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®, 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. Graphical Abstract