载紫杉醇的聚乙二醇-聚乳酸-聚-β-氨基酯纳米胶束药动学及其在小鼠体内分布研究

Pharmacokinetics and mouse tissue distribution of paclitaxel-loaded polyethylene glycol-polylactic acid-poly-β-amino ester micelles

目的:建立测定小鼠血液及各组织样品中紫杉醇含量测定的HPLC方法,考察比较包载紫杉醇(paclitaxel,PTX)的聚乙二醇-聚乳酸-聚-β-氨基酯(PELA-PBAE)与聚乙二醇-聚乳酸(PELA)纳米胶束在正常小鼠体内各组织的分布情况及药动学参数。方法:采用尾静脉注射法给予小鼠紫杉醇注射液(PTX injection)、PELA/PTX纳米胶束和PELA-PBAE/PTX纳米胶束,给药量为5 mg·kg^(-1)(以紫杉醇计),比较其药动学参数。结果:与紫杉醇注射液相比,2种纳米胶束在小鼠体内的AUC增大,平均滞留时间延长,在血、肺中蓄积量增多,在心脏蓄积减少;与非p H敏感性紫杉醇纳米胶束PELA/PTX相比,PELA-PBAE/PTX各药动学参数没有显著变化。结论:聚-β-氨基酯的引入没有改变原有胶束的优异性能,同样可以降低网状内皮系统对胶束的吞噬,可提高紫杉醇的生物利用度、延长药物的作用时间并降低紫杉醇的潜在心脏毒性。

Objective： To establish an HPLC method for determining the content of paclitaxel in mouse plasma and other tissues,and investigate the pharmacokinetics and tissue distribution of paclitaxel（ PTX） in drugloaded PELA-PBAE（ PELA-PBAE / PTX） and PELA（ PELA / PTX） micelles in comparison with the commercially available PTX injection. Methods： The healthy female Balb / c mice were intravenously injected with PTX injection,PELA / PTX and PELA-PBAE / PTX via the tail vein,respectively. An HPLC method was established to determine the concentration of PTX in plasma and tissue samples. Results： Compared with the commercial PTX injection,the main pharmacokinetic parameters such as the AUC and MRT of both PELA / PTX and PELA-PBAE / PTX were significantly increased. After injection,PTX in the drug-loaded nano-micelles was mainly distributed in plasma and lung,whereas the PTX injection was primarily in liver and spleen. Conclusion： The p H-responsive PELAPBAEmicelles,as well as PELA micelles,could help the drug to escape from the capture of reticuloendothelial system（ RES）,increase the bioavailability,prolong the circulation time in plasma,and minimize the potential cardio-toxicity of PTX.