伊立替康（Irinotecan）是一种抗癌拓扑异构酶I抑制剂，作为活性代谢产物SN-38的前药。不幸的是，伊立替康的有限效用归因于其依赖于 pH 的稳定性、短半衰期和剂量限制毒性。为解决这个问题，合成了一种新型的三价聚乙二醇化前药（PEG-[伊立替康]3），并将其全方位药代动力学、抗肿瘤活性和毒性与伊立替康进行了比较。结果显示，静脉注射PEG-[伊立替康]3后，PEG-[伊立替康]3逐步失去伊立替康形成PEG-[伊立替康]3‒x（x = 1, 2）和PEG-[连接体]，此期间释放的伊立替康经历了转化为SN-38。与传统伊立替康相比，PEG-[伊立替康]3显示出更长时间释放伊立替康，并有效形成SN-38，其AUC和半衰期显著改善。在裸鼠结直肠癌模型中，PEG-[伊立替康]3产生的肿瘤中伊立替康和SN-38的浓度，在48小时时分别比伊立替康产生的高出86.2倍和2293倍。总之，PEG-[伊立替康]3具有优越的药代动力学特性和抗肿瘤活性，毒性较低，支持PEG-[伊立替康]3是一种优于伊立替康的抗癌药物，并已进入第二期临床试验阶段。© 2023 中国药学会和中国医学科学院药物研究所，由Elsevier B.V.进行产品和托管。

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 phase II trial stage.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.