Full Text Available It is important to understand the physicochemical mechanisms that are responsible for the morphological changes in the cell membrane in the presence of various stimuli such as osmotic pressure. Lipid rafts are believed to play a crucial role in various cellular processes. It is well established that Ctb (Cholera toxin B subunit recognizes and binds to GM1 (monosialotetrahexosylganglioside on the cell surface with high specificity and affinity. Taking advantage of Ctb-GM1 interaction, we examined how Ctb and GM1 molecules affect the dynamic movement of liposomes. GM1 a natural ligand for cholera toxin, was incorporated into liposome and the interaction between fluorescent Ctb and the liposome was analyzed. The interaction plays an important role in determining the various surface interaction phenomena. Incorporation of GM1 into membrane leads to an increase of the line tension leading to either rupture of liposome membrane or change in the morphology of the membrane. This change in morphology was found to be GM1 concentration specific. The interaction between Ctb-GM1 leads to fast and easy rupture or to morphological changes of the liposome. The interactions of Ctb and the glycosyl chain are believed to affect the surface and the curvature of the membrane. Thus, the results are highly beneficial in the study of signal transduction processes.

Liposomes containing cationic dimethyl dioctadecyl ammonium bromide: formulation, quality control, and lipofection efficiency.

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Dass, Crispin R; Walker, Todd L; Burton, Mark A

2002-01-01

This article describes a novel, simple, and relatively inexpensive method to prepare cationic liposomes using an ethanol injection/pressure extrusion method. The study also demonstrated that binding erythrosine dye to cationic liposomes results in a shift of the absorption maximum of the dye from 528 nm to 549 nm at pH 4.25, allowing quantification and visualization of these vesicles. In addition, a relatively simple Ficoll-based gradient centrifugation method for separation of lipoplexes from unbound molecules is presented. Laboratory-formulated dimethyl dioctadecyl ammonium bromide (DDAB) containing liposomes were just as efficient in complexing nucleic acids as commercially available types, and binding increased as the positive to neutral lipid ratio was increased. Transfection efficiency of the DDAB-containing liposomes increased as the ratio of cationic to neutral lipid was increased from 1:1 to 4:1 with either PtdChol or DOPE as the neutral lipid. A concomitant increase in cytotoxicity of CSU-SA1 cancer cells was noted as the ratio of positive to neutral lipid of the liposomes was increased. Nevertheless, our present study showed that the 2:1 liposome is a good choice since it delivers functional plasmids at a comparable rate to commercial liposome formulations, has similar toxicities to the less harmful commercial liposomes, and is at least 1000-fold more economical to prepare inhouse, a major factor to be considered in preclinical and clinical studies with these carriers.

Liposome-encapsulated EF24-HPβCD inclusion complex: a preformulation study and biodistribution in a rat model

International Nuclear Information System (INIS)

Agashe, H.; Lagisetty, P.; Sahoo, K.; Bourne, D.; Grady, B.; Awasthi, V.

2011-01-01

3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24) is an anti-proliferative diphenyldifluoroketone analog of curcumin with more potent activity. The authors describe a liposome preparation of EF24 using a “drug-in-CD-in liposome” approach. An aqueous solution of EF24 and hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex (IC) was used to prepare EF24 liposomes. The liposome size was reduced by a combination of multiple freeze–thaw cycles. Co-encapsulation of glutathione inside the liposomes conferred them with the capability of labeling with imageable radionuclide Tc-99m. Phase solubility analysis of EF24-HPβCD mixture provided k 1:1 value of 9.9 M −1 . The enhanced aqueous solubility of EF24 (from 1.64 to 13.8 mg/mL) due to the presence of HPβCD helped in the liposome preparation. About 19% of the EF24 IC was encapsulated inside the liposomes (320.5 ± 2.6 nm) by dehydration–rehydration technique. With extrusion technique, the size of 177 ± 6.5 nm was obtained without any effect on encapsulation efficiency. The EF24-liposomes were evaluated for anti-proliferative activity in lung adenocarcinoma H441 and prostate cancer PC-3 cells. The EF24-liposomes demonstrated anti-proliferative activity superior to that of plain EF24 at 10 μM dose. When injected in rats, the Tc-99m-labeled EF24-liposomes cleared from blood with an α-t 1/2 of 21.4 min and β-t 1/2 of 397 min. Tissue radioactivity counting upon necropsy showed that the majority of clearance was due to the uptake in liver and spleen. The results suggest that using “drug-in-CD-in liposome” approach is a feasible strategy to formulate an effective parenteral preparation of EF24. In vitro studies show that the liposomal EF24 remains anti-proliferative, while presenting an opportunity to image its biodistribution.

Protection of the organism with 2'-deoxycytidine hydrochloride encapsulated in liposomes, in the process of experimental radioprotective chemotherapy with cytosine arabinoside

International Nuclear Information System (INIS)

Bukhman, V.M.; Bekman, E.M.; Koval'skaya, N.I.

1986-01-01

The development of methods of selective protection of the organism from the toxic and immunodepressive effect of cytostatics is directed toward improvement of the results of the therapy of malignant neoplasms. In this work, the authors demonstrate the promise of the use of liposomes as a phagocytizable carrier for the protector substance, on the model of developing T-cell lymphoma EL4 of mice. The production of liposomes and 2'-Deoxycytidine hydrochloride encapsulated in liposomes is discussed

Antimalarial Activity of Orally Administered Curcumin Incorporated in Eudragit®-Containing Liposomes

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Elisabet Martí Coma-Cros

2018-05-01

Full Text Available Curcumin is an antimalarial compound easy to obtain and inexpensive, having shown little toxicity across a diverse population. However, the clinical use of this interesting polyphenol has been hampered by its poor oral absorption, extremely low aqueous solubility and rapid metabolism. In this study, we have used the anionic copolymer Eudragit® S100 to assemble liposomes incorporating curcumin and containing either hyaluronan (Eudragit-hyaluronan liposomes or the water-soluble dextrin Nutriose® FM06 (Eudragit-nutriosomes. Upon oral administration of the rehydrated freeze-dried nanosystems administered at 25/75 mg curcumin·kg−1·day−1, only Eudragit-nutriosomes improved the in vivo antimalarial activity of curcumin in a dose-dependent manner, by enhancing the survival of all Plasmodium yoelii-infected mice up to 11/11 days, as compared to 6/7 days upon administration of an equal dose of the free compound. On the other hand, animals treated with curcumin incorporated in Eudragit-hyaluronan liposomes did not live longer than the controls, a result consistent with the lower stability of this formulation after reconstitution. Polymer-lipid nanovesicles hold promise for their development into systems for the oral delivery of curcumin-based antimalarial therapies.

Efficacy and safety of ifosfamide-based chemotherapy for osteosarcoma: a meta-analysis

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Fan XL

2015-11-01

Full Text Available Xiao-Liang Fan,1,* Guo-Ping Cai,2,* Liu-Long Zhu,1 Guo-Ming Ding1 1Department of Orthopaedics, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, 2Department of Orthopaedics, Jinshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: The efficacy of ifosfamide-based chemotherapy in the treatment of osteosarcoma has been investigated; however, results are inconsistent. Therefore, we reviewed the relevant studies and conducted a meta-analysis to assess the efficacy of ifosfamide-based chemotherapy in patients with osteosarcoma.Methods: A systematic literature search on PubMed, Embase, and Web of Science databases was performed. Eligible studies were clinical trials of patients with osteosarcoma who received ifosfamide-based chemotherapy. Hazard ratios (HRs were pooled to compare event-free survival (EFS and overall survival (OS. Risk ratios (RRs were pooled to compare good histologic response rates and adverse event incidence. Meta-analysis was performed using a fixed-effects model or a random-effects model according to heterogeneity.Results: A total of seven randomized controlled trials were included in this meta-analysis. Pooled results showed that ifosfamide-based chemotherapy significantly improved EFS (HR=0.72, 95% confidence interval [CI]: 0.63, 0.82; P=0.000 and OS (HR=0.83, 95% CI: 0.70, 0.99; P=0.034; furthermore, this form of chemotherapy increased good histologic response rate (RR=1.27, 95% CI: 1.10, 1.46; P=0.001. In addition, patients in the ifosfamide group exhibited a significantly higher incidence of fever (RR=2.23, 95% CI: 1.42, 3.50; P=0.000 and required more frequent platelet transfusion (RR=1.92, 95% CI: 1.23, 3.01; P=0.004.Conclusion: This meta-analysis confirmed that ifosfamide-based chemotherapy can significantly improve EFS and OS; this chemotherapy can also increase good histologic response rate in patients with osteosarcoma

E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy.

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Jennifer L Major

Full Text Available The E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme β-hydroxybutyrate dehydrogenase I (BDH1 is a potential biomarker.To define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM with a focus on BDH1.We previously developed transgenic (Tg mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43 levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70% in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone β-hydroxybutyrate (β-OHB showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to β-OHB.The data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1. We

pH and temperature dual-sensitive liposome gel based on novel cleavable mPEG-Hz-CHEMS polymeric vaginal delivery system

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Chen, Daquan; Sun, Kaoxiang; Mu, Hongjie; Tang, Mingtan; Liang, Rongcai; Wang, Aiping; Zhou, Shasha; Sun, Haijun; Zhao, Feng; Yao, Jianwen; Liu, Wanhui

2012-01-01

Background In this study, a pH and temperature dual-sensitive liposome gel based on a novel cleavable hydrazone-based pH-sensitive methoxy polyethylene glycol 2000-hydrazone-cholesteryl hemisuccinate (mPEG-Hz-CHEMS) polymer was used for vaginal administration. Methods The pH-sensitive, cleavable mPEG-Hz-CHEMS was designed as a modified pH-sensitive liposome that would selectively degrade under locally acidic vaginal conditions. The novel pH-sensitive liposome was engineered to form a thermogel at body temperature and to degrade in an acidic environment. Results A dual-sensitive liposome gel with a high encapsulation efficiency of arctigenin was formed and improved the solubility of arctigenin characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. The dual-sensitive liposome gel with a sol-gel transition at body temperature was degraded in a pH-dependent manner, and was stable for a long period of time at neutral and basic pH, but cleavable under acidic conditions (pH 5.0). Arctigenin encapsulated in a dual-sensitive liposome gel was more stable and less toxic than arctigenin loaded into pH-sensitive liposomes. In vitro drug release results indicated that dual-sensitive liposome gels showed constant release of arctigenin over 3 days, but showed sustained release of arctigenin in buffers at pH 7.4 and pH 9.0. Conclusion This research has shed some light on a pH and temperature dual-sensitive liposome gel using a cleavable mPEG-Hz-CHEMS polymer for vaginal delivery. PMID:22679372

Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides

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Sun J

2017-02-01

Full Text Available Jiawei Sun,1 Lei Jiang,2 Yi Lin,3 Ethan Michael Gerhard,4 Xuehua Jiang,1 Li Li,3 Jian Yang,4 Zhongwei Gu3 1West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 2Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu, 3National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Biomedical Engineering Materials Research Institute, The Huck Institutes of The Life Sciences, The Pennsylvania State University, University Park, PA, USA Abstract: Mitochondria serve as both “energy factories” and “suicide weapon stores” of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Here, multistage tumor-targeting liposomes containing two targeted peptide-modified lipids, cRGD-PEG2000-DSPE and KLA-PEG2000-DSPE, were developed for encapsulation of the anticancer drug paclitaxel (PTX, RGD-KLA/PTX-Lips. Compared with Taxol (free PTX, RGD/PTX-Lips and KLA/PTX-Lips, the half-maximal inhibitory concentration (IC50 value of RGD-KLA/PTX-Lips in vitro was 1.9-, 36.7- and 22.7-fold lower with 4T1 cells, respectively, because of higher levels of cellular uptake. Similar results were also observed with human umbilical vascular endothelial cells (HUVECs. An apoptosis assay showed that the total apoptotic ratio of RGD-KLA/PTX-Lips was the highest because of the mitochondria-targeted drug delivery and the activation of mitochondrial apoptosis pathways, as evidenced by visible mitochondrial localization, decreased mitochondrial membrane potential, release of cytochrome c and increased activities of caspase-9 and caspase-3. The strongest tumor growth inhibition (TGI; 80.6% and antiangiogenesis effects without systemic toxicity were also observed in RGD-KLA/PTX-Lip-treated 4T1 tumor xenograft BALB/c mice. In conclusion, these multistage

Co-encapsulation of chrysophsin-1 and epirubicin in PEGylated liposomes circumvents multidrug resistance in HeLa cells.

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Lo, Yu-Li; Tu, Wei-Chen

2015-12-05

Chrysophsin-1, an amphipathic alpha-helical antimicrobial peptide, is isolated from the gills of the red sea bream and possesses different structure and mechanism(s) in comparison with traditional multidrug resistance (MDR) modulators. For the purpose of reducing off-target normal cell toxicity, it is rational to incorporate chrysophsin-1 and epirubicin in a PEGylated liposomal formulation. In the present study, we report a multifunctional liposomes with epirubicin as an antineoplastic agent and an apoptosis inducer, as well as chrysophsin-1 as a MDR transporter inhibitor and an apoptosis modulator in human cervical cancer HeLa cells. Co-incubation of HeLa cells with PEGylated liposomal formulation of epirubicin and chrysophsin-1 resulted in a significant increase in the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or chrysophsin-1 were shown to considerably improve the intracellular H2O2 and O2(-) levels of HeLa cells. Furthermore, these treatments were found to extensively reduce mRNA expression levels of MDR1, MRP1, and MRP2. The addition of chrysophsin-1 in liposomes was demonstrated to substantially enhance the intracellular accumulation of epirubicin in HeLa cells. Moreover, the PEGylated liposomes of epirubicin and chrysophsin-1 were also found to significantly increase the mRNA expressions of p53, Bax, and Bcl-2. The ratio of Bax to Bcl-2 was noticeably amplified in the presence of these formulations. Apoptosis induction was also validated by chromatin condensation, a reduction in mitochondrial membrane potential, the increased sub-G1 phase of cell cycle, and more populations of apoptosis using annexin V/PI assay. These formulations were verified to increase the activity and mRNA expression levels of caspase-9 and caspases-3. Collectively, our findings provide the first evidence that cotreatment with free or liposomal chrysophsin-1 and epirubicin leads to cell death in human cervical cancer cells through the ROS

Comparison of anthracycline-based combination chemotherapy with or without all-trans retinoic acid in acute promyelocytic leukemia

International Nuclear Information System (INIS)

Raza, S.; Ahmed, P.; Khan, B.

2008-01-01

To compare survival in Acute Promyelocytic Leukemia (APL) patients treated with or without All-Trans Retinoic Acid (ATRA). Longitudinal, comparative study. All consecutive newly diagnosed patients of acute promyelocytic leukemia, treated at Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan, between May 2001 and April 2007, were included and given chemotherapy according to availability of ATRA. Diagnosis was confirmed on morphology/ karyotyping/ molecular analysis. Eligibility criteria included confirmed morphologic diagnosis and/or by demonstration of t(15;17) and/or PML/RAR macro re-arrangement, no prior chemotherapy, normal hepatic and renal function, Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 and no contraindications to ATRA (history of sensitivity to Vit. A or other retinoids). All patients having history of cardiac failure (LVEF 150 macro mol/L and pregnancy were excluded from this study. Survival was calculated from the date of chemotherapy to death or last follow-up according to Kaplan-Meier and Cox (Proportional hazard) regression analysis methods. During the 6 years study period, 31 newly diagnosed patients with acute promyelocytic leukemia received treatment at AFBMTC. Seventeen patients received anthracycline-based remission induction and consolidation chemotherapy, while 14 received ATRA-based remission induction, consolidation and by two years maintenance therapy. Overall Survival (OS), Disease Free Survival (DFS) and mortality were 29.4%, 29.4% and 70.6% respectively in 17 patients who received anthracycline based chemotherapy, whereas in patients who received ATRA-based chemotherapy OS, DFS and mortality was 71.4%, 64.2% and 28.6% respectively. Major causes of mortality were septicemia and chemotherapy related toxicity. Response to ATRA-based chemotherapy in patient cohort was better as compared with anthracycline based chemotherapy (71.4% vs. 29.4%) in terms of survival and mortality. (author)

Estimation of an optimal chemotherapy utilisation rate for cancer: setting an evidence-based benchmark for quality cancer care.

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Jacob, S A; Ng, W L; Do, V

2015-02-01

There is wide variation in the proportion of newly diagnosed cancer patients who receive chemotherapy, indicating the need for a benchmark rate of chemotherapy utilisation. This study describes an evidence-based model that estimates the proportion of new cancer patients in whom chemotherapy is indicated at least once (defined as the optimal chemotherapy utilisation rate). The optimal chemotherapy utilisation rate can act as a benchmark for measuring and improving the quality of care. Models of optimal chemotherapy utilisation were constructed for each cancer site based on indications for chemotherapy identified from evidence-based treatment guidelines. Data on the proportion of patient- and tumour-related attributes for which chemotherapy was indicated were obtained, using population-based data where possible. Treatment indications and epidemiological data were merged to calculate the optimal chemotherapy utilisation rate. Monte Carlo simulations and sensitivity analyses were used to assess the effect of controversial chemotherapy indications and variations in epidemiological data on our model. Chemotherapy is indicated at least once in 49.1% (95% confidence interval 48.8-49.6%) of all new cancer patients in Australia. The optimal chemotherapy utilisation rates for individual tumour sites ranged from a low of 13% in thyroid cancers to a high of 94% in myeloma. The optimal chemotherapy utilisation rate can serve as a benchmark for planning chemotherapy services on a population basis. The model can be used to evaluate service delivery by comparing the benchmark rate with patterns of care data. The overall estimate for other countries can be obtained by substituting the relevant distribution of cancer types. It can also be used to predict future chemotherapy workload and can be easily modified to take into account future changes in cancer incidence, presentation stage or chemotherapy indications. Copyright © 2014 The Royal College of Radiologists. Published by

Evidence-based guideline recommendations on treatment strategies for localized Ewing's sarcoma of bone following neo-adjuvant chemotherapy.

