Encapsulation of the topoisomerase I inhibitor GL147211C in pegylated (STEALTH) liposomes: Pharmacokinetics and antitumor activity in HT29 colon tumor xenografts

The topoisomerase I inhibitor GL147211C {7-[(4-methylpiperazino)methyl]-10, 11-(ethylenedioxy)-(20S)-camptothecin trifluoroacetate}, a camptothecin ana logue, has significant activity in tumor cell cytotoxicity assays in vitro and antitumor activity in both animal tumor models and human patients, Its toxicity is significant, however, effectively limiting the amount of drug t hat can be administered and its clinical utility. To determine whether the therapeutic index of GL147211C could be improved, the drug was encapsulated in long-circulating pegylated (STEALTH) liposomes (SPI-355), The pharmacok inetics and antitumor activity of SPI-355, were compared to those of nonlip osomal GL147211C. The plasma pharmacokinetics of SPI-355 in rats were typic al of those of other pegylated liposomal formulations, with significantly i ncreased blood circulation time; the dose-corrected area under the curve an d C-max of SPI-355 (10 mg/kg) were 1250- and 35-fold higher, respectively, than those of nonliposomal GL14711C (8.72 mg/kg), The comparative antitumor activity of SPI-355 and nonliposomal GL1472211C was evaluated in nude mice implanted with HT29 colon carcinoma xenografts, SPI-355 was 20-fold more e ffective than GL147211C in inhibiting tumor growth (1 mg/kg SPI-355 and 20 mg/kg GL147211C) and produced durable complete remissions of tumors at well -tolerated dose levels that were >5-fold lower than the maximally tolerated dose of GL147211C, which induced no durable complete responses. Signs of t oxicity were similar between the two drugs, but liposome encapsulation incr eased the toxicity of drug similar to 4-fold, with increased weight loss an d several deaths with SPI-355 (5 mg/kg SPI-355 versus 20 mg/kg GL147211C). Despite the increased toxicity seen with SPI-355, the therapeutic index of the liposomal formulation was increased similar to 5-fold over that of nonl iposomal GL147211C, suggesting that such a pegylated liposomal formulation could demonstrate increased therapeutic index in human patients.