Antitumor effects of CPT-11 liposomes on HT-29 Xenograft and PK/PD correlation evaluation

摘要

Objective: To investigate inhibitory effects of CPT-11 liposome (lipoCPT-11) on human colon HT-29 xenografts in nude mice, and measure concentrations of parent drug CPT-11 and it's active metabolite SN-38 in plasma and tumor tissue, so as to evaluate the PK/PD correlation of lipoCPT-11. Methods: HT-29 colon cells were inoculated subcutaneously to nude mice to establish xenografts model. In efficacy study, lipoCPT-11 was administered at doses of 5, 25 and 50 mg·kg-1 while commercial common formulation of irinotecan (cCPT-11) was dosed at 50 mg·kg-1, with the same schedule of iv, twice weekly for three weeks. In PK/PD research, lipoCPT-11 was intravenously injected at 50 and 50 mg·kg-1, compared with cCPT-11 of 50 mg·kg-1, and tumor tissue and plasma were collected at designed timepoints, thereafter CPT-11 and SN-38 concentrations were measured respectively by the validated LC-MS/MS methods. Results: lipoCPT-11 could distinctly inhibit growth of HT-29 xenografts with a significant dose-dependent manner at dose of 5, 25 and 50 mg·kg-1. At the equivalent dose of 50 mg·kg-1, lipoCPT-11 was of higher potency than that of cCPT-11. After lipoCPT-11 was administrated, the retention time of CPT-11 and SN-38 in tumor and plasma were longer than cCPT-11, with increased AUC0-t of 426.1 and 5.0-fold in plasma and 9.5 and 5.0 fold in tumor, and interestingly, at the 1/10 dose of 50 mg·kg-1 cCPT-11, lipoCPT-11 possessed 31.1 and 0.4-fold exposure of CPT-11 in plasma and tumor, and in the case of SN-38, the ratios were both 1.0-fold. Conclusion: lipoCPT-11 could strongly increase antitumor activity of cCPT-11, which was well elucidated by its long retention time and improved effective exposure in plasma and tumor, therefore exhibited pivotal clinical application value and promising development prospects.

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