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Werier, Joel; Yao, Xiaomei; Caudrelier, Jean-Michel; di Primio, Gina; Ghert, Michelle; Gupta, Abha A; Kandel, Rita; Verma, Shailendra

2016-06-01

(1) To provide recommendations regarding the choice of surgery, radiation therapy (RT), or the combination of surgery plus RT in patients with localized Ewing's sarcoma of bone following neoadjuvant chemotherapy. (2) To determine the appropriate surgical planning imaging (pre-chemotherapy magnetic resonance imaging [MRI] or post-chemotherapy MRI) to identify optimal resection margins in patients with localized Ewing's sarcoma who undergo surgery following neoadjuvant chemotherapy. MEDLINE, EMBASE, the Cochrane Library (1999 to February 2015), main guideline websites, and relevant annual meeting abstracts (2012 to January 2015) were searched. Internal and external reviews were conducted. 1. Recommendation (1) - In patients with localized Ewing's sarcoma of bone following neoadjuvant chemotherapy: (a) Surgery alone or RT alone are two reasonable treatment options; the combination of surgery plus RT is not recommended as an initial treatment option. (b) The local treatment for an individual patient should be decided by a multidisciplinary tumour board together with the patient after consideration of the following: (1) patient characteristics (e.g., age, tumour location, tumour size, response to neoadjuvant chemotherapy, and existing comorbidities), (2) the potential benefit weighed against the potential complications from surgery and/or toxicities associated with RT, and (3) patient preferences. 2. Recommendation (2) - In patients with localized Ewing's sarcoma who will undergo surgery: (a) Both pre-chemotherapy and post-chemotherapy MRI scans should be taken into consideration for surgical planning. In certain anatomic locations with good chemotherapy response, the post-chemotherapy MRI may be the appropriate imaging modality to plan surgical resection margins. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacogenetic predictors of toxicity to platinum based chemotherapy in non-small cell lung cancer patients.

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Pérez-Ramírez, Cristina; Cañadas-Garre, Marisa; Alnatsha, Ahmed; Villar, Eduardo; Delgado, Juan Ramón; Faus-Dáder, María José; Calleja-Hernández, Miguel Ÿngel

2016-09-01

Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3-4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR Real-Time with Taqman(®) probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3-4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Preparation and ocular pharmacokinetics of ganciclovir liposomes.

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Shen, Yan; Tu, Jiasheng

2007-12-07

Ophthalmic liposomes of ganciclovir (GCV) were prepared by the reverse phase evaporation method, and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV solution. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the solution. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs solution dosing. The aqueous humor concentration-time profiles of both liposomes and solution were well described by 2-compartmental pharmacokinetics with first-order absorption. The area under the curve of the aqueous humor concentration-time profiles of GCV liposomes was found to be 1.7-fold higher than that of GCV solution. Ocular tissue distribution of GCV from liposomes was 2 to 10 times higher in the sclera, cornea, iris, lens, and vitreous humor when compared with those observed after solution dosing. These results suggested that liposomes may hold some promise in ocular GCV delivery.

[A case of breast cancer with multiple hepatic metastasis successfully treated with S-1/PTX and S-1 chemotherapy].

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Hashimoto, Masakazu; Moriyuki, Toshio; Kuranishi, Fumito; Niitsu, Hiroaki; Fujikuni, Nobuaki; Iwako, Hiroshi; Kuroda, Yoshinori

2010-06-01

The case is a woman in her 50's. A total glandectomy was performed for her breast cancer on August 8, 1998, and subsequently chemotherapy(5'-DFUR, CMF, uracil.tegafur, CEF, and docetaxel)as well as radiation therapy and surgical resection have been performed for local recurrence. With multiple hepatic metastasis recognized in September, 2007, chemotherapy combined with S-1/paclitaxel(PTX)has been performed. In view of the side effects such as reduction in appetite and leukocyte, the dosage has been reduced as of the second course of treatment. With the disappearance of hepatic metastasis on CT, 6 courses of S-1monotherapy have been performed after completing 6 courses of chemotherapy combined with S-1/ PTX. As of March, 2009, the therapeutic effect shows that continuous CR and outpatient follow-up have been performed while maintaining QOL. Since any chemotherapy after thirdline treatment for recurrent breast cancer has not been established yet, chemotherapy combined with S-1/PTX is considered to be one of the regimens and therefore, the second and thirdphase clinical tests ahead are expected to bring better outcomes.

Use of Liposomal Bupivacaine for Postoperative Analgesia in an Incisional Pain Model in Rats (Rattus norvegicus).

Science.gov (United States)

Kang, Stacey C; Jampachaisri, Katechan; Seymour, Travis L; Felt, Stephen A; Pacharinsak, Cholawat

2017-01-01

The local anesthetic bupivacaine is valuable for perioperative analgesia, but its use in the postoperative period is limited by its short duration of action. Here, we evaluated the application of a slow-release liposomal formulation of bupivacaine for postoperative analgesia. The aim was to assess whether liposomal bupivacaine effectively attenuates postoperative mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats (n = 36) were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC every 12 h for 2 d; buprenorphine HCl, 0.05 mg/kg SC every 12 h for 2 d (Bup HCl); 0.5% bupivacaine, 2 mg/kg SC local infiltration once (Bupi); liposomal bupivacaine, 1 mg/kg SC local infiltration once (Exp1); and liposomal bupivacaine, 6 mg/kg SC local infiltration once (Exp6). Mechanical and thermal hypersensitivity were evaluated daily on days -1, 0, 1, 2, 3, and 4. The saline group exhibited both hypersensitivities through all 4 evaluated postoperative days. Bup HCl attenuated mechanical hypersensitivity for 2 d and thermal hypersensitivity for 1 d. Bupi attenuated only thermal hypersensitivity for 4 d. Rats in the Exp1 group showed attenuation of both mechanical and thermal hypersensitivity for 4 d, and those in the Exp6 group had attenuation of mechanical hypersensitivity on day 0 and thermal hypersensitivity for 4 d. These data suggest that a single local infiltration of liposomal bupivacaine at a dose of 1 mg/kg SC effectively attenuates postoperative mechanical and thermal hypersensitivity for 4 d in a rat model of incisional pain.

Gd(III)-DOTA-modified sonosensitive liposomes for ultrasound-triggered release and MR imaging

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Jung, Suk Hyun; Na, Kyunga; Lee, Seul A.; Cho, Sun Hang; Seong, Hasoo; Shin, Byung Cheol

2012-08-01

Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl- sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities ( r 1) of GdSL were 6.6 to 7.8 mM-1 s-1, which were higher than that of MR-bester®. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.

Binding of Diphtheria Toxin to Phospholipids in Liposomes

Science.gov (United States)

Alving, Carl R.; Iglewski, Barbara H.; Urban, Katharine A.; Moss, Joel; Richards, Roberta L.; Sadoff, Jerald C.

1980-04-01

Diphtheria toxin bound to the phosphate portion of some, but not all, phospholipids in liposomes. Liposomes consisting of dimyristoyl phosphatidylcholine and cholesterol did not bind toxin. Addition of 20 mol% (compared to dimyristoyl phosphatidylcholine) of dipalmitoyl phosphatidic acid, dicetyl phosphate, phosphatidylinositol phosphate, cardiolipin, or phosphatidylserine in the liposomes resulted in substantial binding of toxin. Inclusion of phosphatidylinositol in dimyristol phosphatidylcholine / cholesterol liposomes did not result in toxin binding. The calcium salt of dipalmitoyl phosphatidic acid was more effective than the sodium salt, and the highest level of binding occurred with liposomes consisting only of dipalmitoyl phosphatidic acid (calcium salt) and cholesterol. Binding of toxin to liposomes was dependent on pH, and the pattern of pH dependence varied with liposomes having different compositions. Incubation of diphtheria toxin with liposomes containing dicetyl phosphate resulted in maximal binding at pH 3.6, whereas binding to liposomes containing phosphatidylinositol phosphate was maximal above pH 7. Toxin did not bind to liposomes containing 20 mol% of a free fatty acid (palmitic acid) or a sulfated lipid (3-sulfogalactosylceramide). Toxin binding to dicetyl phosphate or phosphatidylinositol phosphate was inhibited by UTP, ATP, phosphocholine, or p-nitrophenyl phosphate, but not by uracil. We conclude that (a) diphtheria toxin binds specifically to the phosphate portion of certain phospholipids, (b) binding to phospholipids in liposomes is dependent on pH, but is not due only to electrostatic interaction, and (c) binding may be strongly influenced by the composition of adjacent phospholipids that do not bind toxin. We propose that a minor membrane phospholipid (such as phosphatidylinositol phosphate or phosphatidic acid), or that some other phosphorylated membrane molecule (such as a phosphoprotein) may be important in the initial binding of

Analysis of Perioperative Chemotherapy in Resected Pancreatic Cancer: Identifying the Number and Sequence of Chemotherapy Cycles Needed to Optimize Survival.

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Epelboym, Irene; Zenati, Mazen S; Hamad, Ahmad; Steve, Jennifer; Lee, Kenneth K; Bahary, Nathan; Hogg, Melissa E; Zeh, Herbert J; Zureikat, Amer H

2017-09-01

Receipt of 6 cycles of adjuvant chemotherapy (AC) is standard of care in pancreatic cancer (PC). Neoadjuvant chemotherapy (NAC) is increasingly utilized; however, optimal number of cycles needed alone or in combination with AC remains unknown. We sought to determine the optimal number and sequence of perioperative chemotherapy cycles in PC. Single institutional review of all resected PCs from 2008 to 2015. The impact of cumulative number of chemotherapy cycles received (0, 1-5, and ≥6 cycles) and their sequence (NAC, AC, or NAC + AC) on overall survival was evaluated Cox-proportional hazard modeling, using 6 cycles of AC as reference. A total of 522 patients were analyzed. Based on sample size distribution, four combinations were evaluated: 0 cycles = 12.1%, 1-5 cycles of combined NAC + AC = 29%, 6 cycles of AC = 25%, and ≥6 cycles of combined NAC + AC = 34%, with corresponding survival. 13.1, 18.5, 37, and 36.8 months. On MVA (P cycles AC, receipt of 0 cycles [HR 3.57, confidence interval (CI) 2.47-5.18] or 1-5 cycles in any combination (HR 2.37, CI 1.73-3.23) was associated with increased hazard of death, whereas receipt of ≥6 cycles in any sequence was associated with optimal and comparable survival (HR 1.07, CI 0.78-1.47). Receipt of 6 or more perioperative cycles of chemotherapy either as combined neoadjuvant and adjuvant or adjuvant alone may be associated with optimal and comparable survival in resected PC.

Liposomal curcumin and its application in cancer

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Feng T

2017-08-01

Full Text Available Ting Feng,1,* Yumeng Wei,1,* Robert J Lee,2 Ling Zhao1 1Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA *These authors contributed equally to this work Abstract: Curcumin (CUR is a yellow polyphenolic compound derived from the plant turmeric. It is widely used to treat many types of diseases, including cancers such as those of lung, cervices, prostate, breast, bone and liver. However, its effectiveness has been limited due to poor aqueous solubility, low bioavailability and rapid metabolism and systemic elimination. To solve these problems, researchers have tried to explore novel drug delivery systems such as liposomes, solid dispersion, microemulsion, micelles, nanogels and dendrimers. Among these, liposomes have been the most extensively studied. Liposomal CUR formulation has greater growth inhibitory and pro-apoptotic effects on cancer cells. This review mainly focuses on the preparation of liposomes containing CUR and its use in cancer therapy. Keywords: curcumin, liposomes, drug delivery, bioavailability, cancer 

Isotope Shifts and Hyperfine Structure in the[Xe]4f(7)5d 6s(2) D-2(J)->[Xe]4f(7)5d 6s 6p F-9(J+1) Transitions of Gadolinium

International Nuclear Information System (INIS)

Blaum, K.; Bushaw, Bruce A.; Diel, S; Geppert, Ch; Kuschnick, A; Muller, P.; Nortershauser, W.; Schmitt, A.; Wendt, K.

1999-01-01

High-resolution resonance ionization mass spectrometry has been used to measure isotope shifts and hyperfine structure in all[Xe] 4f 7 5d 6s2 9DJ ---[Xe] 4f 7 5d 6s 6p 9FJ+1 (J= 2-6) and the[Xe] 4f 7 5d 6s2 9D6---[Xe] 4f 7 5d 6s 6p 9D5 transitions of gadolinium (Gd I). Gadolinium atoms in an atomic beam were excited with a tunable single-frequency laser in the wavelength range of 422 - 429 nm. Resonant excitation was followed by photoionization with the 363.8 nm line of an argon ion laser and resulting ions were mass separated and detected with a quadrupole mass spectrometer. Isotope shifts for all stable gadolinium isotopes in these transitions have been measured for the first time. Additionally, the hyperfine structure constants of the upper states have been derived for the isotopes 155, 157Gd and are compared with previous work. Using prior experimental values for the mean nuclear charge radii, derived from the combination of muonic atoms and electron scattering data, field shift a nd specific mass shift coefficients for the investigated transitions have been determined and nuclear charge parameters l for the minor isotopes 152, 154Gd have been calculated

Improved Antitumor Efficacy and Pharmacokinetics of Bufalin via PEGylated Liposomes

Science.gov (United States)

Yuan, Jiani; Zhou, Xuanxuan; Cao, Wei; Bi, Linlin; Zhang, Yifang; Yang, Qian; Wang, Siwang

2017-11-01

Bufalin was reported to show strong pharmacological effects including cardiotonic, antiviral, immune-regulation, and especially antitumor effects. The objective of this study was to determine the characterization, antitumor efficacy, and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity, which were prepared by FDA-approved pharmaceutical excipients. Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high-pressure homogenization method. Their mean particle sizes were 127.6 and 155.0 nm, mean zeta potentials were 2.24 and - 18.5 mV, and entrapment efficiencies were 76.31 and 78.40%, respectively. In vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that in bufalin-loaded liposomes. The cytotoxicity of blank liposomes has been found within acceptable range, whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity. In vivo pharmacokinetics indicated that bufalin-loaded PEGylated liposomes could extend or eliminate the half-life time of bufalin in plasma in rats. The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma.

Efficacy of Ginger in Control of Chemotherapy Induced Nausea and Vomiting in Breast Cancer Patients Receiving Doxorubicin-Based Chemotherapy.

Science.gov (United States)

Ansari, Mansour; Porouhan, Pezhman; Mohammadianpanah, Mohammad; Omidvari, Shapour; Mosalaei, Ahmad; Ahmadloo, Niloofar; Nasrollahi, Hamid; Hamedi, Seyed Hasan

2016-01-01

Nausea and vomiting are among the most serious side effects of chemotherapy, in some cases leading to treatment interruption or chemotherapy dose reduction. Ginger has long been known as an antiemetic drug, used for conditions such as motion sickness, nausea-vomiting in pregnancy, and post-operation side effects. One hundred and fifty female patients with breast cancer entered this prospective study and were randomized to receive ginger (500 mg ginger powder, twice a day for 3 days) or placebo. One hundred and nineteen patients completed the study: 57 of them received ginger and 62 received ginger for the frst 3 chemotherapy cycles. Mean age in all patients was 48.6 (25-79) years. After 1st chemotherapy, mean nausea in the ginger and control arms were 1.36 (±1.31) and 1.46 (±1.28) with no statistically significant difference. After the 2nd chemotherapy session, nausea score was slightly more in the ginger group (1.36 versus 1.32). After 3rd chemotherapy, mean nausea severity in control group was less than ginger group [1.37 (±1.14), versus 1.42 (±1.30)]. Considering all patients, nausea was slightly more severe in ginger arm. In ginger arm mean nausea score was 1.42 (±0.96) and in control arm it was 1.40 (±0.92). Mean vomiting scores after chemotherapy in ginger arm were 0.719 (±1.03), 0.68 (±1.00) and 0.77 (±1.18). In control arm, mean vomiting was 0.983 (±1.23), 1.03 (±1.22) and 1.15 (±1.27). In all sessions, ginger decreased vomiting severity from 1.4 (±1.04) to 0.71 (±0.86). None of the differences were significant. In those patients who received the AC regimen, vomiting was less severe (0.64±0.87) compared to those who received placebo (1.13±1.12), which was statistically significant (p-value <0.05). Further and larger studies are needed to draw conclusions.

