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.