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

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®, plasma PTX exposure is two orders of magnitude higher for Abraxane® 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®, demonstrating heightened plasma metabolite exposure for enhanced antitumor efficacy.