Delivery of Doxorubicin to Solid Tumors Using Thermosensitive Liposomes

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 1,2-dipalmitoyi-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, PEGylated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, cholesterol and a-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.