Plasma Stability and Plasma Metabolite Concentration-Time Profiles of Oligo(Lactic Acid)8-Paclitaxel Prodrug Loaded Polymeric Micelles

Paclitaxel ( PTX) is a frequently prescribed chemotherapy drug used to treat a wide variety of solid tumors. Oligo(lactic acid)8-PTX prodrug (o( LA)(8)- 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)(8)-PTX-loaded PEG-b-PLA micelles and its pharmacokinetics after IV injection in rats. In rat plasma, o(LA)(8)-PTX prodrug is metabolized into o(LA)(1)- PTX and PTX. In human plasma, o(LA)(8)PTX is metabolized more slowly into o(LA)(2)-PTX, o(LA)(1)-PTX, and PTX. After IV injection of 10 mg/kg PTX- equiv of o(LA)(8)-PTX prodrug loaded PEG-b-PLA micelles in Sprague-Dawley rats, metabolite abundance in plasma follows the order: o(LA)(1)- PTX > o(LA)(2)-PTX > o(LA)(4)-PTX > o(LA)(6)-PTX. Bile metabolite profiles of the o(LA)(8)-PTX prodrug is similar to plasma metabolite profiles. In comparison to equivalent doses of Abraxane (R), plasma PTX exposure is two orders of magnitude higher for Abraxane (R) than PTX from o(LA)(8)-PTX prodrug loaded PEG-b-PLA micelles, and plasma o(LA)(1)-PTX exposure is fivefold higher than PTX from Abraxane (R), demonstrating heightened plasma metabolite exposure for enhanced antitumor efficacy.

Automated summary

PTX is a commonly used chemotherapy drug for treating various solid tumors. o(LA)(8)-PTX prodrug-loaded PEG-b-PLA micelles have higher loading, slower release, and greater antitumor efficacy compared to PTX-loaded PEG-b-PLA micelles. This study investigates the plasma stability and pharmacokinetics of o(LA)(8)-PTX-loaded PEG-b-PLA micelles in rats. The prodrug is metabolized into o(LA)(1)-PTX and PTX in rat plasma, while in human plasma, it is metabolized into o(LA)(2)-PTX, o(LA)(1)-PTX, and PTX. The abundance of metabolites in rat plasma after IV injection follows the order: o(LA)(1)-PTX > o(LA)(2)-PTX > o(LA)(4)-PTX > o(LA)(6)-PTX. Bile metabolite profiles are similar to plasma metabolite profiles. Compared to Abraxane, plasma exposure to PTX is 100 times higher for Abraxane, and plasma exposure to o(LA)(1)-PTX is five times higher, indicating enhanced antitumor efficacy.