Treatment response evaluation with {sup 18}F-FDG PET/CT and {sup 18}F-NaF PET/CT in multiple myeloma patients undergoing high-dose chemotherapy and autologous stem cell transplantation

Energy Technology Data Exchange (ETDEWEB)

Sachpekidis, Christos [German Cancer Research Center (DKFZ), Medical PET Group-Biological Imaging, Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany); University of Bern, Department of Nuclear Medicine, Inselspital, Bern University Hospital, Bern (Switzerland); Hillengass, J.; Wagner, B. [University Hospital Heidelberg, Department of Internal Medicine V, Heidelberg (Germany); Goldschmidt, H. [University Hospital Heidelberg, Department of Internal Medicine V, Heidelberg (Germany); National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg (Germany); Haberkorn, U. [German Cancer Research Center (DKFZ), Medical PET Group-Biological Imaging, Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany); University of Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Kopka, K. [German Cancer Research Center (DKFZ), Department of Radiopharmaceutical Chemistry, Heidelberg (Germany); Dimitrakopoulou-Strauss, A. [German Cancer Research Center (DKFZ), Medical PET Group-Biological Imaging, Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany)

2017-01-15

The aim of this study was to assess the combined use of the radiotracers {sup 18}F-FDG and {sup 18}F-NaF in treatment response evaluation of a group of multiple myeloma (MM) patients undergoing high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) by means of static (whole-body) and dynamic PET/CT (dPET/CT). Thirty-four patients with primary, previously untreated MM scheduled for treatment with HDT followed by ASCT were enrolled in the study. All patients underwent PET/CT scanning with {sup 18}F-FDG and {sup 18}F-NaF before and after therapy. Treatment response by means of PET/CT was assessed according to the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria. The evaluation of dPET/CT studies was based on qualitative evaluation, semi-quantitative (SUV) calculation, and quantitative analysis based on two-tissue compartment modelling and a non-compartmental approach leading to the extraction of fractal dimension (FD). An analysis was possible in 29 patients: three with clinical complete response (CR) and 26 with non-CR (13 patients near complete response-nCR, four patients very good partial response-VGPR, nine patients partial response-PR). After treatment, {sup 18}F-FDG PET/CT was negative in 14/29 patients and positive in 15/29 patients, showing a sensitivity of 57.5 % and a specificity of 100 %. According to the EORTC 1999 criteria, {sup 18}F-FDG PET/CT-based treatment response revealed CR in 14 patients ({sup 18}F-FDG PET/CT CR), PR in 11 patients ({sup 18}F-FDG PET/CT PR) and progressive disease in four patients ({sup 18}F-FDG PET/CT PD). In terms of {sup 18}F-NaF PET/CT, 4/29 patients (13.8 %) had a negative baseline scan, thus failed to depict MM. Regarding the patients for which a direct lesion-to-lesion comparison was feasible, {sup 18}F-NaF PET/CT depicted 56 of the 129 {sup 18}F-FDG positive lesions (43 %). Follow-up {sup 18}F-NaF PET/CT showed persistence of 81.5 % of the baseline {sup 18}F-NaF

Can GSTM1 and GSTT1 polymorphisms predict clinical outcomes of chemotherapy in gastric and colorectal cancers? A result based on the previous reports

Directory of Open Access Journals (Sweden)

Liu H

2016-06-01

Full Text Available Haixia Liu,1,* Wei Shi,2,* Lianli Zhao,3 Dianlu Dai,4 Jinghua Gao,5 Xiangjun Kong6 1Department of Ultrasound, 2Office of Medical Statistics, 3Human Resource Department, 4Department of Surgical Oncology, 5Department of Medical Oncology, 6Central Laboratory, Cangzhou Central Hospital, Yunhe District, Cangzhou, People’s Republic of China *These authors contributed equally to this study and should be considered cofirst authors Background: Gastric and colorectal cancers remain the major causes of cancer-related death. Although chemotherapy improves the prognosis of the patients with gastrointestinal cancers, some patients do not benefit from therapy and are exposed to the adverse effects. The polymorphisms in genes including GSTM1 and GSTT1 have been explored to predict therapeutic efficacy; however, the results were inconsistent and inconclusive. Materials and methods: A systematic review and meta-analysis was performed by searching relevant studies about the association between the GSTM1 and GSTT1 polymorphisms and chemotherapy efficacy in gastrointestinal cancers in databases such as PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure, and Wanfang database up to January 10, 2016. Subgroup analyses were also performed according to ethnicity, cancer type, evaluation criteria, study type, chemotherapy type, and age. Results: A total of 19 articles containing 3,217 cases were finally included. Overall analysis suggested that no significance was found between overall toxicity, neurotoxicity, neutropenia, gastrointestinal toxicity, tumor response, and progression-free survival, and the polymorphisms in GSTM1 and GSTT1, while GSTM1 polymorphism associated with overall survival (OS; hazard ratio =1.213, 95% confidence interval =1.060–1.388, P=0.005. Subgroup analyses suggested that neurotoxicity was associated with GSTM1 polymorphism in the Asian population, neutropenia was associated with GSTM1 polymorphism in palliative

Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye

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Natarajan JV

2012-01-01

Full Text Available Jayaganesh V Natarajan1*, Marcus Ang2*, Anastasia Darwitan1, Sujay Chattopadhyay3, Tina T Wong2, Subbu S Venkatraman1 1Materials Science and Engineering, Nanyang Technological University, Singapore; 2Singapore Eye Research Institute, Singapore; 3Polymer Division, Indian Institute of Technology Roorkee, India*These authors contributed equally to this workPurpose: To report the development and therapeutic evaluation of a liposomal nanocarrier for sustained release of latanoprost, in the rabbit eye.Methods: We fabricated latanoprost-loaded egg-phosphatidylcholine (EggPC liposomes using the film hydration technique. The delivery vehicles were nano-sized (Z avg = 109 ± 18 nm, had a narrow poly dispersity index (PDI = 0.19 ± 0.04, and a very high loading efficiency (94% ± 5%. Based on in vitro data, we evaluated this formulation for lowering intraocular pressure (IOP in rabbit eyes. Following a single subconjunctival injection of the latanoprost loaded formulation, the eyes were clinically monitored and the IOP recorded.Results: Latanoprost-loaded EggPC liposomes demonstrated a high drug/lipid mole ratio of 0.181, remained stable for at least 6 months on storage (4°C, and at least 1 month at 25°C. A slow and sustained release of 60% of latanoprost was achieved by 14 days in the in vitro release study. The same formulation demonstrated a greater sustained IOP lowering effect compared with daily administration of topical latanoprost beyond 90 days (4.8 ± 1.5 vs 2.5 ± 0.9 mmHg; P < 0.001. No signs of inflammation were evident in the eyes from slit-lamp examination analysis.Conclusion: The loading required for a long-term sustained delivery of latanoprost for up to 90 days in the rabbit eyes was achieved with EggPC liposomes. A single injection of latanoprost-loaded EggPC liposomes can lower the IOP for up to 90 days, with a greater IOP lowering effect than daily topical administration of latanoprost.Keywords: nanomedicine, nanoliposomes, Egg

Photochemical removal of NpF6 and PuF6 from UF6 gas streams

International Nuclear Information System (INIS)

Beitz, J.V.; Williams, C.W.

1990-01-01

A novel photochemical method of removing reactive fluorides from UF 6 gas has been discovered. This method reduces generated waste to little more than the volume of the removed impurities, minimizes loss of UF 6 , and can produce a recyclable by-product, fluorine gas. In our new method, impure UF 6 , is exposed to ultraviolet light which dissociates the UF 6 to UF 5 and fluorine atom. Impurities which chemically react with UF 5 are reduced and form solid compounds easily removed from the gas while UF 5 is converted back to UF 6 . Proof-of-concept testing involved UF 6 containing NpF 6 and PuF 6 with CO added as a fluorine atom scavenger. In a single photolysis step, greater than 5000-fold reduction of PuF 6 was demonstrated while reducing NpF 6 by more than 40-fold. This process is likely to remove corrosion and fission product fluorides that are more reactive than UF 6 and has been demonstrated without an added fluorine atom scavenger by periodically removing photogenerated fluorine gas. 44 refs., 3 figs., 2 tabs

HYPERDIRE. HYPERgeometric functions DIfferential REduction. MATHEMATICA based packages for differential reduction of generalized hypergeometric functions {sub p}F{sub p-1}, F{sub 1}, F{sub 2}, F{sub 3}, F{sub 4}

Energy Technology Data Exchange (ETDEWEB)

Bytev, Vladimir V.; Kalmykov, Mikhail Yu. [Hamburg Univ. (Germany). 2. Inst. fuer Theoretische Physik; Joint Institute for Nuclear Research, Dubna (Russian Federation); Kniehl, Bernd A. [Hamburg Univ. (Germany). 2. Inst. fuer Theoretische Physik

2013-05-15

HYPERDIRE is a project devoted to the creation of a set of Mathematica based programs for the differential reduction of hypergeometric functions. The current version includes two parts: one, pfq, is relevant for manipulations of hypergeometric functions {sub p+1}F{sub p}, and the second one, AppellF1F4, for manipulations with Appell hypergeometric functions F{sub 1}, F{sub 2}, F{sub 3}, F{sub 4} of two variables.

Safety and feasibility of fasting in combination with platinum-based chemotherapy.

Science.gov (United States)

Dorff, Tanya B; Groshen, Susan; Garcia, Agustin; Shah, Manali; Tsao-Wei, Denice; Pham, Huyen; Cheng, Chia-Wei; Brandhorst, Sebastian; Cohen, Pinchas; Wei, Min; Longo, Valter; Quinn, David I

2016-06-10

Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients. 3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state. The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period. Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An onging randomized trial is studying the effect of 72 h of fasting. NCT00936364 , registered propectively on July 9, 2009.

Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel

Science.gov (United States)

Berliere, Martine; Dalenc, Florence; Malingret, Nathalie; Vindevogel, Anita; Piette, Philippe; Roche, Henry; Donnez, Jacques; Symann, Michel; Kerger, Joseph; Machiels, Jean-Pascal

2008-01-01

Background To determine the incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel. Methods We studied the incidence and duration of amenorrhea induced by two chemotherapy regimens: (i) 6 cycles of 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks (6FEC) and (ii) 3 cycles of FEC 100 followed by 3 cycles of docetaxel 100 mg/m2 on day 1 every 3 weeks (3FEC/3D). Reversible amenorrhea was defined as recovery of regular menses and, where available (101 patients), premenopausal hormone values (luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol) in the year following the end of chemotherapy. Results One hundred and fifty-four premenopausal patients were included: 84 treated with 6FEC and 70 with 3FEC/3D. The median age was 43.5 years (range: 28–58) in the 6FEC arm and 44 years (range: 29–53) in the 3FEC/3D arm. Seventy-eight percent of patients were treated in the context of the PACS 01 trial. The incidence of chemotherapy-induced amenorrhea at the end of chemotherapy was similar in the two groups: 93 % in the 6FEC arm and 92.8 % in the 3FEC/3D arm. However, in the year following the end of chemotherapy, more patients recovered menses in the 3FEC/3D arm than in the 6FEC arm: 35.5 % versus 23.7 % (p = 0.019). Among the 101 patients for whom hormone values were available, 43 % in the 3FEC/3D arm and 29 % in the 6FEC arm showed premenopausal levels one year after the end of chemotherapy (p amenorrhea than 6FEC. The clinical relevance of these findings needs to be investigated further. PMID:18291033

Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel

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Donnez Jacques

2008-02-01

Full Text Available Abstract Background To determine the incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel. Methods We studied the incidence and duration of amenorrhea induced by two chemotherapy regimens: (i 6 cycles of 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks (6FEC and (ii 3 cycles of FEC 100 followed by 3 cycles of docetaxel 100 mg/m2 on day 1 every 3 weeks (3FEC/3D. Reversible amenorrhea was defined as recovery of regular menses and, where available (101 patients, premenopausal hormone values (luteinizing hormone (LH, follicle-stimulating hormone (FSH and estradiol in the year following the end of chemotherapy. Results One hundred and fifty-four premenopausal patients were included: 84 treated with 6FEC and 70 with 3FEC/3D. The median age was 43.5 years (range: 28–58 in the 6FEC arm and 44 years (range: 29–53 in the 3FEC/3D arm. Seventy-eight percent of patients were treated in the context of the PACS 01 trial. The incidence of chemotherapy-induced amenorrhea at the end of chemotherapy was similar in the two groups: 93 % in the 6FEC arm and 92.8 % in the 3FEC/3D arm. However, in the year following the end of chemotherapy, more patients recovered menses in the 3FEC/3D arm than in the 6FEC arm: 35.5 % versus 23.7 % (p = 0.019. Among the 101 patients for whom hormone values were available, 43 % in the 3FEC/3D arm and 29 % in the 6FEC arm showed premenopausal levels one year after the end of chemotherapy (p Conclusion Our study suggests that 3FEC/3D treatment induces more reversible amenorrhea than 6FEC. The clinical relevance of these findings needs to be investigated further.

Neurologic complications of intrathecal liposomal cytarabine administered prophylactically to patients with non-Hodgkin lymphoma.

Science.gov (United States)

Gállego Pérez-Larraya, Jaime; Palma, José Alberto; Carmona-Iragui, María; Fernández-Torrón, Roberto; Irimia, Pablo; Rodríguez-Otero, Paula; Panizo, Carlos; Martínez-Vila, Eduardo

2011-07-01

Central nervous system (CNS) prophylaxis is required during initial treatment of non-Hodgkin lymphoma (NHL) subtypes that carry a high risk of CNS involvement. Intrathecal (IT) liposomal cytarabine, a formulation with prolonged half-life, has been shown to be safe and effective in the treatment of meningeal disease in patients with high-grade lymphoma. We retrospectively reviewed all adult patients with high-grade NHL that received prophylactic therapy with IT liposomal cytarabine and developed neurologic complications in our institution between April 2007 and May 2009. We recorded information on hospital admission, chemotherapy regimens, clinical features, neuroimaging, cerebrospinal fluid, neurophysiology data, and outcome. Neurotoxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Four of fourteen patients (28%) developed moderate or severe neurotoxicity (grades 2 and 3 of the NCI-CTC), manifested as conus medullaris/cauda equine syndrome or pseudotumour cerebri-like syndrome, after a median of 3.5 IT courses of liposomal cytarabine. All patients had received corticosteroids to prevent arachnoiditis. Liposomal cytarabine given via the IT route, even with concomitant corticosteroid administration, can result in significant neurotoxicity in some patients. We discuss the potential pathogenesis of these effects and suggest hypothetical therapeutic measures to prevent these complications. Specialists should be aware of these possible complications when administering prophylactic IT liposomal cytarabine in high-grade NHL patients, and additional prospective studies should be conducted to more clearly delineate the frequency and characteristics of these complications.

Photophysical studies of zinc phthalocyanine and chloroaluminum phthalocyanine incorporated into liposomes in the presence of additives

Directory of Open Access Journals (Sweden)

S.M.T. Nunes

2004-02-01

Full Text Available The photophysical properties of zinc phthalocyanine (ZnPC and chloroaluminum phthalocyanine (AlPHCl incorporated into liposomes of dimyristoyl phosphatidylcholine in the presence and absence of additives such as cholesterol or cardiolipin were studied by time-resolved fluorescence, laser flash photolysis and steady-state techniques. The absorbance of the drugs changed linearly with drug concentration, at least up to 5.0 µM in homogeneous and heterogeneous media, indicating that aggregation did not occur in these media within this concentration range. The incorporation of the drugs into liposomes increases the dimerization constant by one order of magnitude (for ZnPC, 3.6 x 10(4 to 1.0 x 10(5 M-1 and for AlPHCl, 3.7 x 10(4 to 1.5 x 10(5 M-1, but this feature dose does not rule out the use of this carrier, since the incorporation of these hydrophobic drugs into liposomes permits their systemic administration. Probe location in biological membranes and predominant positions of the phthalocyanines in liposomes were inferred on the basis of their fluorescence and triplet state properties. Both phthalocyanines are preferentially distributed in the internal regions of the liposome bilayer. The additives affect the distribution of these drugs within the liposomes, a fact that controls their delivery when both are used in a biological medium, retarding their release. The addition of the additives to the liposomes increases the internalization of phthalocyanines. The interaction of the drugs with a plasma protein, bovine serum albumin, was examined quantitatively by the fluorescence technique. The results show that when the drugs were incorporated into small unilamellar liposomes, the association with albumin was enhanced when compared with organic media, a fact that should increase the selectivity of tumor targeting by these phthalocyanines (for ZnPC, 0.71 x 10(6 to 1.30 x 10(7 M-1 and for AlPHCl, 4.86 x 10(7 to 3.10 x 10(8 M-1.

Hyperthermal K--TeF6 molecular beam scattering

International Nuclear Information System (INIS)

Wagner, A.F.; Young, C.E.; Pobo, L.G.; Wexler, S.

