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Effective Prodrug Liposome and Conversion to Active Metabolite

[ Vol. 1 , Issue. 1 ]


Y. Sadzuka   Pages 31 - 48 ( 18 )


Some antitumor agents encapsulated in liposomes have been used clinically. However, the usefulness of liposomes is limited to the liposomalization of active compounds. Irinotecan hydrochloride (CPT-11) is a prodrug of closed lactone ring form of SN-38, which is an active metabolite with antitumor activity and side toxicity. The plasma concentrations of closed CPT-11 and SN-38 increased with the liposomalization, and their blood circulation was prolonged by the polyethyleneglycol (PEG) modification. The antitumor activity of CPT-11 increased due to the elevated tumor distribution of closed CPT-11 and SN-38 levels by the PEG-modified liposomes. In the tumor, CPT-11 was converted to SN-38. Thus, it is considered that passive targeting to the tumor by liposomalization elevated the SN-38 level in the tumor especially and increased the antitumor activity of CPT-11. The closed/total ratio of SN-38 in the tumors of the liposomes group was greater than that of the CPT-11 solution group. Namely, SN- 38 was thought to be generated in intact liposomes containing CPT-11. The generation of SN-38 in the liposomal membrane was shown after the incubation of liposome containing CPT-11 with carboxylesterase. It is therefore considered that part of CPT-11 is converted to SN-38 in intact liposomes. Furthermore, intestinal disorder, a side toxicity of CPT-11, decreased to depend on the closed SN-38 concentrations in the bile by liposomalization. Although the liposomes induce the improved tissue distribution of the prodrug, the tissue distribution of active metabolites do not always improve. However, CPT-11 entrapped liposome was useful.

, Effective, Prodrug, Liposome, and, Conversion, to, Active, Metabolite


University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

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