(266b) Preparation of Temperature-Sensitive Liposomes for Delivery of Anticancer Drugs by Use of Thermosensitive Amphiphilic Block Copolymer

Recently, we have shown that surface modification with block copolymers of (2-ethoxy)ethoxy ethyl vinyl ether (EOEOVE) and octadecyl vinyl ether (ODVE) gives liposomes temperature-sensitive properties, such as contents release and surface hydrophobicity-hydrophilicity [1]. In this study, we investigated feasibility of the copolymer-modified liposomes as delivery system of anticancer drug adriamycin (ADR) to tumor. The copolymer with the average molecular weight of 15000 was prepared by living cationic polymerization. The copolymer underwent a coil-globule transition at ca. 40ºC in the presence of a membrane of egg yolk phosphatidylcholine (EYPC). The copolymer-modified EYPC liposomes encapsulating ADR released little ADR below 40ºC, whereas the release was strongly enhanced above this temperature, indicating that dehydrated copolymer chains destabilized the liposome membrane. Similarly, surface modification with the copolymer gave temperature-controlled release property to liposomes having poly(ethylene glycol) (PEG) grafts, which exhibit long circulating property. The copolymer-modified liposomes showed the temperature-controlled ADR release in the presence of serum or even in cells when taken up by a cell. Next, delivery of ADR to tumor of mice was examined. The ADR-loaded liposomes modified with the copolymer and PEG were injected to tumor-bearing mice from tail vein and the tumor was heated at 45ºC for 10 min 12 h after the injection of the liposomes. It was found that the growth of the tumor was strongly suppressed by the injection of the ADR-loaded temperature-responsive liposomes and heating of tumor site. When the tumor site was not heated after the injection of the ADR-loaded temperature-sensitive liposomes, the tumor growth was hardly suppressed. Because the heating of the tumor at 45ºC for 10 min did not affect the tumor growth, it is likely that the temperature-sensitive liposomes released ADR at the tumor site heated at 45ºC. Therefore, the liposomes modified with the copolymer and PEG have potential usefulness as a delivery system of anticancer drugs to tumor.

1) K. Kono, T. Murakami, T. Yoshida, Y. Haba, S. Kanaoka, T. Takagishi, S. Aoshima, Bioconjugate Chem., 16, 1367-1374 (2005).