1982-01-01

Angular distributions of K + product ions from collisions of a beam of hyperthermal K atoms with a cross beam of thermal TeF 6 molecules were determined at 13.7 and 23.7 eV (lab). The angular yields of K atom products from the same system were too low to permit measurement of angular distributions. From the integrated yields, the K + ion/K atom branching ratio was determined to be greater than 10 3 . In addition to the extremely large branching ratio, the differential cross sections exhibited several other unusual characteristics: (a) the lack of small angle scattering, corresponding to virtual absence of covalent scattering, (b) two peaks in the differential cross section with an outer rainbow feature at very large scattering angles (approx.275 eV deg). The observations are unexpected from previous experimental and theoretical studies of electron transfer reactions and from the electronic and structural properties of TeF 6 and TeF - 6 . A simplified dynamics model based on formation of electronically excited TeF - 6 in the initial electron transfer, followed by inner crossings leading to formation of electronically and vibrationally unexcited TeF - 6 or dissociation to TeF - 5 and other ionic products, has been developed which accounts for the experimental results. The model suggests that the observed two peaks in the differential cross section are due to the production of TeF - 6 (inner peak) or TeF - 5 and other ionic dissociation products (outer peak). The model also suggests that the observed branching ratio requires a vertical electron affinity of < or =1.9 eV, much lower than its adiabatic electron affinity of 3.3 eV

S-phase induction by interleukin-6 followed by chemotherapy in patients with refractory multiple myeloma

DEFF Research Database (Denmark)

de Nully Brown, P; Jensen, P O; Diamant, M

1998-01-01

.0 microg/kg (n = 6) by subcutaneous injection once daily for 5 days and chemotherapy was administered on the last day of rhIL-6 injection. The effect of rhIL-6 treatment on labeling index (LI) was heterogeneous, but no statistically significant change was noted for this particular group as a whole. In two......The plasma cell labeling index (PCLI) in patients with multiple myeloma (MM) is relatively low and this has been associated with the low rate of remission following chemotherapy. Interleukin-6 (IL-6) has been demonstrated to be a major growth factor of myeloma cells. In order to increase the S......-phase proportion of myeloma cells, which might increase the sensitivity to chemotherapy, we gave rhIL-6 followed by chemotherapy to 15 myeloma patients with refractory disease. A total of 25 treatment cycles were administered since ten patients had two cycles. The rhIL-6 dose was 2.5 (n = 3), 5.0 (n = 6) and 10...

Two cycles of cisplatin-based chemotherapy for low-volume stage II seminoma: results of a retrospective, single-center case series.

Science.gov (United States)

Pichler, Renate; Leonhartsberger, Nicolai; Stöhr, Brigitte; Horninger, Wolfgang; Steiner, Hannes

2012-01-01

To report on the oncological outcome and toxicity of patients treated with 2 cycles of cisplatin-based chemotherapy for low-volume metastatic stage II seminoma. We retrospectively identified a case series of 15 patients with seminoma stage IIA (26.7%) and IIB (73.3%) who underwent chemotherapy consisting of 2 cycles of cisplatin, etoposide and bleomycin (PEB) (cisplatin 20 mg/m(2) on days 1-5, etoposide 100 mg/m(2) on days 1-5, bleomycin 30 mg on days 1, 8 and 15) according to patient preference (refusing a 3rd cycle of PEB) or institutional practice in the last decades. Complete staging before chemotherapy was available in all patients. Patient age, the side and diameter of the primary tumor, the size of the lymph nodes before and after chemotherapy, acute and late toxicity of chemotherapy, the incidence of second malignancies, the relapse-free rate and cancer-specific mortality were recorded. Chemotherapy was well tolerated and no episode of febrile neutropenia occurred. Thrombocytopenia grade 4 was not seen in any patient, while leukopenia grade 4 was observed in 4 (26.6%) patients. The mean (range) lymph node size decreased significantly from 2.54 cm (1.1-4.0) before chemotherapy to 0.75 cm (0.4-2.2) after chemotherapy (p < 0.001). After a median (range) follow-up of 60 (13-185) months, no patient had relapsed, no patient had died as a result of seminoma and second malignancy was seen in only 1 (6.6%) patient. These excellent long-term results from a retrospective case series of 2 cycles of PEB in stage IIA/IIB seminoma patients represent a hint for further research with a view to reducing treatment burden. However, these incidental findings should be studied in prospective trials prior to drawing any conclusions. Copyright © 2013 S. Karger AG, Basel.

Polydiacetylene-Based Liposomes: An "Optical Tongue" for Bacteria Detection and Identification

Science.gov (United States)

West, Matthew R.; Hanks, Timothy W.; Watson, Rhett T.

2009-01-01

Food- and water-borne bacteria are a major health concern worldwide. Current detection methods are time-consuming and require sophisticated equipment that is not always readily available. However, new techniques based on nanotechnology are under development that will result in a new generation of sensors. In this experiment, liposomes are…

The role of cavitation in liposome formation.

Science.gov (United States)

Richardson, Eric S; Pitt, William G; Woodbury, Dixon J

2007-12-15

Liposome size is a vital parameter of many quantitative biophysical studies. Sonication, or exposure to ultrasound, is used widely to manufacture artificial liposomes, yet little is known about the mechanism by which liposomes are affected by ultrasound. Cavitation, or the oscillation of small gas bubbles in a pressure-varying field, has been shown to be responsible for many biophysical effects of ultrasound on cells. In this study, we correlate the presence and type of cavitation with a decrease in liposome size. Aqueous lipid suspensions surrounding a hydrophone were exposed to various intensities of ultrasound and hydrostatic pressures before measuring their size distribution with dynamic light scattering. As expected, increasing ultrasound intensity at atmospheric pressure decreased the average liposome diameter. The presence of collapse cavitation was manifested in the acoustic spectrum at high ultrasonic intensities. Increasing hydrostatic pressure was shown to inhibit the presence of collapse cavitation. Collapse cavitation, however, did not correlate with decreases in liposome size, as changes in size still occurred when collapse cavitation was inhibited either by lowering ultrasound intensity or by increasing static pressure. We propose a mechanism whereby stable cavitation, another type of cavitation present in sound fields, causes fluid shearing of liposomes and reduction of liposome size. A mathematical model was developed based on the Rayleigh-Plesset equation of bubble dynamics and principles of acoustic microstreaming to estimate the shear field magnitude around an oscillating bubble. This model predicts the ultrasound intensities and pressures needed to create shear fields sufficient to cause liposome size change, and correlates well with our experimental data.

The Results of Radiation Therapy Alone vs Radiation Plus Chemotherapy of Uterine Cervix Cancer

International Nuclear Information System (INIS)

Lee, Myung Za; Choi, Suk Young; Chun, Ha Jeong

1995-01-01

Purpose : Radiation therapy(RT) is conventionally standard treatment for locally advanced stage for uterine cervix cancer. Recently to improve treatment results, combined chemotherapy and radiation therapy was tried. We retrospectively analysed our experience of 122 patients. Comparison of the results in 45 patients treated with RT alone and 77 patients treated with RT plus chemotherapy was made. Materials and Methods : from January 1985 to December 1991, 122 patients with cervix cancer were treated with whole pelvic external RT and ICR(34 1 ICR, 77 2 ICR, 11 high dose rate ICR) in our department. Forty five patients were treated with RT alone, and 77 patients were treated with combined plus chemotherapy. Mean age was 58 years(range:29-81). Histologic types were 111 squamous cell carcinoma, large cell carcinoma, 3 adenocarcinoma, and 2 adenosquamous cell carcinoma. According to the FIGO stage 6 had stage IA94.9%, 11 had IIA(9.0%), 37 had IIB(30.3%), 3 had IIA(2.5%), 63 had IIB(51.6%), and 2 had stage IV(1.6%). In 77 patients with RT plus chemotherapy, 36 patients were treated with VBP(vinblastin, bleoycin, cisplainum), 39 patients with cisplatinum plus 5-FU and 2 patients with 5-FU. Results : Complete response after external RT(3960cGy-5500cGy)was achieved in 61 patients(50%). He actuarial 5 year and 9 year survival rate was 57.8% and 53.9%, respectively. Five year actuarial survival rate was 63.1% with RT alone(n=45) and 55.9% with RT plus chemotherapy(n=77). Their 5 year survival rate was 35.5% for 1 course of ICR and 67% for 2 courses of ICR. There was statistically significant advantage of survival with RT alone group who were treated with 2 coursed of ICR and dose to the A point≥8000cGy(4/25 died). In RT plus chemotherapy group, dose response was not seen and there was no difference in 5 year survival between 1 course and 2 course of ICR(50% vs 56.8%), and dose to point A less than 8000cGy and more than 8000 cGy(55.6% vs 55.7%). There was no significant

Systemic study of solvent-assisted active loading of gambogic acid into liposomes and its formulation optimization for improved delivery.

Science.gov (United States)

Tang, Wei-Lun; Tang, Wei-Hsin; Szeitz, Andras; Kulkarni, Jayesh; Cullis, Pieter; Li, Shyh-Dar

2018-06-01

The solvent-assisted active loading technology (SALT) was developed for encapsulating a water insoluble weak base into the liposomal core in the presence of 5% DMSO. In this study, we further examined the effect of various water miscible solvents in promoting active loading of other types of drugs into liposomes. To achieve complete drug loading, the amount of solvent required must result in complete drug solubilization and membrane permeability enhancement, but must be below the threshold that induces liposomal aggregation or causes bilayer disruption. We then used the SALT to load gambogic acid (GA, an insoluble model drug that shows promising anticancer effect) into liposomes, and optimized the loading gradient and lipid composition to prepare a stable formulation (Lipo-GA) that displayed >95% drug retention after incubation with serum for 3 days. Lipo-GA contained a high drug-to-lipid ratio of 1/5 (w/w) with a mean particle size of ∼75 nm. It also displayed a prolonged circulation half-life (1.5 h vs. 18.6 h) and enhanced antitumor activity in two syngeneic mice models compared to free GA. Particularly, complete tumor regression was observed in the EMT6 tumor model for 14 d with significant inhibition of multiple oncogenes including HIF-1α, VEGF-A, STAT3, BCL-2, and NF-κB. Copyright © 2018 Elsevier Ltd. All rights reserved.

Designing of 14C, 3H-labeled liposomal preparations and their distribution in inner organs of experimental animals

International Nuclear Information System (INIS)

Isaev, E.I.; Kamalova, M.E.; Isakova, A.V.; Mirakhmedov, F.K.; Saatov, T.S.

2004-01-01

Full text: Development of methods for introduction of drug liposomal forms into practice is an urgent task for medicine and radiobiology. Per oral way of administration of the medications has been unexplored properly yet. Preservation of their stability in the gastro-intestinal tract is the essential requirement to the liposomes. Literature data and our studies showed that the elevated saturation of fatty acids and viscosity of liposomal membrane bilayer increases their stability to acidic and alkaline media of the digestive system. To prepare the liposome we used 14C,H-labeled lipids isolated from tissues by means of preparative chromatography after administration of D(1-614C)glucose (specific radioactivity 100 mkCu/mM) as well as of D(1-3H)-galactose (specific radioactivity 900 mkCU/mM) to 10 rats. Organ-specific liposomes were prepared in accordance with the special method without ultrasound processing to administered them with milk per orally to rats by means of a gastric probe. Before administration of 14C,3H liposomes the animals were not fed for 16-20 hours for complete emptying of the gastrointestinal tract. Under these conditions 1-1.5 hours after administration of liposomes their maximum amount was absorbed from he intestine. We found tissue specificity of the liposome administered. If the amount of administered liposomes for each tissue to be taken for 100%, in target organs their distribution (in %) would be as follows: 0.30/0.39 in the heart, 0.54/0.06 in the skeletal muscle, 0.4/0.6 in the brain, 4.2/10.2 in the spleen, 2.9/6.1 in the pancreas, 5.1/1.2 in the kidney. In these experiments liposomes had covering of 14 C, 3 H-glycosphingolipids of the spleen. Under these conditions 3H-cAMP in the form of liposomes was administered to mice per orally to measure radioactivity (in cpm 100mg of tissue) in the organs. The values were as follows: 77±6.3 in the liver, 750±47 in the spleen, 250±19 in the kidney, 70±77 in the heart, 267±21 in the lung and 95

The predictive value of 53BP1 and BRCA1 mRNA expression in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy

Science.gov (United States)

Bonanno, Laura; Costa, Carlota; Majem, Margarita; Sanchez, Jose Javier; Gimenez-Capitan, Ana; Rodriguez, Ignacio; Vergenegre, Alain; Massuti, Bartomeu; Favaretto, Adolfo; Rugge, Massimo; Pallares, Cinta; Taron, Miquel; Rosell, Rafael

2013-01-01

Platinum-based chemotherapy is the standard first-line treatment for non-oncogene-addicted non-small cell lung cancers (NSCLCs) and the analysis of multiple DNA repair genes could improve current models for predicting chemosensitivity. We investigated the potential predictive role of components of the 53BP1 pathway in conjunction with BRCA1. The mRNA expression of BRCA1, MDC1, CASPASE3, UBC13, RNF8, 53BP1, PIAS4, UBC9 and MMSET was analyzed by real-time PCR in 115 advanced NSCLC patients treated with first-line platinum-based chemotherapy. Patients expressing low levels of both BRCA1 and 53BP1 obtained a median progression-free survival of 10.3 months and overall survival of 19.3 months, while among those with low BRCA1 and high 53BP1 progression-free survival was 5.9 months (P <0.0001) and overall survival was 8.2 months (P=0.001). The expression of 53BP1 refines BRCA1-based predictive modeling to identify patients most likely to benefit from platinum-based chemotherapy. PMID:24197907

Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment.

Science.gov (United States)

van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Haselberg, Rob; van der Veeken, Joris; Roovers, Rob C; van Bergen en Henegouwen, Paul M P; Storm, Gert; Hennink, Wim E; Schiffelers, Raymond M; Kok, Robbert J

2012-04-30

The epidermal growth factor receptor (EGFR) is a validated target for anti-cancer therapy and several EGFR inhibitors are used in the clinic. Over the years, an increasing number of studies have reported on the crosstalk between EGFR and other receptors that can contribute to accelerated cancer development or even acquisition of resistance to anti-EGFR therapies. Combined targeting of EGFR and insulin-like growth factor 1 receptor (IGF-1R) is a rational strategy to potentiate anti-cancer treatment and possibly retard resistance development. In the present study, we have pursued this by encapsulating the kinase inhibitor AG538 in anti-EGFR nanobody-liposomes. The thus developed dual-active nanobody-liposomes associated with EGFR-(over)expressing cells in an EGFR-specific manner and blocked both EGFR and IGF-1R activation, due to the presence of the EGFR-blocking nanobody EGa1 and the anti-IGF-1R kinase inhibitor AG538 respectively. AG538-loaded nanobody-liposomes induced a strong inhibition of tumor cell proliferation even upon short-term exposure followed by a drug-free wash-out period. Therefore, AG538-loaded nanobody-liposomes are a promising anti-cancer formulation due to efficient intracellular delivery of AG538 in combination with antagonistic and downregulating properties of the EGa1 nanobody-liposomes. Copyright © 2011 Elsevier B.V. All rights reserved.

Liposome-Based Adjuvants for Subunit Vaccines: Formulation Strategies for Subunit Antigens and Immunostimulators

DEFF Research Database (Denmark)

Schmidt, Signe Tandrup; Foged, Camilla; Korsholm, Karen Smith

2016-01-01

be classified into delivery systems or immunostimulators. Liposomes are versatile delivery systems for antigens, and they can carefully be customized towards desired immune profiles by combining them with immunostimulators and optimizing their composition, physicochemical properties and antigen-loading mode......The development of subunit vaccines has become very attractive in recent years due to their superior safety profiles as compared to traditional vaccines based on live attenuated or whole inactivated pathogens, and there is an unmet medical need for improved vaccines and vaccines against pathogens...... of immunostimulators and antigens, respectively, into liposomes, and the choice of immunostimulator should ideally be based on knowledge regarding the specific PRR expression profile of the target APCs. Here, we review state-of-the-art formulation approaches employed for the inclusion of immunostimulators and subunit...

Platinum-based chemotherapy with or without thoracic radiation therapy in patients with unresectable thymic carcinoma

International Nuclear Information System (INIS)

Nakamura, Yoichi; Kunitoh, Hideo; Kubota, Kaoru

2000-01-01

Thymic carcinoma is a rare mediastinal neoplasm with poor prognosis. Although the clinical benefit of chemotherapy for thymic carcinoma is controversial, cisplatin-based chemotherapy with or without radiation therapy is ordinarily adopted in advanced cases. We evaluated the clinical outcome of platinum-based chemotherapy with or without radiation therapy in unresectable thymic carcinoma patients. Ten patients with unresectable thymic carcinoma were treated with platinum-based chemotherapy with or without radiation therapy in the National Cancer Center Hospital between 1989 and 1998. We reviewed the histological type, treatment, response and survival of these patients. Four of the 10 patients responded to chemotherapy and both the median progression-free survival period and the median response duration were 6.0 months. The median survival time was 11.0 months. There was no relationship between histological classification and prognosis. Platinum-based chemotherapy with or without thoracic radiation is, regardless of tumor histology, marginally effective in advanced thymic carcinoma patients, giving only a modest tumor response rate and short response duration and survival. (author)

A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus).

Science.gov (United States)

Weiss, Glen J; Waypa, Jordan; Blaydorn, Lisa; Coats, Jessica; McGahey, Kayla; Sangal, Ashish; Niu, Jiaxin; Lynch, Cynthia A; Farley, John H; Khemka, Vivek

2017-06-27

Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy. Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted. Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types. Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.

Construction of a Liposome Dialyzer for preparation of high-value, small-volume liposome formulations

OpenAIRE

Adamala, Katarzyna; Engelhart, Aaron E.; Kamat, Neha P.; Jin, Lin; Szostak, Jack W.

2015-01-01

The liposome dialyzer is a small-volume equilibrium dialysis device, built from commercially available materials, that is designed for rapid exchange of small volumes of an extraliposomal reagent pool against a liposome preparation. The dialyzer is prepared by modification of commercially available dialysis cartridges and consists of a reactor with two 300 µL chambers and a 1.56 cm2 dialysis surface area. The dialyzer is prepared in three stages: 1) disassembly of dialysis cartridges to obtai...

