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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 the inhibitory effect of CPT-11 liposomes (lipoCPT-11) on human colon cancer HT-29 xenografts in nude mice and analyze the material basis for this effect, ie, pharmacokinetic-drug efficacy . Methods: The model of HT-29 xenografts in nude mice was established. LipoCPT-11 was administrated at 5, 25 and 50 mg · kg-1, respectively. The dosage of cCPT-11 was 50 mg · kg -1, iv, twice a week for 3 weeks. LipoCPT-11 and CPT-11 were administered iv at 5, 50 and 50 mg · kg-1 respectively in the pharmacokinetics test, Tumor tissues and plasma were collected before and at different times after administration, and the concentrations of CPT-11 and SN-38 were determined by a validated LC-MS / MS method. Results: The inhibitory effect of lipoCPT-11 on HT-29 xenografts was significantly dose-dependent. The efficacy of 5 mg · kg -1 group was comparable to that of cCPT-11 50 mg · kg -1, and the dose of 50 mg · kg -1 group The inhibitory rate of CPT-11 and SN-38 in tumor and plasma of lipoCPT-11 group was longer than that of cCPT-11, and the AUC0-t of 50, 5 and 5 mg · kg-1 groups were cCPT- 426.1 and 31.1 folds (plasma) and 9.5 and 0.4 folds (tumors) of SN-11 (50 mg · kg -1) and 5.0 and 1.0 folds (plasma) and 5.4 folds and 1.0 folds (tumors) of SN- Conclusions: The inhibitory effect of lipoCPT-11 on HT-29 xenografts was significantly higher than that of cCPT-11, consistent with the prolongation of the in vivo residence time of the active ingredient as well as the increased effective exposure in tumor and plasma with liposomal formulations, with Important clinical value and development prospects.