Effects of Lipid Composition and Preparation Conditions on Physical-Chemical Properties, Technological Parameters and In Vitro Biological Activity of Gemcitabine-Loaded Liposomes (original) (raw)
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Pharmaceutical Development and Technology, 2017
The aim of this study is to formulate and compare the physicochemical properties of negatively-charged liposomes and poly-lactide-co-glycolide (PLGA) nanoparticles loaded with gemcitabine hydrochloride. The influence of the formulation variables on the liposome and nanoparticle properties on particle size, zeta potential, encapsulation efficiency and drug release were evaluated. Although the PEGylated nanoparticles and PEGylated liposomes were of the same size (~200 nm), the encapsulation efficiency was 1.4 times higher for PEGylated liposomes than for PEGylated nanoparticles. The optimized formulation of PEGylated liposomes and PEGylated nanoparticles had 26.1 ± 0.18 and 18.8 ± 1.52% encapsulation efficiency, respectively. The release of drug from the PEGylated liposomes and PEGylated nanoparticles exhibited a biphasic pattern that was characterized by a fast initial release during the first 2 h followed by a slower continuous release. Transmission electron microscopy (TEM) images identified separate circular structures of the liposomes and nanoparticles. The in vitro cytotoxicity of the optimized formulations was assessed in MCF-7 and MDA-MB-231 cells, the results showed that the cytotoxicity effect of the gemcitabine hydrochloride loaded liposomes and nanoparticles were more than commercial product Gemko ® and gemcitabine hydrochloride solution.
Gemcitabine-loaded liposomes: rationale, potentialities and future perspectives
International Journal of Nanomedicine, 2012
This review describes the strategies used in recent years to improve the biopharmaceutical properties of gemcitabine, a nucleoside analog deoxycytidine antimetabolite characterized by activity against many kinds of tumors, by means of liposomal devices. The main limitation of using this active compound is the rapid inactivation of deoxycytidine deaminase following administration in vivo. Consequently, different strategies based on its encapsulation/complexation in innovative vesicular colloidal carriers have been investigated, with interesting results in terms of increased pharmacological activity, plasma half-life, and tumor localization, in addition to decreased side effects. This review focuses on the specific approaches used, based on the encapsulation of gemcitabine in liposomes, with particular attention to the results obtained during the last 5 years. These approaches represent a valid starting point in the attempt to obtain a novel, commercializable drug formulation as already achieved for liposomal doxorubicin (Doxil ® , Caelyx ®).
Journal of Nanoscience and Nanotechnology, 2008
Anaplastic thyroid carcinoma is one of the most aggressive and lethal solid carcinomas affecting humans. A major limit of the chemotherapeutic agents is represented by their low therapeutic index. In this work, we investigated the possibility of improving the anti-tumoral activity of gemcitabine by using pegylated unilamellar liposomes. Liposomes were made up of 1,2-dipalmitoyl-sn-glycero-3-phospocholine monohydrate/cholesterol/N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (6:3:1 molar ratio) and they were prepared with a pH gradient to improve the gemcitabine loading capacity. The anti-tumoral efficacy of the liposomal formulation was tested in vitro on human anaplastic thyroid carcinoma cells (ARO) in culture, comparing the effects with those of the free drug. Gemcitabine-loaded unilamellar liposomes had a mean size ∼200 nm with a zeta potential ∼–2mV. The liposomal carrier noticeably improved the anti-tumoral activity of gemcitabine ...