Effect of chitosan coating on the characteristics of DPPC liposomes

Directory of Open Access Journals (Sweden)

Mohsen M. Mady

2010-07-01

Full Text Available Because it is both biocompatible and biodegradable, chitosan has been used to provide a protective capsule in new drug formulations. The present work reports on investigations into some of the physicochemical properties of chitosan-coated liposomes, including drug release rate, transmission electron microscopy (TEM, zeta potential and turbidity measurement. It was found that chitosan increases liposome stability during drug release. The coating of DPPC liposomes with a chitosan layer was confirmed by electron microscopy and the zeta potential of liposomes. The coating of liposomes by chitosan resulted in a marginal increase in the size of the liposomes, adding a layer of (92 ± 27.1 nm. The liposomal zeta potential was found to be increasingly positive as chitosan concentration increased from 0.1% to 0.3% (w/v, before stabilising at a relatively constant value. Turbidity studies revealed that the coating of DPPC liposomes with chitosan did not significantly modify the main phase transition temperature of DPPC at examined chitosan concentrations. The appropriate combination of liposomal and chitosan characteristics may produce liposomes with specific, prolonged and controlled release.

Nanotechnology for Cancer Therapy Based on Chemotherapy

OpenAIRE

Chen-Yang Zhao; Rui Cheng; Zhe Yang; Zhong-Min Tian

2018-01-01

Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover,...

Prediction of chemotherapy outcome in patients with metastatic soft tissue sarcomas based on dynamic FDG PET (dPET) and a multiparameter analysis

International Nuclear Information System (INIS)

Dimitrakopoulou-Strauss, Antonia; Strauss, Ludwig G.; Vasamiliette, Julie; Egerer, Gerlinde; Schmitt, Thomas; Kasper, Bernd; Haberkorn, Uwe

2010-01-01

Dynamic PET studies with 18 F-FDG were performed in patients with metastatic soft tissue sarcomas who received conventional chemotherapy with doxorubicin hydrochloride (Adriamycin) and ifosfamide (AI-G). The goal of the study was to evaluate the impact of full kinetic analysis and assess its value with regard to the therapy outcome based on survival data. The evaluation included 17 patients with 29 metastatic lesions of soft tissue sarcomas, who were treated with chemotherapy consisting of an AI-G regimen prior to high-dose chemotherapy and peripheral blood stem cell transplantation where applicable. Patients were examined prior to onset of therapy and after completion of the first cycle of AI-G. Restaging data (n = 17) based on Response Evaluation Criteria in Solid Tumors were available. Survival data (n = 14) served for reference. The following parameters were retrieved from the dynamic PET studies: standardized uptake value (SUV), fractal dimension, two-compartment model with computation of k1, k2, k3, k4 (unit: 1/min), the fractional blood volume and the FDG influx calculated according to Patlak. The mean SUV was 6.9 prior to therapy and 4.7 after one cycle. The mean influx was 0.066 prior to therapy in comparison to 0.058 after one cycle. We dichotomized the patients according to the median survival time of 320 days into response (n = 6) and non-response (n = 8). The mean SUV was 7.6 in the group of responders and 5.4 in the group of non-responders prior to therapy. Responders revealed a mean SUV of 3.8 after therapy as compared to 5.0 SUV for non-responders. We used discriminant analysis to classify the patients into the two response groups. The classification of the non-responders was generally higher (negative predictive value > 61%) than for the responders. Finally, the combined use of the four predictor variables, namely mean SUV and k1 of both studies led to the highest accuracy of 90% for both groups. The data demonstrate that only a multiparameter

Novel liposomal technology applied in esophageal cancer treatment

Science.gov (United States)

Yeh, Chia-Hsien; Hsieh, Yei-San; Yang, Pei-wen; Huang, Leaf; Hsu, Yih-Chih

2018-02-01

Cisplatin (CDDP) has been commonly used as a chemotherapeutic drug, mainly used for the treatment of malignant epithelial cell tumors. We have developed a new method based on innovative lipid calcium phosphate, which encapsulated hydrophobic drugs to form liposomal nanoparticles. Esophageal cancer xenograft model was used to investigate the efficacy of liposomal nanoparticles. and it showed good therapeutic efficacy with lower side effects. Liposomal nanoparticles exhibited a better therapeutic effect than that of conventional CDDP.

Optimisation of preparation conditions and properties of phytosterol liposome-encapsulating nattokinase.

Science.gov (United States)

Dong, Xu-Yan; Kong, Fan-Pi; Yuan, Gang-You; Wei, Fang; Jiang, Mu-Lan; Li, Guang-Ming; Wang, Zhan; Zhao, Yuan-Di; Chen, Hong

2012-01-01

Phytosterol liposomes were prepared using the thin film method and used to encapsulate nattokinase (NK). In order to obtain a high encapsulation efficiency within the liposome, an orthogonal experiment (L9 (3)(4)) was applied to optimise the preparation conditions. The molar ratio of lecithin to phytosterols, NK activity and mass ratio of mannite to lecithin were the main factors that influenced the encapsulation efficiency of the liposomes. Based on the results of a single-factor test, these three factors were chosen for this study. We determined the optimum extraction conditions to be as follows: a molar ratio of lecithin to phytosterol of 2 : 1, NK activity of 2500 U mL⁻¹ and a mass ratio of mannite to lecithin of 3 : 1. Under these optimised conditions, an encapsulation efficiency of 65.25% was achieved, which agreed closely with the predicted result. Moreover, the zeta potential, size distribution and microstructure of the liposomes prepared were measured, and we found that the zeta potential was -51 ± 3 mV and the mean diameter was 194.1 nm. From the results of the scanning electron microscopy, we observed that the phytosterol liposomes were round and regular in shape and showed no aggregation.

Development of Liposomal Bubbles with Perfluoropropane Gas as Gene Delivery Carriers

Science.gov (United States)

Maruyama, Kazuo; Suzuki, Ryo; Sawamura, Kaori; Takizawa, Tomoko; Utoguchi, Naoki; Negishi, Yoichi

2007-05-01

Liposomes have some advantages as drug, antigen and gene delivery carriers. Their size can be easily controlled and they can be modified to add a targeting function. Based on liposome technology, we developed novel liposomal bubbles (Bubble liposomes) containing the ultrasound imaging gas, perfluoropropane. We assessed the feasibility of Bubble liposomes as carriers for gene delivery after cavitation induced by ultrasound. At first, we investigated their ability to deliver genes with Bubble liposomes and ultrasound to various types of cells such as mouse sarcoma cells, mouse melanoma cells, human T cell line and human umbilical vein endothelial cells. The results showed that the Bubble liposomes could deliver plasmid DNA to many cell types without cytotoxicity. In addition, we found that Bubble liposomes could effectively deliver plasmid DNA into mouse femoral artery in vivo. The gene transduction with Bubble liposomes was more effectively than conventional lipofection. We conclude that Bubble liposomes are unique and efficient gene delivery carriers in vitro and in vivo.

Atmospheric-pressure guided streamers for liposomal membrane disruption

International Nuclear Information System (INIS)

Svarnas, P.; Aleiferis, Sp.; Matrali, S. H.; Gazeli, K.; Clément, F.; Antimisiaris, S. G.

2012-01-01

The potential to use liposomes (LIPs) as a cellular model in order to study interactions of cold atmospheric-pressure plasma with cells is herein investigated. Cold atmospheric-pressure plasma is formed by a dielectric-barrier discharge reactor. Large multilamellar vesicle liposomes, consisted of phosphatidylcholine and cholesterol, are prepared by the thin film hydration technique, to encapsulate a small hydrophilic dye, i.e., calcein. The plasma-induced release of calcein from liposomes is then used as a measure of liposome membrane integrity and, consequently, interaction between the cold atmospheric plasma and lipid bilayers. Physical mechanisms leading to membrane disruption are suggested, based on the plasma characterization including gas temperature calculation.

Evaluation of low-grade glioma structural changes after chemotherapy using DTI-based histogram analysis and functional diffusion maps

Energy Technology Data Exchange (ETDEWEB)

Castellano, Antonella; Iadanza, Antonella; Falini, Andrea [San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Neuroradiology Unit and CERMAC, Milano (Italy); Donativi, Marina [University of Salento, Department of Mathematics and Physics ' ' Ennio De Giorgi' ' and A.D.A.M. (Advanced Data Analysis in Medicine), Lecce (Italy); Ruda, Roberta; Bertero, Luca; Soffietti, Riccardo [University of Torino, Department of Neuro-oncology, Turin (Italy); De Nunzio, Giorgio [University of Salento, Department of Mathematics and Physics ' ' Ennio De Giorgi' ' and A.D.A.M. (Advanced Data Analysis in Medicine), Lecce (Italy); INFN (National Institute of Nuclear Physics), Lecce (Italy); Riva, Marco; Bello, Lorenzo [Universita degli Studi di Milano, Milan, and Humanitas Research Hospital, Department of Medical Biotechnology and Translational Medicine, Rozzano, MI (Italy); Rucco, Matteo [University of Camerino, School of Science and Technology, Computer Science Division, Camerino, MC (Italy)

2016-05-15

To explore the role of diffusion tensor imaging (DTI)-based histogram analysis and functional diffusion maps (fDMs) in evaluating structural changes of low-grade gliomas (LGGs) receiving temozolomide (TMZ) chemotherapy. Twenty-one LGG patients underwent 3T-MR examinations before and after three and six cycles of dose-dense TMZ, including 3D-fluid-attenuated inversion recovery (FLAIR) sequences and DTI (b = 1000 s/mm{sup 2}, 32 directions). Mean diffusivity (MD), fractional anisotropy (FA), and tensor-decomposition DTI maps (p and q) were obtained. Histogram and fDM analyses were performed on co-registered baseline and post-chemotherapy maps. DTI changes were compared with modifications of tumour area and volume [according to Response Assessment in Neuro-Oncology (RANO) criteria], and seizure response. After three cycles of TMZ, 20/21 patients were stable according to RANO criteria, but DTI changes were observed in all patients (Wilcoxon test, P ≤ 0.03). After six cycles, DTI changes were more pronounced (P ≤ 0.005). Seventy-five percent of patients had early seizure response with significant improvement of DTI values, maintaining stability on FLAIR. Early changes of the 25th percentiles of p and MD predicted final volume change (R{sup 2} = 0.614 and 0.561, P < 0.0005, respectively). TMZ-related changes were located mainly at tumour borders on p and MD fDMs. DTI-based histogram and fDM analyses are useful techniques to evaluate the early effects of TMZ chemotherapy in LGG patients. (orig.)

Ultrasound triggered drug delivery with liposomal nested microbubbles.

Science.gov (United States)

Wallace, N; Wrenn, S P

2015-12-01

When ultrasound contrast agent microbubbles are nested within a liposome, damage to the liposome membrane caused by both stable and inertial cavitation of the microbubble allows for release of the aqueous core of the liposome. Triggered release was not accomplished unless microbubbles were present within the liposome. Leakage was tested using fluorescence assays developed specifically for this drug delivery vehicle and qualitative measurements using an optical microscope. These studies were done using a 1 MHz focused ultrasound transducer while varying parameters including peak negative ultrasound pressure, average liposome diameter, and microbubble concentration. Two regimes exist for membrane disruption caused by cavitating microbubbles. A faster release rate, as well as permanent membrane damage are seen for samples exposed to high pressure (2.1-3.7 MPa). A slower release rate and dilation/temporary poration are characteristic of stable cavitation for low pressure studies (0.54-1.7 MPa). Copyright © 2015 Elsevier B.V. All rights reserved.

Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma

Science.gov (United States)

Little, Richard F.; Aleman, Karen; Kumar, Pallavi; Wyvill, Kathleen M.; Pluda, James M.; Read-Connole, Elizabeth; Wang, Victoria; Pittaluga, Stefania; Catanzaro, Andrew T.; Steinberg, Seth M.

2007-01-01

Thirty-six patients with AIDS-associated Kaposi sarcoma (KS) requiring chemotherapy were treated for six 3-week cycles of pegylated liposomal doxorubicin (20 mg/m2) plus interleukin-12 (IL-12; 300 ng/kg subcutaneously twice weekly), followed by 500 ng/kg subcutaneous IL-12 twice weekly for up to 3 years. All received highly active antiretroviral therapy (HAART). Twenty-two had poor-prognosis KS (T1S1). Thirty patients had a major response, including 9 with complete response, yielding an 83.3% major response rate (95% confidence interval: 67.2%-93.6%). Median time to first response was 2 cycles. Median progression was not reached at median potential follow-up of 46.9 months. Of 27 patients with residual disease when starting maintenance IL-12, 15 had a new major response compared with this new baseline. The regimen was overall well tolerated; principal toxicities were neutropenia, anemia, transaminitis, and neuropsychiatric toxicity. Patients had increases in serum IL-12, interferon gamma, and inducible protein-10 (IP-10), and these remained increased at weeks 18 and 34. The regimen of IL-12 plus liposomal doxorubicin yielded rapid tumor responses and a high response rate in patients with AIDS-KS receiving HAART, and responses were sustained on IL-12 maintenance therapy. A randomized trial of IL-12 in this setting may be warranted. This study is registered at http://www.clinicaltrials.gov as no. NCT00020449. PMID:17846226

Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells.

Science.gov (United States)

Sriraman, Shravan Kumar; Pan, Jiayi; Sarisozen, Can; Luther, Ed; Torchilin, Vladimir

2016-02-01

Current research in cancer therapy is beginning to shift toward the use of combinational drug treatment regimens. However, the efficient delivery of drug combinations is governed by a number of complex factors in the clinical setting. Therefore, the ability to synchronize the pharmacokinetics of the individual therapeutic agents present in combination not only to allow for simultaneous tumor accumulation but also to allow for a synergistic relationship at the intracellular level could prove to be advantageous. In this work, we report the development of a novel folic acid-targeted liposomal formulation simultaneously co-loaded with C6 ceramide and doxorubicin [FA-(C6+Dox)-LP]. In vitro cytotoxicity assays showed that the FA-(C6+Dox)-LP was able to significantly reduce the IC50 of Dox when compared to that after the treatment with the doxorubicin-loaded liposomes (Dox-LP) as well as the untargeted drug co-loaded (C6+Dox)-LP on HeLa, A2780-ADR, and H69-AR cells. The analysis of the cell cycle distribution showed that while the C6 liposomes (C6-LP) did not cause cell cycle arrest, all the Dox-containing liposomes mediated cell cycle arrest in HeLa cells in the G2 phase at Dox concentrations of 0.3 and 1 μM and in the S phase at the higher concentrations. It was also found that this arrest in the S phase precedes the progression of the cells to apoptosis. The targeted FA-(C6+Dox)-LP were able to significantly enhance the induction of apoptotic events in HeLa cell monolayers as compared to the other treatment groups. Next, using time-lapse phase holographic imaging microscopy, it was found that upon treatment with the FA-(C6+Dox)-LP, the HeLa cells underwent rapid progression to apoptosis after 21 h as evidenced by a drastic drop in the average area of the cells after loss of cell membrane integrity. Finally, upon evaluation in a HeLa spheroid cell model, treatment with the FA-(C6+Dox)-LP showed significantly higher levels of cell death compared to those with C6-LP and

Benchmarking of Sterilizing grade filters with liposome Filtration.

Science.gov (United States)

Loewe, Thomas; Mundlamuri, Ramesh; Loewe, Thomas; Mundrigi, Ashok; Handt, Sebastian; Singh, Bhuwan

2017-12-14

Cytotoxic drugs can be encapsulated in liposomes vesicles, which act as drug delivery vehicles and reduce the risk of exposure of drug to healthy cells(1). The sterility of such liposome solutions is typically ensured using 0.2μm rated sterilizing grade membranes, but due to the high viscosity and low surface tension of these formulations, they can cause pre-mature blocking and increased risk of bacterial penetration through a 0.2μm sterilizing grade membrane(2). The low surface tension of liposome solutions affects the contact angle with membrane and reduces bubble point leading to bacterial penetration through the membrane. This poses a great challenge to select an appropriate sterilizing grade membrane for a given process and for filter manufacturers to develop a sterilizing grade membrane that specifically addresses these needs. In this study, the influence of different variables that could affect the total throughput and bacterial retention performance of different membranes types on processing of liposome solutions have been evaluated. Based on the results, we conclude that the membrane properties e.g., surface porosity, surface tension, pore size, symmetry/asymmetry, hydrophilicity and liposome properties e.g., composition, lipid size and concentration affect bacterial retention and total throughput capacity. Process parameters such as temperature, pressure and flow should also be optimized to improve process efficiency. Copyright © 2017, Parenteral Drug Association.

The role of {sup 18}F-FDG PET/CT in evaluation of early response to neoadjuvant chemotherapy in patients with locally advanced breast cancer

Energy Technology Data Exchange (ETDEWEB)

Kumar, Amandeep; Seenu, Vathalaru; Mehta, Sada Nand [All India Institute of Medical Sciences, Department of Surgical disciplines, New Delhi (India); Kumar, Rakesh; Chawla, Madhavi; Malhotra, Arun [All India Institute of Medical Sciences, Department of Nuclear Medicine, New Delhi (India); Gupta, Sidharatha Datta [All India Institute of Medical Sciences, Department of Pathology, New Delhi (India)

2009-06-15

We evaluated the role of 18F-FDG PET/CT for the assessment of response after two cycles of neo-adjuvant chemotherapy (NACT) for breast cancer. Twenty-three women with locally advanced breast cancer were included in this study. Early response to NACT was evaluated after two cycles using clinical examination, CT, and 18F-FDG PET/CT. Final histopathology following surgery after six cycles of NACT served as reference. Baseline PET/CT demonstrated a total of 26 lesions in 23 patients. The size of the primary tumor ranged from 1.90 cm to 11.60 cm, and the maximum value of the standardized uptake value of FDG (SUVmax) ranged from 3.6 to 38.6 (mean, 11.7). Post-chemotherapy PET/CT examinations were done after two cycles of NACT. The size of the primary tumor on follow-up PET/CT examinations ranged from 0.0 cm to 7.6 cm, and SUVmax ranged from 0.0 to 12.0 (mean, 3.96). On clinical, CT, and PET/CT examinations, 50% reduction in the parameters was taken as the cutoff value to differentiate between responders and non-responders. Post-NACT PET/CT demonstrated that 16 patients were responders and 7 non-responders. Among 16 responders on PET/CT scan, 14 were true positive and 2 were false positive when compared with histopathology. Among seven non-responder patients, six were true negative, and one was false negative. The sensitivity, specificity, and accuracy of PET/CT in detecting responders were 93%, 75%, and 87%, respectively. In conclusion, 18F-FDG PET/CT can differentiate responders from non-responders with high accuracy after two cycles of NACT in patients with LABC. (orig.)

