Effective Irinotecan (CPT‐11)‐containing Liposomes: Intraliposomal Conversion to the Active Metabolite SN‐38

Irinotecan hydrochloride (CPT‐11) is a prodrug of SN‐38, which is an active metabolite with anti‐tumor activity and side toxicity. The activities of CPT‐11 and SN‐38 depend on the closed lactone ring form of SN‐38. We have examined the tissue distributions of the closed and open forms of CPT‐11 and SN‐38 in Lewis lung carcinoma‐bearing mice after the administration of liposomal CPT‐11 (S‐Lip) and polyethyleneglycol (PEG)‐modified S‐Lip (S‐PEG). The plasma concentrations of closed CPT‐11 and SN‐38 were increased by liposomalization, and their blood circulation was prolonged by the PEG modification. The concentrations of closed CPT‐11 and SN‐38 in tumors were elevated by both the liposomalization and PEG modification. The closed/total ratio of SN‐38 in the tumors of the S‐PEG group was greater than that of the CPT‐11 solution (Sol) group. Thus, SN‐38 was thought to be generated in intact liposomes containing CPT‐11. The bile concentration of closed SN‐38, which is responsible for CPT‐11‐induced intestinal disorder, was decreased by liposomalization. In an in vitro experiment, the SN‐38/CPT‐11 ratio in the tumor cells of the S‐Lip group was found to be higher than that of the Sol group, and the ratio of the closed form of SN‐38 was increased by the liposomalization. Laser scanning confocal microscopy showed the generation of SN‐38 in the liposomal membrane after the incubation of S‐Lip with carboxylesterase. It is therefore considered that a part of CPT‐11 is converted to SN‐38 in the intact liposomes.