Polyethylene glycol-complexed cationic liposome for enhanced cellular uptake and anticancer activity
ABSTRACT Liposomes as one of the efficient drug carriers have some shortcomings such as their relatively short blood circulation time, fast clearance from human body by reticuloendothelial system (RES) and limited intracellular uptake to target cells. In this study, polyethylene glycol (PEG)-complexed cationic liposomes (PCL) were prepared by ionic complex of cationically charged liposomes with carboxylated polyethylene glycol (mPEG-COOH). The cationic liposomes had approximately 98.6+/-1.0 nm of mean particle diameter and 45.5+/-1.1 mV of zeta potential value. While, the PCL had 110.1+/-1.2 nm of mean particle diameter and 18.4+/-0.8 mV of zeta potential value as a result of the ionic complex of mPEG-COOH with cationic liposomes. Loading efficiency of model drug, doxorubicin, into cationic liposomes or PCL was about 96.0+/-0.7%. Results of intracellular uptake evaluated by flow cytometry and fluorescence microscopy studies showed higher intracellular uptake of PCL than that of Doxil. In addition, in vitro cytotoxicity of PCL was comparable to cationic liposomes. In pharmacokinetic study in rats, PCL showed slightly lower plasma level of DOX than that of Doxil. In vivo antitumor activity of DOX-loaded PCL was comparable to that of Doxil against human SKOV-3 ovarian adenocarcinoma xenograft rat model. Consequently, the PCL, of which surface was complexed with PEG by ionic complex may be applicable as drug delivery carriers for increasing therapeutic efficacy of anticancer drugs.
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ABSTRACT: The transfection agent polycation polyethylenimine (PEI) has been rarely used to construct liposomes for chemical antitumor drugs. In this study, it was introduced into cisplatin (CDDP) encapsulated neutral liposomes (CDDP-NL) by amphiphilic PEI-cholesterol (PEI-Chol) to investigate its effect on the antitumor activity in A549 cells. The IC50 was 0.65 +/- 0.02, 2.94 +/- 0.21 and 2.03 +/- 0.15 microg/ml for CDDP-cationic liposomes (CDDP-CL), CDDP-NL and free CDDP, respectively. The enhanced anticancer activity was attributed to the addition of PEI-Chol which influenced cellular processing of CDDP. With the help of inhibitors, we found that besides clathrin dependent and actin dependent uptake pathways, caveolae-mediated endocytosis was involved in the internalization of CDDP-CL. Improved internalization of CDDP was observed. Intracellular Pt accumulations were 6.5 times and 3 times of those in CDDP-NL and free CDDP groups, respectively. The differences of intracellular location caused by endocytosis routes and lysosomes escape capacity of PEL-Chol was observed by fluorescence colocalization studies. PEI-Chol also decreased the Pt fraction exported out of cells and extended the cellular Pt retention of CDDP liposomes. In conclusion, cationic modification of liposomes with PEI is a potential and promising way for antitumor drug delivery.Pharmazie 05/2012; 67(5):426-31. DOI:10.1691/ph.2012.1116 · 1.00 Impact Factor
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ABSTRACT: Celecoxib, a selective cyclooxygenase-2 inhibitor, has shown potential anticancerous activity against majority of solid tumors especially on patients with colon cancer. However, associations of serious side effects limit the usage of celecoxib in colon cancer treatment. To address this issue and provide an alternative strategy to increase the efficacy of celecoxib, liposomal formulation of celecoxib was prepared and characterized. Anticancer activity of liposomal celecoxib on colon cancer cell HCT 15 was evaluated in vitro. Furthermore, tumor inhibition efficiency by liposomal celecoxib was studied on 7,12-dimethyl benz(a)anthracene (DMBA)-induced tumor in rat model. In order to elucidate the antioxidant activity of celecoxib-loaded liposomes, antioxidant superoxide dismutase (SOD) generation and lipid peroxide (LPx) formation in both liver and kidney tissues were examined. Characterization of the formed unilamellar liposomes revealed the formation of homogeneous suspension of neutral (empty) or anionic (celecoxib-loaded) liposomes with a well-defined spherical shape which have a mean size of 103.5 nm (empty liposome) and 169 nm (liposomal celecoxib). High-performance liquid chromatography (HPLC) analysis and hemolytic assay demonstrated 46% of celecoxib entrapment efficiency and significantly low hemolysis, respectively. Liposomal celecoxib exhibited dose-dependent cytotoxicity and apoptotic activity against HCT 15 cells which are comparable to free celecoxib. In vivo study demonstrated inhibition of tumor growth. Biochemical analysis of the liposomal celecoxib-treated group significantly inhibited the LPx formation (oxygen-free radicals) and increased the activity of SOD. Our results present the potential of inhibiting colon cancer in vitro and DMBA-induced tumor in rat model in vivo by liposomal celecoxib.12/2011; DOI:10.1007/s12645-011-0017-5
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ABSTRACT: Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.Pharmaceutical Research 03/2010; 27(7):1171-83. DOI:10.1007/s11095-010-0110-1 · 3.95 Impact Factor