Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,SN-38.Unfortunately,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life a...Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,SN-38.Unfortunately,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life and dose-limiting toxicity.To address this problem,a novel trivalent PEGylated prodrug(PEG-[Irinotecan]3)has been synthesized and its full-profile pharmacokinetics,antitumor activity and toxicity compared with those of irinotecan.The results show that after intravenous administration to rats,PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3-x(x=1,2)and PEG-[linker]during which time the released irinotecan undergoes conversion to SN-38.As compared with conventional irinotecan,PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life.In a colorectal cancer-bearing model in nude mice,the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan.In summary,PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan.This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phaseⅡtrial stage.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82030107 and 81872831)the National Science and Technology Major Projects for significant new drugs creation of the 13th five-year plan(2017ZX09101001 and 2018ZX09721002007,China)。
文摘Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,SN-38.Unfortunately,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life and dose-limiting toxicity.To address this problem,a novel trivalent PEGylated prodrug(PEG-[Irinotecan]3)has been synthesized and its full-profile pharmacokinetics,antitumor activity and toxicity compared with those of irinotecan.The results show that after intravenous administration to rats,PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3-x(x=1,2)and PEG-[linker]during which time the released irinotecan undergoes conversion to SN-38.As compared with conventional irinotecan,PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life.In a colorectal cancer-bearing model in nude mice,the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan.In summary,PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan.This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phaseⅡtrial stage.