Pharmaceutical Research, 2014
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Enhanced Tumor Targeting and Antitumor Activity of Gemcitabine Encapsulated Stealth Liposome’s
Indian Journal of Pharmaceutical Education and Research, 2015
Introduction Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. Cancer is not just one disease but many diseases. There are more than 200 different types of cancer [1-4]. For instance, although there are numerous anticancer agents that are highly cytotoxic to tumor cells in vitro, the lack of selective antitumor effect in vivo precludes their use in clinic. One of the major limitations of antineoplastic drugs is their low therapeutic index (TI), i.e. the dose required to produce anti-tumor effect is toxic to normal tissues. Liposomes are spherical vesicles composed of lipid bilayers arranged around a central aqueous core. The particle size of liposomes ranges from 20 nm to 10 μm in diameter. They can be composed of natural constituents such as phospholipids and may mimic naturally occurring cell membranes. Liposomes have the ability to incorporate lipophilic and hydrophilic drugs within their phospholipid membrane or they can encapsulate hydrophilic compounds within the aqueous core [6]. Gemcitabine is new cytotoxic drug but some of limitations while its use likes it suppress the activity of bone marrow i.e. effect on blood forming cells. Higher water solubility needs to improve encapsulation efficiency for better therapeutics effect. Stealth liposomes by pH gradient technology lower half life-7-18 min, unable to deliver by oral and other route. Higher dose-1000-1250 mg/m2 require against malignancies are effective against various solid tumor like colon, lungs, breast etc [7, 8]. Sterically stabilized liposomes can be formulated by incorporating hydrophilic long-chain polymers (PEG) in the bilayer which can form a coat on the liposome surface and repel opsonin penetration and adsorption. Reduction in 'marking' by opsonins leads to slower uptake of these liposomes (LCL) by the cells of reticuloendothelial system (RES) [9]. In present investigation focuses on to perform innovative research work is to avoid the problem associated with gemcitabine use and effective against solid tumor with minimum toxic effect by incorporating it in stealth liposomes. Materials and Methods Materials Gemcitabine was obtained as gift sample from Sun Pharma Pvt Ltd, Vadodara, (DPPC) 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine, Soya PC, (DSPE-MPEG-2000) 1,2-Distearoyl-sn-glycero-3phosphoethanolamine-methyl-polyethyleneglycol conjugate-2000 Na+ salt, Cholesterol was obtained from Lipoid GmbH, Ludwigshafen, Germany, Chloroform, Methanol, and other chemical was purchased from Loba Chemicals, Mumbai. All other solvent and reagents were of analytical grade.
Tumor-specific delivery of gemcitabine with activatable liposomes
Journal of Controlled Release, 2019
Gemcitabine delivery to pancreatic ductal adenocarcinoma is limited by poor pharmacokinetics, dense fibrosis and hypo-vascularization. Activatable liposomes, with drug release resulting from local heating, enhance serum stability and circulation, and the released drug retains the ability to diffuse within the tumor. A limitation of liposomal gemcitabine has been the low loading efficiency. To address this limitation, we used the superior solubilizing potential of copper(II) gluconate to form a complex with gemcitabine at copper:gemcitabine (1:4). Thermosensitive liposomes composed of DPPC:DSPC:DSPE-PEG2k (80:15:5, mole%) then reached 12 weight % loading, 4-fold greater than previously reported values. Cryo transmission electron microscopy confirmed the presence of a liquid crystalline gemcitabine-copper mixture. The optimized gemcitabine liposomes released 60% and 80% of the gemcitabine within 1 and 5 min, respectively, at 42°C. Liposomal encapsulation resulted in a circulation half-life of ~2 h in vivo (compared to reported circulation of 16 min for free gemcitabine in mice), and free drug was not detected within the plasma. The resulting gemcitabine liposomes were efficacious against both murine breast cancer and pancreatic cancer in vitro. Three repeated treatments of activatable gemcitabine liposomes plus ultrasound hyperthermia regressed or eliminated tumors in the neu deletion model *
Development of liposomal gemcitabine with high drug loading capacity
Molecular Pharmaceutics
Liposomes are widely used for systemic delivery of chemotherapeutic agents to reduce their nonspecific side effects. Gemcitabine (Gem) makes a great candidate for liposomal encapsulation due to the short half-life and non-specific side effects; however, it has been difficult to achieve liposomal Gem with high drug loading capacity. Remote loading, which uses a transmembrane pH
Hyaluronic acid-coated liposomes for active targeting of gemcitabine
European Journal of Pharmaceutics and Biopharmaceutics, 2013
The aim of this work was the preparation, characterization, and preliminary evaluation of the targeting ability toward pancreatic adenocarcinoma cells of liposomes containing the gemcitabine lipophilic prodrug [4-(N)-lauroyl-gemcitabine, C12GEM]. Hyaluronic acid (HA) was selected as targeting agent since it is biodegradable, biocompatible, and can be chemically modified and its cell surface receptor CD44 is overexpressed on various tumors.