Interaction of dipalmitoyl phosphatidylcholine (DPPC) liposomes and insulin

Science.gov (United States)

Mady, Mohsen M.; Elshemey, Wael M.

2011-06-01

Insulin, a peptide that has been used for decades in the treatment of diabetes, has well-defined properties and delivery requirements. Liposomes, which are lipid bilayer vesicles, have gained increasing attention as drug carriers which reduce the toxicity and increase the pharmacological activity of various drugs. The molecular interaction between (uncharged lipid) dipalmitoyl phosphatidylcholine (DPPC) liposomes and insulin has been characterized by using Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction. The characteristic protein absorption band peaks, Amide I (at about 1660 cm-1) and Amide II band (at about 1546 cm-1) are potentially reduced in the liposome insulin complex. Wide-angle x-ray scattering measurements showed that the association of insulin with DPPC lipid of liposomes still maintains the characteristic DPPC diffraction peaks with almost no change in relative intensities or change in peak positions. The absence of any shift in protein peak positions after insulin being associated with DPPC liposomes indicates that insulin is successfully forming complex with DPPC liposomes with possibly no pronounced alterations in the structure of insulin molecule.

Switch maintenance chemotherapy using S-1 with or without bevacizumab in patients with advanced non-small cell lung cancer: a phase II study.

Science.gov (United States)

Niho, Seiji; Ohe, Yuichiro; Ohmatsu, Hironobu; Umemura, Shigeki; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

2017-06-01

We conducted this single-institute; prospective, non-randomized parallel two-arm phase II study to evaluate the efficacy and safety of switch maintenance chemotherapy with S-1 after induction therapy with a platinum-based regimen in patients with advanced non-small cell lung cancer (NSCLC). Patients not showing disease progression after induction platinum-based chemotherapy received S-1 at the dose of 40mg/m 2 twice daily for 14 consecutive days, every three weeks, with or without bevacizumab (Bev) at the dose of 15mg/kg. In cases where the induction chemotherapy regimen contained Bev, Bev was used as continuation maintenance chemotherapy where appropriate. The efficacy/toxicity of switch maintenance chemotherapy with S-1 and S-1+Bev was evaluated separately. The primary end point of this study was the treatment success rate at three months after the start of S-1 treatment. Between July 2010 and January 2014, 79 patients were enrolled, of which 78 were found to be eligible for inclusion in this study. The treatment success rate at three months was 28.2% (90% confidence interval (CI), 7.1-17.1%) in the S-1 group and 64.1% (90% CI, 50.0-76.8%) in the S-1+Bev group. The primary endpoint was met in the S-1+Bev group. The median PFS and OS were 2.6 months and 11.0 months in the S-1 group, and 4.6 months and 19.9 months in the S-1+Bev group, respectively. The most common grade three toxicity was neutropenia (10% incidence in the S-1+Bev group). There were no cases of febrile neutropenia. Switch maintenance chemotherapy with S-1 in combination with continuation maintenance chemotherapy with bevacizumab yielded modest efficacy with mild and acceptable toxicities. Copyright © 2017. Published by Elsevier B.V.

Liposomal Conjugates for Drug Delivery to the Central Nervous System

Directory of Open Access Journals (Sweden)

Frieder Helm

2015-04-01

Full Text Available Treatments of central nervous system (CNS diseases often fail due to the blood–brain barrier. Circumvention of this obstacle is crucial for any systemic treatment of such diseases to be effective. One approach to transfer drugs into the brain is the use of colloidal carrier systems—amongst others, liposomes. A prerequisite for successful drug delivery by colloidal carriers to the brain is the modification of their surface, making them invisible to the reticuloendothelial system (RES and to target them to specific surface epitopes at the blood–brain barrier. This study characterizes liposomes conjugated with cationized bovine serum albumin (cBSA as transport vectors in vitro in porcine brain capillary endothelial cells (PBCEC and in vivo in rats using fluorescently labelled liposomes. Experiments with PBCEC showed that sterically stabilized (PEGylated liposomes without protein as well as liposomes conjugated to native bovine serum albumin (BSA were not taken up. In contrast, cBSA-liposomes were taken up and appeared to be concentrated in intracellular vesicles. Uptake occurred in a concentration and time dependent manner. Free BSA and free cBSA inhibited uptake. After intravenous application of cBSA-liposomes, confocal fluorescence microscopy of brain cryosections from male Wistar rats showed fluorescence associated with liposomes in brain capillary surrounding tissue after 3, 6 and 24 h, for liposomes with a diameter between 120 and 150 nm, suggesting successful brain delivery of cationized-albumin coupled liposomes.

Arabidopsis dynamin-related protein 1A polymers bind, but do not tubulate, liposomes

International Nuclear Information System (INIS)

Backues, Steven K.; Bednarek, Sebastian Y.

2010-01-01

The Arabidopsis dynamin-related protein 1A (AtDRP1A) is involved in endocytosis and cell plate maturation in Arabidopsis. Unlike dynamin, AtDRP1A does not have any recognized membrane binding or protein-protein interaction domains. We report that GTPase active AtDRP1A purified from Escherichia coli as a fusion to maltose binding protein forms homopolymers visible by negative staining electron microscopy. These polymers interact with protein-free liposomes whose lipid composition mimics that of the inner leaflet of the Arabidopsis plasma membrane, suggesting that lipid-binding may play a role in AtDRP1A function. However, AtDRP1A polymers do not appear to assemble and disassemble in a dynamic fashion and do not have the ability to tubulate liposomes in vitro, suggesting that additional factors or modifications are necessary for AtDRP1A's in vivo function.

A novel liposome-based nanocarrier loaded with an LPS-dsRNA cocktail for fish innate immune system stimulation.

Directory of Open Access Journals (Sweden)

Angels Ruyra

Full Text Available Development of novel systems of vaccine delivery is a growing demand of the aquaculture industry. Nano- and micro- encapsulation systems are promising tools to achieve efficient vaccines against orphan vaccine fish diseases. In this context, the use of liposomal based-nanocarriers has been poorly explored in fish; although liposomal nanocarriers have successfully been used in other species. Here, we report a new ∼125 nm-in-diameter unilamellar liposome-encapsulated immunostimulant cocktail containing crude lipopolysaccharide (LPS from E. coli and polyinosinic:polycytidylic acid [poly (I:C], a synthetic analog of dsRNA virus, aiming to be used as a non-specific vaccine nanocarrier in different fish species. This liposomal carrier showed high encapsulation efficiencies and low toxicity not only in vitro using three different cellular models but also in vivo using zebrafish embryos and larvae. We showed that such liposomal LPS-dsRNA cocktail is able to enter into contact with zebrafish hepatocytes (ZFL cell line and trout macrophage plasma membranes, being preferentially internalized through caveolae-dependent endocytosis, although clathrin-mediated endocytosis in ZFL cells and macropinocytocis in macrophages also contribute to liposome uptake. Importantly, we also demonstrated that this liposomal LPS-dsRNA cocktail elicits a specific pro-inflammatory and anti-viral response in both zebrafish hepatocytes and trout macrophages. The design of a unique delivery system with the ability to stimulate two potent innate immunity pathways virtually present in all fish species represents a completely new approach in fish health.

Liposome-based DNA carriers may induce cellular stress response and change gene expression pattern in transfected cells

Science.gov (United States)

2011-01-01

Background During functional studies on the rat stress-inducible Hspa1b (hsp70.1) gene we noticed that some liposome-based DNA carriers, which are used for transfection, induce its promoter activity. This observation concerned commercial liposome formulations (LA), Lipofectin and Lipofectamine 2000. This work was aimed to understand better the mechanism of this phenomenon and its potential biological and practical consequences. Results We found that a reporter gene driven by Hspa1b promoter is activated both in the case of transient transfections and in the stably transfected cells treated with LA. Using several deletion clones containing different fragments of Hspa1b promoter, we found that the regulatory elements responsible for most efficient LA-driven inducibility were located between nucleotides -269 and +85, relative to the transcription start site. Further studies showed that the induction mechanism was independent of the classical HSE-HSF interaction that is responsible for gene activation during heat stress. Using DNA microarrays we also detected significant activation of the endogenous Hspa1b gene in cells treated with Lipofectamine 2000. Several other stress genes were also induced, along with numerous genes involved in cellular metabolism, cell cycle control and pro-apoptotic pathways. Conclusions Our observations suggest that i) some cationic liposomes may not be suitable for functional studies on hsp promoters, ii) lipofection may cause unintended changes in global gene expression in the transfected cells. PMID:21663599

Liposome-based DNA carriers may induce cellular stress response and change gene expression pattern in transfected cells

Directory of Open Access Journals (Sweden)

Lisowska Katarzyna Marta

2011-06-01

Full Text Available Abstract Background During functional studies on the rat stress-inducible Hspa1b (hsp70.1 gene we noticed that some liposome-based DNA carriers, which are used for transfection, induce its promoter activity. This observation concerned commercial liposome formulations (LA, Lipofectin and Lipofectamine 2000. This work was aimed to understand better the mechanism of this phenomenon and its potential biological and practical consequences. Results We found that a reporter gene driven by Hspa1b promoter is activated both in the case of transient transfections and in the stably transfected cells treated with LA. Using several deletion clones containing different fragments of Hspa1b promoter, we found that the regulatory elements responsible for most efficient LA-driven inducibility were located between nucleotides -269 and +85, relative to the transcription start site. Further studies showed that the induction mechanism was independent of the classical HSE-HSF interaction that is responsible for gene activation during heat stress. Using DNA microarrays we also detected significant activation of the endogenous Hspa1b gene in cells treated with Lipofectamine 2000. Several other stress genes were also induced, along with numerous genes involved in cellular metabolism, cell cycle control and pro-apoptotic pathways. Conclusions Our observations suggest that i some cationic liposomes may not be suitable for functional studies on hsp promoters, ii lipofection may cause unintended changes in global gene expression in the transfected cells.

Studies on liposomes with Chlorophyll for monitoring the electromagnetic influence at molecular level

International Nuclear Information System (INIS)

Tugulea, Laura; Miclaus, Simona; Iacovache, Ioan

2001-01-01

The liposomes with Chlorophyll are excellent model membranes and could be successfully used to study the electromagnetic influence at molecular level. The strong visible absorption and fluorescence of Chlorophyll allow its use as sensor for the interactions at molecular level and as a fluorescence marker; it reflects certain aspects of the supramolecular structure of the lipid phase: fluidity, lipid and liposomes aggregation. The objective of our work was to evidence athermal effect of low level, pulsed microwave (MW) fields on liposomes and to evidence the possible mechanism of interaction at molecular level. Unilamellar liposomes were obtained from multilamellar vesicles by the hand-shaken method and sonication for 30 minutes. The multilamellar vesicles were prepared using Chla /lipid films with specific molar ratio (lipid/Chla 1/10 and 1/100) and different lipids (Dipalmitoyl phosphatidylcholine, Dimirystoyl Phosphatidylcholine and Dioleoyl Phosphatidylcholine-Sigma). The films were dispersed in buffer solutions of different pH (6.2 - 7.6). The Chlorophyll was freshly extracted from spinach leaves and separated by the chromatographic method. Portions of liposome suspension (0.6 ml) were inserted into Teflon cuvettes. The samples were irradiated in series, for periods of 5-30 minutes. The exposure system was: MW generator + adapted load (shortened rectangular waveguide) + Teflon cuvette filled with sample liquid. The effect of MW irradiation is not observable on multilamellar vesicles, but only on small unilamellar vesicles. The MW effect is athermal, verified by conventional heating in the same range of temperatures and results in enlarging the size of vesicles. The enlarging effect of MW is opposed to the effect of ultrasounds exposure. It is not clear if effects due to MW are proportional with exposure duration; it seems that this mostly depends on the type of lipid in vesicles. The UV and VIS spectra were recorded to observe the oxidation state of the

ExternE: Externalities of energy Vol. 1. Summary

International Nuclear Information System (INIS)

Holland, M.; Berry, J.

1995-01-01

energy use in the transport and domestic sectors and a number of non-environmental externalities. Phase 3 of the project will be undertaken within the European Commission's 4th Framework Programme (1995-1998) and will concentrate on the application of the accounting framework in support of policy issues and decision making. A major result of this work is the methodology which has been developed. This is a significant advance on earlier studies of the external costs of energy. It provides a transparent basis on which different impacts, technologies and locations may be compared. It is suitable for evaluation of the health and environmental damages due to increments in electricity production, with or without monetary valuation of the impacts. This report reviews this methodology and presents the major results obtained in its application to seven important fuel cycles, namely the coal, lignite, oil, gas, nuclear, hydro and wind fuel cycles. Chapter 2 reviews the methodology developed for the quantification of impacts and discusses the associated issues. Chapter 3 discusses the methodological issues associated with the economic valuation of impacts. Chapters 4 and 5 report in detail on the assessment of the coal and nuclear fuel cycles. Chapter 6 summarises the progress that has been made to date on the ExternE Project and presents a comparison of the results obtained for the four fossil fuel cycles together with results from the nuclear and renewable fuel cycles. This project is at the forefront of work in this area. It has drawn together an extensive multidisciplinary team of environmental scientists, energy technologists, health and ecology experts, atmospheric modellers, economists and computer analysts. The results obtained are based on thorough review of scientific and economic studies. This does not mean that exact values have been established for external costs. Indeed, one of our most important conclusions is that the uncertainties are large. Previous analyses

Dual drug delivery using “smart” liposomes for triggered release of anticancer agents

International Nuclear Information System (INIS)

Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K.

2013-01-01

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel–topotecan (Pac–Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-α) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG 2000 –DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG 2000 –DSPE:DSPE–PEG–folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 ± 0.5 °C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 ± 1 °C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac–Top free (20:1, w/w) to be more toxic (GI 50 = 6.5 μg/ml) than positive control (Adriamycin, GI 50 = 9.1 μg/ml) and FR-targeted PEGylated liposomes GI 50 (14.7 μg/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called “smart liposomes” which has not only mediated effective targeting to FR-α but also triggered release of drugs upon hyperthermia

Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.

Science.gov (United States)

Gobin, Y Pierre; Dunkel, Ira J; Marr, Brian P; Brodie, Scott E; Abramson, David H

2011-06-01

To determine whether intra-arterial chemotherapy is safe and effective in advanced intraocular retinoblastoma. Retinoblastoma often presents with advanced intraocular disease and, despite conventional treatment with intravenous chemotherapy and external beam radiation therapy, may still require enucleation. Single-arm, prospective registry from May 30, 2006, to May 30, 2010, at an ophthalmic oncology referral center with ambulatory care. A total of 95 eyes of 78 patients with unilateral or bilateral retinoblastoma were treated. The intervention was selective catheterization of the ophthalmic artery and injection of chemotherapy, usually melphalan with or without topotecan. Drug dosage was determined by age and angioanatomy. The main outcome measures were procedural success, event-free (enucleation or radiotherapy) ocular survival, and ocular and extraocular complications. Catheterization succeeded in 98.5% of procedures. There were 289 chemotherapy injections (median, 3 per eye). The Kaplan-Meier estimates of ocular event-free survival rates at 2 years were 70.0% (95% confidence interval, 57.9%-82.2%) for all eyes, 81.7% (95% confidence interval, 66.8%-96.6%) for eyes that received intra-arterial chemotherapy as primary treatment, and 58.4% (95% confidence interval, 39.5%-77.2%) for eyes that had previous treatment failure with intravenous chemotherapy and/or external beam radiation therapy. There were no permanent extraocular complications. Our experience suggests that intra-arterial chemotherapy is safe and effective in the treatment of advanced intraocular retinoblastoma.

