Delivery of Doxorubicin to Solid Tumors Using Thermosensitive Liposomes
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1140-HH13-14
Delivery of Doxorubicin to Solid Tumors Using Thermosensitive Liposomes
Elizaveta V. Tazina, Alevtina P. Polozkova, Elena V. Ignatieva, Olga L. Orlova, Valeria V. Mescherikova, Adolf A. Wainson, Natalia A. Oborotova, Anatoliy Yu. Baryshnikov Research Institute of Experimental Diagnostics and Therapy of Tumors, N.N. Blokhin Russian Cancer Research Center of RAMS, 24 Kashirskoye shosse, 115478, Moscow, Russian Federation ABSTRACT Liposomal drugs currently in clinical use are characterized primarily by their decreased side effects rather than improved therapeutic potency. Significant improvements in the efficacy of liposomal drug therapy may be obtained using thermosensitive liposomes (TSL) in combination with local hyperthermia (HT). The purpose of present work was preparation of TSL loaded with doxorubicin (Dox) and investigation of their effect on B-16 mouse melanoma and Ehrlich (line ELD) carcinoma in combination with HT. TSL were prepared using 1,2dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, PEGylated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, cholesterol and α-tocopherol acetate in molar ratios of 9:1:0.02:0.2:0.2 (composition 1); 9:1:0.1:0.5 (composition 2); 9:1:0.2:0.75 (composition 3); 9:1:0.3:1 (composition 4); 9:1:0.4:1.2 (composition 5). Dox was loaded into TSL by ammonium ion gradient. Efficacy of Dox encapsulation in TSL of compositions 4 and 5 was 60 % (diameter of vesicles was 175 ± 10 nm). TSL of compositions 2 and 3 encapsulated 88 % and 86 % of Dox, respectively (diameter of vesicles was 160 ± 10 nm). TSL of composition 1 trapped 88-94 % of Dox (diameter of vesicles was 175 ± 15 nm). Anticancer efficacy of Dox-TSL (composition 1) and free Dox was compared in biological experiments. The doubling time of B-16 melanoma was 9 days after heating on a background of Dox injection at dose of 9 mg/kg, while heating of tumors after injection of Dox-TSL at doses of 4.5 and 9 mg/kg increased tumor doubling time up to 12 and 16 days, respectively. The doubling time of Ehrlich carcinoma increased from 3 days in the control group up to 14 days for the group of mice administered 9 mg/kg of Dox-TSL followed by HT in 15-20 min. Thus, Dox-TSL in combination with HT has shown more efficiency than free Dox in suppression of tumor growth. INTRODUCTION Liposomes are lipid vesicles with an aqueous interior size between 50 nm and 200 nm in diameter. They form spontaneously when certain lipids are dispersed in aqueous medium. To circumvent the rapid uptake of liposomes in liver and spleen after intravenous application, the surface of liposomes has been modified with poly(ethylene glycol) (PEG) [1]. These PEGliposomes show extended plasma half lives of several hours in humans enabling passive
accumulation of liposomes in solid tumors, where the microvessels are leakier (Enhanced Permeability and Retention (EPR) effect) [2]. Liposomes are now recognized for their ability to increase the therapeutic activity and/or reduce the toxicity of selected encapsulated chemoth
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