Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, Wisconsin, 53705, USA.
Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research Sponsored By the National Cancer Institute, Frederick, Maryland, 21702, USA.
AAPS J. 2023 Apr 11;25(3):39. doi: 10.1208/s12248-023-00807-4.
Paclitaxel (PTX) is a frequently prescribed chemotherapy drug used to treat a wide variety of solid tumors. Oligo(lactic acid)-PTX prodrug (o(LA)-PTX) loaded poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) micelles have higher loading, slower release and higher antitumor efficacy in murine tumor models over PTX-loaded PEG-b-PLA micelles. The goal of this work is to study plasma stability of o(LA)-PTX-loaded PEG-b-PLA micelles and its pharmacokinetics after IV injection in rats. In rat plasma, o(LA)-PTX prodrug is metabolized into o(LA)-PTX and PTX. In human plasma, o(LA)-PTX is metabolized more slowly into o(LA)-PTX, o(LA)-PTX, and PTX. After IV injection of 10 mg/kg PTX-equiv of o(LA)-PTX prodrug loaded PEG-b-PLA micelles in Sprague-Dawley rats, metabolite abundance in plasma follows the order: o(LA)-PTX > o(LA)-PTX > o(LA)-PTX > o(LA)-PTX. Bile metabolite profiles of the o(LA)-PTX prodrug is similar to plasma metabolite profiles. In comparison to equivalent doses of Abraxane®, plasma PTX exposure is two orders of magnitude higher for Abraxane® than PTX from o(LA)-PTX prodrug loaded PEG-b-PLA micelles, and plasma o(LA)-PTX exposure is fivefold higher than PTX from Abraxane®, demonstrating heightened plasma metabolite exposure for enhanced antitumor efficacy.
紫杉醇（PTX）是一种常用于治疗多种实体瘤的常用化疗药物。聚乙二醇-b-聚乳酸（PEG-b-PLA）载紫杉醇（PTX）的两亲性嵌段共聚物胶束（o(LA)-PTX-载 PEG-b-PLA 胶束）与载 PTX 的 PEG-b-PLA 胶束相比，具有更高的载药量、更慢的释放速度和更高的抗肿瘤疗效。本工作旨在研究 o(LA)-PTX-载 PEG-b-PLA 胶束在大鼠体内的血浆稳定性及其静脉注射后的药代动力学。在大鼠血浆中，o(LA)-PTX 前药代谢为 o(LA)-PTX 和 PTX。在人血浆中，o(LA)-PTX 代谢为 o(LA)-PTX、o(LA)-PTX 和 PTX 的速度较慢。在 Sprague-Dawley 大鼠静脉注射 10mg/kg 紫杉醇当量的 o(LA)-PTX 载 PEG-b-PLA 胶束后，血浆中代谢物的丰度顺序为：o(LA)-PTX>o(LA)-PTX>o(LA)-PTX>o(LA)-PTX。o(LA)-PTX 前药的胆汁代谢产物与血浆代谢产物相似。与 Abraxane®的等效剂量相比，Abraxane®的血浆 PTX 暴露量比 o(LA)-PTX 载 PEG-b-PLA 胶束中的 PTX 高两个数量级，而 o(LA)-PTX 载 PEG-b-PLA 胶束中的 o(LA)-PTX 暴露量比 Abraxane®高五倍，表明提高了血浆代谢产物的暴露量，从而提高了抗肿瘤疗效。