European Journal of Pharmaceutics and Biopharmaceutics, 2014
Stealth pH-responsive liposomes for the delivery of therapeutic proteins to the bladder epithelium were prepared using methoxy-poly(ethylene glycol) 5kDa-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (mPEG 5kDa-DSPE) and stearoyl-poly(ethylene glycol)-poly(methacryloyl sulfadimethoxine) copolymer (stearoyl-PEG-polySDM), which possesses an apparent pKa of 7.2. Liposomes of 0.2:0.6:100, 0.5:1.5:100 and 1:3:100 mPEG 5kDa-DSPE/stearoyl-PEG-polySDM/(soybean phosphatidylcholine + cholesterol) molar ratios were loaded with bovine serum albumin (BSA) as a protein model. The loading capacity was 1.3% w/w BSA/lipid. At pH 7.4, all liposome formulations displayed a negative zeta-potential and were stable for several days. By pH decrease or addition to mouse urine, the zeta potential strongly decreased, and the liposomes underwent a rapid size increase and aggregation. Photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM) analyses showed that the extent of the aggregation depended on the stearoyl-PEG-polySDM/lipid molar ratio. Cytofluorimetric analysis and confocal microscopy showed that at pH 6.5, the incubation of MB49 mouse bladder cancer cells and macrophages with fluorescein isothiocyanate-labelled-BSA (FITC-BSA) loaded and N-(Lissamine Rhodamine B sulfonyl)-1, 2-dihexadecanoyl-sn-glycero-3phosphoethanolamine triethylammonium salt (rhodamine-DHPE) labelled 1:3:100 mPEG 5kDa-DSPE/stearoyl-PEG-polySDM/lipid molar ratio liposomes resulted in a time-dependent liposome association with the cells. At pH 7.4, the association of BSA-loaded liposomes with the MB49 cells and macrophages was remarkably lower than at pH 6.5. Confocal images of bladder sections revealed that 2 h after the instillation, liposomes at pH 7.4 and control non-responsive liposomes at pH 7.4 or 6.5 did not associate nor delivered FITC-BSA to the bladder epithelium. On the contrary, the pH-responsive liposome formulation set at pH 6.5 and soon administered to mice by bladder instillation showed that, 2 h after administration, the pH-responsive liposomes efficiently delivered the loaded FITC-BSA to the bladder epithelium.
Journal of Controlled Release, 2010
The systemic efficacy of the chemotherapeutic agents presently used to treat solid tumors is limited by their low therapeutic index. Previously, our research group improved the in vitro antitumoral activity of gemcitabine, an anticancer agent rapidly deaminated to the inactive metabolite 2′,2′-difluorodeoxyuridine, entrapping it into unilamellar pegylated liposomes made up of 1,2-dipalmitoyl-snglycero-3-phosphocholine monohydrate/cholesterol/N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3phosphoethanolamine (6:3:1 molar ratio). In this work, we investigated the in vivo efficiency of the gemcitabine liposomal formulation (5 mg/kg) with respect to the antitumoral commercial product GEMZAR ® (50 mg/kg) on an anaplastic thyroid carcinoma xenograft model obtaining similar effects in terms of inhibition of tumor mass proliferation after 4 weeks of treatment. The investigation of the carrier biodistribution and the drug pharmacokinetic profile furnished the rationalization of the efficacy of the vesicular system containing the active compound 10-fold less concentrated; in fact, liposomes promoted the concentration of the drug inside the tumor and they increased its plasmatic half-life. In addition, no signs of blood toxicity were observed when vesicular devices of effective doses of the drug were used.