Aespoe Task Force on modelling of groundwater flow and transport of solutes. Review of Tasks 6D, 6E, 6F and 6F2

International Nuclear Information System (INIS)

Hodgkinson, David

2007-09-01

This report forms part of an independent review of the specifications, execution and results of Task 6 of the Aespoe Task Force on Modelling of Groundwater Flow and Transport of Solutes, which is seeking to provide a bridge between site characterization and performance assessment approaches to modelling solute transport in fractured rock. The objectives of Task 6 are: To assess simplifications used in Performance Assessment (PA) models. To determine how, and to what extent, experimental tracer and flow experiments can constrain the range of parameters used in PA models. To support the design of Site Characterisation (SC) programmes to ensure that the results have optimal value for performance assessment calculations. To improve the understanding of site-specific flow and transport behaviour at different scales using site characterisation models. The present report is concerned with Tasks 6D, 6E, 6F and 6F2. It follows on from two previous reviews of Tasks 6A, 6B and 6B2, and Task 6C. In Task 6D the transport of tracers through a fracture network is modelled using the conditions of the C2 TRUE-Block Scale tracer test, based on the synthetic structural model developed in Task 6C. Task 6E extends the Task 6D transport calculations to a reference set of PA time scales and boundary conditions. Task 6F consists of a series of 'benchmark' studies on single features from the Task 6C hydrostructural model in order to improve the understanding of differences between the participating models. Task 6F2 utilises models set up for Tasks 6E and 6F to perform additional sensitivity studies with the aim of increasing the understanding of how models behave, the reason for differences in modelling results, and the sensitivity of models to various assumptions and parameter values. Eight modelling teams representing five organisations participated in this exercise using Discrete Fracture Network (DFN), continuum and channel network concepts implemented in a range of different codes and

Aespoe Task Force on modelling of groundwater flow and transport of solutes. Review of Tasks 6D, 6E, 6F and 6F2

Energy Technology Data Exchange (ETDEWEB)

Hodgkinson, David (Quintessa, Henley-on-Thames (GB))

2007-09-15

This report forms part of an independent review of the specifications, execution and results of Task 6 of the Aespoe Task Force on Modelling of Groundwater Flow and Transport of Solutes, which is seeking to provide a bridge between site characterization and performance assessment approaches to modelling solute transport in fractured rock. The objectives of Task 6 are: To assess simplifications used in Performance Assessment (PA) models. To determine how, and to what extent, experimental tracer and flow experiments can constrain the range of parameters used in PA models. To support the design of Site Characterisation (SC) programmes to ensure that the results have optimal value for performance assessment calculations. To improve the understanding of site-specific flow and transport behaviour at different scales using site characterisation models. The present report is concerned with Tasks 6D, 6E, 6F and 6F2. It follows on from two previous reviews of Tasks 6A, 6B and 6B2, and Task 6C. In Task 6D the transport of tracers through a fracture network is modelled using the conditions of the C2 TRUE-Block Scale tracer test, based on the synthetic structural model developed in Task 6C. Task 6E extends the Task 6D transport calculations to a reference set of PA time scales and boundary conditions. Task 6F consists of a series of 'benchmark' studies on single features from the Task 6C hydrostructural model in order to improve the understanding of differences between the participating models. Task 6F2 utilises models set up for Tasks 6E and 6F to perform additional sensitivity studies with the aim of increasing the understanding of how models behave, the reason for differences in modelling results, and the sensitivity of models to various assumptions and parameter values. Eight modelling teams representing five organisations participated in this exercise using Discrete Fracture Network (DFN), continuum and channel network concepts implemented in a range of different

Reversal of the multidrug resistance by drug combination using multifunctional liposomes

Science.gov (United States)

Patel, Niravkumar R.

One of the major obstacles to the success of cancer chemotherapy is the multi-drug resistance (MDR) that results due mainly to the over-expression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results against MDR. However, P-gp is also expressed in normal tissues like the blood-brain barrier, gastrointestinal tract, liver and kidney. It is therefore important to limit the exposure of P-gp inhibitors to normal tissues and increase their co-localization with anticancer agents in tumor tissues to maximize the efficacy of a P-gp inhibitor. To minimize non-specific binding and increase its delivery to tumor tissues, liposomes, self-assembling phospholipid vesicles, were chosen as a drug delivery vehicle. The liposome has been identified as a system capable of carrying molecules with diverse physicochemical properties. It can also alter the pharmacokinetic profile of loaded molecules which is a concern with both tariquidar and paclitaxel. Liposomes can easily be surface-modified rendering them cell-specific as well as organelle-specific. The main objective of present study was to develop an efficient liposomal delivery system which would deliver therapeutic molecules of interest to tumor tissues and avoid interaction with normal tissues. In this study, the co-delivery of tariquidar and paclitaxel into tumor cells to reverse the MDR using long-circulating cationic liposomes was investigated. SKOV-3TR, the resistant variant of SKOV-3 and MCF-7/ADR, the resistant variant of MCF-7 were used as model cell lines. Uniform liposomal formulations were generated with high incorporation efficiency and no apparent decrease in tariquidar potency towards P-gp. Tariquidar- and paclitaxel- co-loaded long-circulating liposomes showed significant re-sensitization of SKOV-3TR and MCF-7/ADR for paclitaxel in vitro. Further modification of these liposomes with antitumor 2C5 resulted

Chemotherapy-Induced Macrophage Infiltration into Tumors Enhances Nanographene-Based Photodynamic Therapy.

Science.gov (United States)

Zhao, Yang; Zhang, Chenran; Gao, Liquan; Yu, Xinhe; Lai, Jianhao; Lu, Dehua; Bao, Rui; Wang, Yanpu; Jia, Bing; Wang, Fan; Liu, Zhaofei

2017-11-01

Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. Cancer Res; 77(21); 6021-32. ©2017 AACR . ©2017 American Association for Cancer Research.

Bladder uptake of liposomes after intravesical administration occurs by endocytosis.

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Bharathi Raja Rajaganapathy

Full Text Available Liposomes have been used therapeutically and as a local drug delivery system in the bladder. However, the exact mechanism for the uptake of liposomes by bladder cells is unclear. In the present study, we investigated the role of endocytosis in the uptake of liposomes by cultured human UROtsa cells of urothelium and rat bladder. UROtsa cells were incubated in serum-free media with liposomes containing colloidal gold particles for 2 h either at 37°C or at 4°C. Transmission Electron Microscopy (TEM images of cells incubated at 37°C found endocytic vesicles containing gold inside the cells. In contrast, only extracellular binding was noticed in cells incubated with liposomes at 4°C. Absence of liposome internalization at 4°C indicates the need of energy dependent endocytosis as the primary mechanism of entry of liposomes into the urothelium. Flow cytometry analysis revealed that the uptake of liposomes at 37°C occurs via clathrin mediated endocytosis. Based on these observations, we propose that clathrin mediated endocytosis is the main route of entry for liposomes into the urothelial layer of the bladder and the findings here support the usefulness of liposomes in intravesical drug delivery.

Overcoming cellular and tissue barriers to improve liposomal drug delivery

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Kohli, Aditya G.

Forty years of liposome research have demonstrated that the anti-tumor efficacy of liposomal therapies is, in part, driven by three parameters: 1) liposome formulation and lipid biophysics, 2) accumulation and distribution in the tumor, and 3) release of the payload at the site of interest. This thesis outlines three studies that improve on each of these delivery steps. In the first study, we engineer a novel class of zwitterlipids with an inverted headgroup architecture that have remarkable biophysical properties and may be useful for drug delivery applications. After intravenous administration, liposomes accumulate in the tumor by the enhanced permeability and retention effect. However, the tumor stroma often limits liposome efficacy by preventing distribution into the tumor. In the second study, we demonstrate that depletion of hyaluronan in the tumor stroma improves the distribution and efficacy of DoxilRTM in murine 4T1 tumors. Once a liposome has distributed to the therapeutic site, it must release its payload over the correct timescale. Few facile methods exist to quantify the release of liposome therapeutics in vivo. In the third study, we outline and validate a simple, robust, and quantitative method for tracking the rate and extent of release of liposome contents in vivo. This tool should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals. This work highlights aspects of liposome behavior that have prevented successful clinical translation and proposes alternative approaches to improve liposome drug delivery.

[ReF₆]^2-

DEFF Research Database (Denmark)

Pedersen, Kasper Steen; Sigrist, Marc; Sørensen, Mikkel Agerbæk

2014-01-01

studied including the slow relaxation of the magnetization observed below ca. 4 K. This slow dynamic is preserved for the one-dimensional coordination polymer [Zn(viz)4(ReF 6)]1 (2, viz=1-vinylimidazole), demonstrating the irrelevance of low symmetry for such magnetization dynamics in systems with easy......-plane-type anisotropy. The ability of fluoride to mediate significant exchange interactions is exemplified by the isostructural [Ni(viz)4(ReF6)]1 (3) analogue in which the ferromagnetic NiII-ReIV interaction (+10.8 cm-1) dwarfs the coupling present in related cyanide-bridged systems. These results reveal [ReF6...

Predictive role of GSTP1-containing exosomes in chemotherapy-resistant breast cancer.

Science.gov (United States)

Yang, Su-Jin; Wang, Dan-Dan; Li, Jian; Xu, Han-Zi; Shen, Hong-Yu; Chen, Xiu; Zhou, Si-Ying; Zhong, Shan-Liang; Zhao, Jian-Hua; Tang, Jin-Hai

2017-08-05

Anthracycline/taxane-based chemotherapy regimens are usually used as neoadjuvant chemotherapies to decrease tumour size and prevent metastasis of advanced breast cancer. However, patients have a high risk of developing chemo-resistance during treatment through still unknown mechanisms. Glutathione S-transferase P1 (GSTP1), which belongs to the family of phase II metabolic enzymes, has been reported to function in detoxifying several anti-cancer drugs by conjugating them with glutathione. Previous studies have identified GSTP1 as a predictor of prognosis and chemo-resistance in breast cancer patients, but the mechanisms governing GSTP1-dependent drug resistance are still unclear. We have found that GSTP1 expression is much higher in adriamycin-resistant cells and their corresponding exosomes. The role of GSTP1-containing exosomes in conferring drug resistance was analysed through cell apoptosis and immunofluorescence staining assays. Furthermore, we analysed 42 cases of paired breast cancer tissues collected before and after anthracycline/taxane-based neoadjuvant chemotherapy by immunohistochemistry. Higher GSTP1 expression was shown in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in the samples collected before and after the chemotherapy treatment. Interestingly, GSTP1 partly re-localized from the cell nucleus to the cytoplasm upon treatment, and similar results were obtained for the exosomal marker Tumour susceptibility gene 101 protein (TSG101), which also increased in the cytoplasm after chemotherapy. After analysing the serum exosomes of 30 patients treated with anthracycline/taxane-based neoadjuvant chemotherapy, we discovered that the levels of GSTP1 in exosomes from patients in the PD/SD group were significantly higher than those in the PR/CR group. Here, for the first time, we investigated a novel role for GSTP1-containing exosomes and their capability to transfer drug resistance

Dual drug delivery using 'smart' liposomes for triggered release of anticancer agents

Energy Technology Data Exchange (ETDEWEB)

Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K., E-mail: drskjainin@yahoo.com [Dr. Hari Singh Gour Vishwavidyalaya, Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences (India)

2013-07-15

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-{alpha}) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG{sub 2000}-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG{sub 2000}-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 {+-} 0.5 Degree-Sign C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 {+-} 1 Degree-Sign C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI{sub 50} = 6.5 {mu}g/ml) than positive control (Adriamycin, GI{sub 50} = 9.1 {mu}g/ml) and FR-targeted PEGylated liposomes GI{sub 50} (14.7 {mu}g/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called 'smart liposomes' which has not only mediated effective targeting to FR-{alpha} but also triggered release of drugs upon hyperthermia.

Innovative bionanocomposite films of edible proteins containing liposome-encapsulated nisin and halloysite nanoclay.

Science.gov (United States)

Boelter, Juliana Ferreira; Brandelli, Adriano

2016-09-01

Films and coatings based on natural polymers have gained increased interest for food packaging applications. In this work, halloysite and phosphatidylcholine liposomes encapsulating nisin were used to develop nanocomposite films of gelatin and casein. Liposomes prepared with either soybean lecithin or Phospholipon(®) showed particle size ranging from 124 to 178nm and high entrapment efficiency (94-100%). Considering their stability, Phospholipon(®) liposomes with 1.0mg/ml nisin were selected for incorporation into nanocomposite films containing 0.5g/l halloysite. The films presented antimicrobial activity against Listeria monocytogenes, Clostridium perfringens and Bacillus cereus. Scanning electron microscopy revealed that the films had a smooth surface, but showed increased roughness with addition of liposomes and halloysite. Casein films were thinner and slightly yellowish, less rigid and very elastic as compared with gelatin films. Thermogravimetric analysis showed a decrease of the degradation temperature for casein films added with liposomes. The glass transition temperature decreased with addition of liposomes and halloysite. Gelatin and casein films containing nisin-loaded liposomes and halloysite represent an interesting alternative for development of active food packaging. Copyright © 2016 Elsevier B.V. All rights reserved.

Metallochelating liposomes with associated lipophilised norAbuMDP as biocompatible platform for construction of vaccines with recombinant His-tagged 3 antigens: Preparation, structural study and immune response towards rHsp90

Czech Academy of Sciences Publication Activity Database

Mašek, J.; Bartheldyová, E.; Turánek-Knotigová, P.; Škrabalová, M.; Korvasová, Z.; Plocková, J.; Koudelka, Š.; Škodová, P.; Kulich, P.; Křupka, M.; Zachová, K.; Czerneková, L.; Horynová, M.; Kratochvílová, Irena; Miller, A. D.; Zyka, Daniel; Michálek, J.; Vrbová, J.; Šebela, M.; Ledvina, Miroslav; Raška, M.; Turánek, J.

2011-01-01

Roč. 151, č. 2 (2011), s. 193-201 ISSN 0168-3659 R&D Projects: GA ČR(CZ) GAP304/10/1951; GA AV ČR KAN200520703; GA AV ČR KAN200100801 Institutional research plan: CEZ:AV0Z10100520; CEZ:AV0Z40550506 Keywords : recombinant vaccine * liposome Subject RIV: EC - Immunology Impact factor: 5.732, year: 2011 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3D-520M1P7-1&_user=625012&_coverDate=01%2F21%2F2011&_rdoc=1&_fmt=high&_orig=gateway&_origi

18F-DOPA PET/CT for assessment of response to induction chemotherapy in a child with high-risk neuroblastoma

International Nuclear Information System (INIS)

Piccardo, Arnoldo; Lopci, Egesta; Foppiani, Luca; Morana, Giovanni; Conte, Massimo

2014-01-01

Functional imaging plays a crucial role in the assessment of neuroblastoma. The evaluation of response to induction chemotherapy is a cornerstone in scheduling proper treatment management in patients affected by high-risk neuroblastoma. 123 I-metaiodobenzylguanidine has been recognized as the radiopharmaceutical of choice in neuroblastoma assessment. To date, the clinical role of PET/CT in pediatric malignancy is not well established. 18 F-DOPA-PET/CT has been recently used in neuroblastoma, and compared with 123 I-MIBG-scan. Scant new data are available about the role of this tool in the evaluation of treatment response after induction chemotherapy. We investigate the role of 18 F-DOPA-PET/CT in characterizing the response to induction chemotherapy in a child affected by high-risk-neuroblastoma, in whom the rare association of 123 I-MIBG-negative primary tumor and MIBG-positive bone marrow metastases was observed. (orig.)

18F-fluoromisonidazole (FMISO) and 18F-fluorodeoxyglucose (FDG) PET in patients undergoing radiotherapy or chemotherapy following surgery for high-grade glioma

International Nuclear Information System (INIS)

Lee, S. T.

2009-01-01

Full text:Background: Tumour hypoxia is associated with disease progression and resistance to therapy. High grade cerebral gliomas have a poor outcome despite advancements in chemotherapy and radiotherapy. 18F-fluoromisonidazole (18F-FMISO) concentrates in hypoxic cells and is associated with tumour grade in gliomas. The aim of this study was to compare the patterns of uptake of 18F-FDG PET and 18F-FMISO PET post-surgery with MRI and areas of recurrence post-radiotherapy. Methods: Patients with high grade cerebral glioma were recruited into this prospective study. All patients had post-surgical, pre-radiotherapy 18F-FDG, 18F-FMISO and MRI scans, which were all repeated 4-6 weeks post-completion to radiotherapy. The patients were followed-up clinically three monthly and re-imaged if indicated. Results: Ten patients were enrolled in this study, mean age 62 years (range 55-69 years), who all had pre-radiotherapy scans performed. Seven patients had scans done pre- and post-radiotherapy, with 3 patients with only pre-therapy scans. Nine patients had significant FMISO uptake and 8 patients demonstrated abnormal FDG uptake. The areas of FMISO uptake on pre-radiotherapy scans correlated with the most abnormal areas of contrast-enhancement on pre-treatment MRI and areas of locally recurrent disease on post-treatment MRI in eight patients. Nine patients had locally recurrent disease on follow-up MRI. FMISO was more predictive of tumour recurrence compared to FDG. Conclusion: Post-surgical 18F-FMISO PET in patients with cerebral glioma is more predictive of areas of recurrent disease compared to 18F-FDG PET.

Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study

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Zhang Y

2016-01-01

TURBT (P<0.001. The progression rate was 10.6% for patients who underwent intravesical chemotherapy alone and 2.3% for patients who underwent the combined chemotherapies (P=0.003. Kaplan–Meier curves showed significant differences in recurrence-free survival and progression-free survival between the two treatment strategies, with a log-rank P-value of <0.001 and 0.003, respectively. Multivariable analyses revealed that intravenous chemotherapy was the independent prognostic factor for tumor recurrence and progression in the cohort. Conclusion: Intravenous chemotherapy combined with intravesical chemotherapy offers a better oncologic outcome than the intravesical chemotherapy alone for patients with T1G3 bladder urothelial carcinoma after TURBT, and it may be considered as a new therapy strategy for T1G3 bladder cancer. Keywords: bladder, intravenous chemotherapy, recurrence, progression

Assessment of the tumor load as well as toxic and side effects after herceptin combined with doxorubicin liposome treatment of HER-2 positive breast cance

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Guo-Quan Wen

2016-12-01

Full Text Available Objective: To study the effect of herceptin combined with doxorubicin liposome treatment on tumor load as well as toxic and side effects of HER-2 positive breast cancer. Methods: A total of 138 patients with HER-2 positive breast cancer who received chemotherapy in our hospital between July 2014 and December 2015 were selected as the research subjects and randomly divided into two groups, liposome group received herceptin combined with doxorubicin liposome treatment and control group received herceptin combined with doxorubicin treatment. After 8 weeks of treatment, the content of tumor markers, active molecules and myocardial injury markers in serum as well as the expression levels of immune marker molecules in peripheral blood mononuclear cells were detected. Results: After 8 weeks of treatment, CEA, CA199, CA153, CA125, VEGF, nectin-4, TK-1, PF-4, TSGF, CK, CK-MB, cTnI and cTnT content in serum of liposome group were significantly lower than those of control group, and the fluorescence intensity of CD3, CD4, CD8, CD16, CD19 and CD25 on peripheral blood mononuclear cell surface were significantly higher than those of control group. Conclusions: Herceptin combined with doxorubicin liposome treatment of HER-2 positive breast cancer can more effectively reduce the tumor load and cause less toxic and side effects on the heart and the immune system.

Pegylated liposomal doxorubicin (Lipo-Dox®) combined with cyclophosphamide and 5-fluorouracil is effective and safe as salvage chemotherapy in taxane-treated metastatic breast cancer: an open-label, multi-center, non-comparative phase II study

International Nuclear Information System (INIS)

Rau, Kun-Ming; Lin, Yung-Chang; Chen, Yen-Yang; Chen, Jen-Shi; Lee, Kuan-Der; Wang, Cheng-Hsu; Chang, Hsien-Kun

2015-01-01

Anthracycline and taxane are classes of drugs that are frequently used in the adjuvant and palliative settings of metastatic breast cancer (MBC); however, treatment failure occurs in most cases. Limited data demonstrated favorable response in MBC after previous taxane-based treatment. The aim of this study was to evaluate the efficacy and safety of pegylated liposomal doxorubicin (Lipo-Dox®) used as part of a combination salvage therapy for patients with MBC whose tumors progressed during or after taxane-based treatment. Patients with MBC who failed to respond to previous taxane-based treatments were recruited. Treatment with pegylated liposomal doxorubicin (40 mg/m 2 ), cyclophosphamide (500 mg/m 2 ), and 5-fluorouracil (500 mg/m 2 ) was administered every 3 weeks. Tumor response to treatment was determined by using the Response Evaluation Criteria in Solid Tumor criteria version 1.0, and left ventricular ejection fraction was measured before and after treatment using echocardiography. Each patient was followed for 30 days after the last dose of study medication or until resolution/stabilization of any drug-related adverse event. Forty-five patients were recruited. As of December 2012, the median follow-up duration was 29.8 months, the overall response rate was 41.9 %, the median progression-free survival was 8.2 months, and the median overall survival was 36.6 months for all treated patients. Grade 3/4 neutropenia, leucopenia, and neutropenic fever were observed in 14 %, 9 %, and 1 % of the cycles, respectively. Other non-hematologic adverse effects were mild to moderate and were manageable. No decrease in left ventricular ejection function was noted. This regimen of combined of pegylated liposomal doxorubicin, cyclophosphamide, and 5-fluorouracil exhibited a promising overall response rate, progression-free survival rate, and overall survival rate, with a safe cardiac toxicity profile and manageable adverse effects. This regimen could be considered as a

Chemotherapy effectiveness and mortality prediction in surgically treated osteosarcoma dogs: A validation study.

Science.gov (United States)

Schmidt, A F; Nielen, M; Withrow, S J; Selmic, L E; Burton, J H; Klungel, O H; Groenwold, R H H; Kirpensteijn, J

2016-03-01

Canine osteosarcoma is the most common bone cancer, and an important cause of mortality and morbidity, in large purebred dogs. Previously we constructed two multivariable models to predict a dog's 5-month or 1-year mortality risk after surgical treatment for osteosarcoma. According to the 5-month model, dogs with a relatively low risk of 5-month mortality benefited most from additional chemotherapy treatment. In the present study, we externally validated these results using an independent cohort study of 794 dogs. External performance of our prediction models showed some disagreement between observed and predicted risk, mean difference: -0.11 (95% confidence interval [95% CI]-0.29; 0.08) for 5-month risk and 0.25 (95%CI 0.10; 0.40) for 1-year mortality risk. After updating the intercept, agreement improved: -0.0004 (95%CI-0.16; 0.16) and -0.002 (95%CI-0.15; 0.15). The chemotherapy by predicted mortality risk interaction (P-value=0.01) showed that the chemotherapy compared to no chemotherapy effectiveness was modified by 5-month mortality risk: dogs with a relatively lower risk of mortality benefited most from additional chemotherapy. Chemotherapy effectiveness on 1-year mortality was not significantly modified by predicted risk (P-value=0.28). In conclusion, this external validation study confirmed that our multivariable risk prediction models can predict a patient's mortality risk and that dogs with a relatively lower risk of 5-month mortality seem to benefit most from chemotherapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Liposomal Bupivacaine for Pain Control After Anterior Cruciate Ligament Reconstruction: A Prospective, Double-Blinded, Randomized, Positive-Controlled Trial.

Science.gov (United States)

Premkumar, Ajay; Samady, Heather; Slone, Harris; Hash, Regina; Karas, Spero; Xerogeanes, John

2016-07-01

Local anesthetics are commonly administered into surgical sites as a part of multimodal pain control regimens. Liposomal bupivacaine is a novel formulation of bupivacaine designed for slow diffusion of a single dose of local anesthetic over a 72-hour period. While early results are promising in various settings, no studies have compared pain management regimens containing liposomal bupivacaine to traditional regimens in patients undergoing anterior cruciate ligament (ACL) reconstruction. To evaluate liposomal bupivacaine in comparison with 0.25% bupivacaine hydrochloride (HCl) for pain control after ACL reconstruction. Randomized controlled trial; Level of evidence, 1. A total of 32 adult patients undergoing primary ACL reconstruction with a soft tissue quadriceps tendon autograft between July 2014 and March 2015 were enrolled. All patients received a femoral nerve block immediately before surgery. Patients then received either a 40-mL suspension of 20 mL Exparel (1 vial of bupivacaine liposome injectable suspension) and 20 mL 0.9% injectable saline or 20 mL 0.5% bupivacaine HCl and 20 mL 0.9% injectable saline, which was administered into the graft harvest site and portal sites during surgery. Patients were given either a postoperative smartphone application or paper-based journal to record data for 1 week after ACL reconstruction. Of the 32 patients recruited, 29 patients were analyzed (90.6%). Two patients were lost to follow-up, and 1 was excluded because of a postoperative hematoma. There were no statistically significant differences in postoperative pain, medication use, pain location, recovery room time, or mobility between the 2 study groups. There were comparable outcomes with 0.25% bupivacaine HCl at a 200-fold lower cost than liposomal bupivacaine. This study does not support the widespread use of liposomal bupivacaine for pain control after ACL reconstruction in the setting of a femoral nerve block. ClinicalTrials.gov NCT02189317. © 2016 The Author(s).

Directed Evolution of Proteins through In Vitro Protein Synthesis in Liposomes

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Takehiro Nishikawa

2012-01-01

Full Text Available Directed evolution of proteins is a technique used to modify protein functions through “Darwinian selection.” In vitro compartmentalization (IVC is an in vitro gene screening system for directed evolution of proteins. IVC establishes the link between genetic information (genotype and the protein translated from the information (phenotype, which is essential for all directed evolution methods, by encapsulating both in a nonliving microcompartment. Herein, we introduce a new liposome-based IVC system consisting of a liposome, the protein synthesis using recombinant elements (PURE system and a fluorescence-activated cell sorter (FACS used as a microcompartment, in vitro protein synthesis system, and high-throughput screen, respectively. Liposome-based IVC is characterized by in vitro protein synthesis from a single copy of a gene in a cell-sized unilamellar liposome and quantitative functional evaluation of the synthesized proteins. Examples of liposome-based IVC for screening proteins such as GFP and β-glucuronidase are described. We discuss the future directions for this method and its applications.

Liposome imaging agents in personalized medicine

DEFF Research Database (Denmark)

Petersen, Anncatrine Luisa; Hansen, Anders Elias; Gabizon, Alberto

2012-01-01

In recent years the importance of molecular and diagnostic imaging has increased dramatically in the treatment planning of many diseases and in particular in cancer therapy. Within nanomedicine there are particularly interesting possibilities for combining imaging and therapy. Engineered liposomes...... that selectively localize in tumor tissue can transport both drugs and imaging agents, which allows for a theranostic approach with great potential in personalized medicine. Radiolabeling of liposomes have for many years been used in preclinical studies for evaluating liposome in vivo performance and has been...... start to consider how to use imaging for patient selection and treatment monitoring in connection to nanocarrier based medicines. Nanocarrier imaging agents could furthermore have interesting properties for disease diagnostics and staging. Here, we review the major advances in the development...

Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier

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Wang X

2014-10-01

Full Text Available Xiang Wang,1 Ping Liu,1 Weixiao Yang,1 Lu Li,1 Peijing Li,2 Zheng Liu,1 Zhongxiong Zhuo,1 Yunhua Gao1 1Department of Ultrasound, Xinqiao Hospital of the Third Military Medical University, Chongqing, 2Department of Ultrasound, General Hospital of the Jinan Military Area, Jinan, People’s Republic of China Abstract: Methotrexate (MTX is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%±0.86%, and their size (2.64±0.93 µm in diameter was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood–brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3±2.4 µg/g > unmodified ZHIFUXIAN + MTX + ultrasound (18.6±2.2 µg/g > MTX alone (6.97±0.75 µg/g > MTX-liposome-coupled microbubbles (2.92±0.39 µg/g. Therefore

Mild hydrothermal crystal growth of new uranium(IV) fluorides, Na3.13Mg1.43U6F30 and Na2.50Mn1.75U6F30: Structures, optical and magnetic properties

Science.gov (United States)

Yeon, Jeongho; Smith, Mark D.; Tapp, Joshua; Möller, Angela; zur Loye, Hans-Conrad

2016-04-01

Two new uranium(IV) fluorides, Na3.13Mg1.43U6F30 (1) and Na2.50Mn1.75U6F30 (2), were synthesized through an in situ mild hydrothermal route, and were structurally characterized by single crystal X-ray diffraction. The compounds exhibit complex crystal structures composed of corner- or edge-shared UF9 and MF6 (M=Mg, Mn) polyhedra, forming hexagonal channels in the three-dimensional framework, in which ordered or disordered divalent metal and sodium atoms reside. The large hexagonal voids contain the nearly regular M(II)F6 octahedra and sodium ions, whereas the small hexagonal cavities include M(II) and sodium ions on a mixed-occupied site. Magnetic susceptibility measurements yielded effective magnetic moments of 8.36 and 11.6 μB for 1 and 2, respectively, confirming the presence and oxidation states of U(IV) and Mn(II). The large negative Weiss constants indicate the spin gap between a triplet and a singlet state in the U(IV). Magnetization data as a function of applied fields revealed that 2 exhibits paramagnetic behavior due to the nonmagnetic singlet ground state of U(IV) at low temperature. UV-vis diffuse reflectance and X-ray photoelectron spectroscopy data were also analyzed.

Self-rated cognitive functions following chemotherapy in patients with breast cancer: a 6-month prospective study

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Kitahata R

2017-10-01

Full Text Available Ryosuke Kitahata,1 Shinichiro Nakajima,1–4 Hiroyuki Uchida,1,3 Tetsu Hayashida,5 Maiko Takahashi,5 Shintaro Nio,1 Jinichi Hirano,1 Maki Nagaoka,1 Takefumi Suzuki,1 Hiromitsu Jinno,6 Yuko Kitagawa,5 Masaru Mimura1 1Psychopharmacology Research Program, Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan; 2Multimodal Imaging Group – Research Imaging Centre, 3Geriatric Mental Health Division, Centre for Addiction and Mental Health, 4Department of Psychiatry, University of Toronto, Toronto, Canada; 5Department of Surgery, School of Medicine, Keio University, 6Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan Purpose: The purpose of the study was to evaluate subjective (self-rated, family-rated, and objective (researcher-rated cognitive functions in patients with breast cancer after chemotherapy.Method: We conducted a prospective study to trace self-rated cognitive functions in 30 patients with breast cancer at the completion of chemotherapy (T0 and 6 months later (T1. Subjective cognitive functions were assessed with Cognitive Failures Questionnaire (CFQ, Dysexecutive Questionnaire (DEX-S, and Everyday Memory Checklist (EMC-S for attention, executive function, and episodic memory, respectively. Their family members also completed DEX-I and EMC-I for executive function and episodic memory, respectively. We also examined objective cognitive functions. Self-rated cognitive functions were compared with the normative data. They were compared between T0 and T1. We calculated correlation coefficients between self-rated and other cognitive functions.Results: At T0, 6 (20.0% and 2 (6.7% participants showed higher DEX-S and EMC-S scores than the normative data, respectively, while no participant had abnormal CFQ scores. At T1, DEX-S and EMC-S scores were normalized in 3 (50.0% and 2 (100.0% participants, respectively. No participant showed increases in CFQ scores. No changes were found in objective

[18F]FE@SNAP—A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): Microfluidic and vessel-based approaches

Science.gov (United States)

Philippe, Cécile; Ungersboeck, Johanna; Schirmer, Eva; Zdravkovic, Milica; Nics, Lukas; Zeilinger, Markus; Shanab, Karem; Lanzenberger, Rupert; Karanikas, Georgios; Spreitzer, Helmut; Viernstein, Helmut; Mitterhauser, Markus; Wadsak, Wolfgang

2012-01-01

Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable method. After the successful radiosynthesis of [11C]SNAP-7941—the first PET-Tracer for the MCHR1, we aimed to synthesize its [18F]fluoroethylated analogue: [18F]FE@SNAP. Therefore, microfluidic and vessel-based approaches were tested. [18F]fluoroethylation was conducted via various [18F]fluoroalkylated synthons and direct [18F]fluorination. Only the direct [18F]fluorination of a tosylated precursor using a flow-through microreactor was successful, affording [18F]FE@SNAP in 44.3 ± 2.6%. PMID:22921745

Basic hydrolysis of 1, 3, 4, 6-tetra-O-acetyl-2-[18F] fluoro-D-glucose on solid phase extraction

International Nuclear Information System (INIS)

Zhang Jinming; Tian Jiahe; He Yijie; Huan Dingcai; Liu Boli

2003-01-01

A new base hydrolysis method are used for 1, 3, 4, 6-tetra-O-acetyl-2-[ 18 F] fluoro-D-glucose on solid phase extraction. The labeled intermediate is trapped on an active C-18 solid phase extraction cartridge, and hydrolyzed in cartridge with 1 mL 2 mol/L NaOH at room temperature. The results show that there are over 99% of the labeled intermediate being turned into 18 F-FDG within 2 min. It is easy to get 18 F-FDG after neutralized with phosphate buffer, purified by C-18 and Alumina cartridge. The basic hydrolysis on solid extraction is a simple method for preparation of 18 F-FDG

Liposomes to target peripheral neurons and Schwann cells.

Directory of Open Access Journals (Sweden)

Sooyeon Lee

Full Text Available While a wealth of literature for tissue-specific liposomes is emerging, optimal formulations to target the cells of the peripheral nervous system (PNS are lacking. In this study, we asked whether a novel formulation of phospholipid-based liposomes could be optimized for preferential uptake by microvascular endothelia, peripheral neurons and Schwann cells. Here, we report a unique formulation consisting of a phospholipid, a polymer surfactant and cholesterol that result in enhanced uptake by targeted cells. Using fluorescently labeled liposomes, we followed particle internalization and trafficking through a distinct route from dextran and escape from degradative compartments, such as lysosomes. In cultures of non-myelinating Schwann cells, liposomes associate with the lipid raft marker Cholera toxin, and their internalization is inhibited by disruption of lipid rafts or actin polymerization. In contrast, pharmacological inhibition of clathrin-mediated endocytosis does not significantly impact liposome entry. To evaluate the efficacy of liposome targeting in tissues, we utilized myelinating explant cultures of dorsal root ganglia and isolated diaphragm preparations, both of which contain peripheral neurons and myelinating Schwann cells. In these models, we detected preferential liposome uptake into neurons and glial cells in comparison to surrounding muscle tissue. Furthermore, in vivo liposome administration by intramuscular or intravenous injection confirmed that the particles were delivered to myelinated peripheral nerves. Within the CNS, we detected the liposomes in choroid epithelium, but not in myelinated white matter regions or in brain parenchyma. The described nanoparticles represent a novel neurophilic delivery vehicle for targeting small therapeutic compounds, biological molecules, or imaging reagents into peripheral neurons and Schwann cells, and provide a major advancement toward developing effective therapies for peripheral

Multicenter retrospective study of cetuximab plus platinum-based chemotherapy for recurrent or metastatic oral squamous cell carcinoma.

Science.gov (United States)

Yanamoto, Souichi; Umeda, Masahiro; Kioi, Mitomu; Kirita, Tadaaki; Yamashita, Tetsuro; Hiratsuka, Hiroyoshi; Yokoo, Satoshi; Tanzawa, Hideki; Uzawa, Narikazu; Shibahara, Takahiko; Ota, Yoshihide; Kurita, Hiroshi; Okura, Masaya; Hamakawa, Hiroyuki; Kusukawa, Jingo; Tohnai, Iwai

2018-03-01