伊立替康PEO-PPO-PEO胶束的制备和表征及其降低药物消化道毒性的机制研究

张馨欣; 郭仕艳; 李菲菲; 甘勇

伊立替康PEO-PPO-PEO胶束的制备和表征及其降低药物消化道毒性的机制研究

Preparation and characterization of irinotecan hydrochloride loaded PEO-PPO-PEO micelles and its mechanism of decreasing drug intestinal toxicity

摘要

摘要:
本文以具有乳腺癌耐药蛋白 (BCRP) 抑制作用的高分子嵌段共聚物PEO₂₀-PPO₇₀-PEO₂₀为载体材料, 制备了包载伊立替康的PEO-PPO-PEO胶束, 并研究其降低药物迟发性腹泻和肠黏膜损伤的机制。采用高表达转运蛋白BCRP的细胞株MDCKII/BCRP为模型, 在体外考察了高分子材料PEO₂₀-PPO₇₀-PEO₂₀及其制备的胶束对伊立替康跨膜转运的影响, 并在大鼠体内研究了PEO-PPO-PEO胶束对伊立替康经胆汁排泄、腹泻及肠黏膜损伤的作用。结果表明, PEO-PPO-PEO胶束可通过抑制BCRP介导的药物外排, 从而减少伊立替康经胆汁的排泄量, 改善药物引发的迟发性腹泻和肠黏膜损伤, 有望成为降低喜树碱类药物消化道毒性的理想载体。

Abstract:
In this work, we developed PEO-PPO-PEO micelles loaded with irinotecan hydrochloride (CPT-11) using breast cancer resistance protein (BCRP) inhibitory material PEO₂₀-PPO₇₀-PEO₂₀, and studied its mechanism of decreasing CPT-11 induced delayed diarrhea and intestinal toxicity. BCRP-overexpressing MDCKII (MDCKII/BCRP) cells were used to evaluate the effect of PEO₂₀-PPO₇₀-PEO₂₀ and PEO-PPO-PEO micelles on transmembrane transport of CPT-11 in vitro. The biliary excretion, delayed diarrhea and intestinal damage of CPT-11 loaded PEO-PPO-PEO micelles of rats were investigated. The results showed that the obtained micelles could decrease the biliary excretion of CPT-11, ameliorate delayed diarrhea and intestinal toxicity of rats through inhibiting BCRP-mediated CPT-11 efflux. PEO-PPO-PEO micelles were promising carriers to reduce intestinal toxicity of CPTs.

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