CPT-11脂质体对人结肠癌HT-29移植瘤的抗肿瘤活性及药代-药效相关性分析

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

目的:考察CPT-11脂质体(lipoCPT-11)对人结肠癌HT-29裸小鼠移植瘤的抑制作用,并对产生这一作用的物质基础,即药代-药效相关性进行分析。方法:建立HT-29裸鼠移植瘤模型,在药效研究中lipoCPT-11分别以5,25,50 mg·kg-1给药,已上市普通制剂(cCPT-11)剂量为50 mg·kg-1,iv给药,1周2次,连续3周;在药代试验中,lipoCPT-11和CPT-11分别以5,50和50 mg·kg-1经iv给药1次,分别于给药前和给药后不同时间采集肿瘤组织和血浆,采用经验证的LC-MS/MS法检测CPT-11和SN-38的浓度。结果:lipoCPT-11对HT-29移植瘤的抑制作用具有显著的剂量依赖性,5 mg·kg-1组药效与cCPT-11 50 mg·kg-1相当,50 mg·kg-1组肿瘤抑制率显著高于cCPT-11;lipoCPT-11组肿瘤和血浆中CPT-11和SN-38的滞留时间长于cCPT-11,50和5 mg·kg-1组原形药AUC0-t分别是cCPT-11(50 mg·kg-1)的426.1和31.1倍(血浆)及9.5和0.4倍(肿瘤),SN-38的比例分别为5.0和1.0倍(血浆)及5.4倍和1.0倍(肿瘤)。结论:lipoCPT-11对HT-29移植瘤的抑制作用显著高于cCPT-11,这与脂质体制剂延长了活性成分在体内的滞留时间以及提高了肿瘤和血浆中的有效暴露相吻合,具有重要的临床应用价值和开发前景。

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 metaholite 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 ad- ministered at doses of 5, 25 and 50 mg kg-1 while commercial common formulation of irinotecan （ cCPT-11 ） was dosed at 50 rag. 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 respec- tively by the validated LC-MS/MS methods. Results： lipoCPT-11 could distinctly inhibit growth of HT-29 xeno- grafts 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 reten- tion 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 l. 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.