Abstract
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
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Acknowledgements
The authors thank the Nanotechnology Characterization Laboratory (NCL) for characterization support of this project; the formulation described herein was characterized by the NCL’s free Assay Cascade characterization service for cancer nanomedicines. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. Additionally, authors thank the Tang Lab at the University of Wisconsin-Madison School of Pharmacy for generously allowing us to use the semi prep HPLC for production of standards for LCMS.
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This project has been funded in part or in whole with federal funds from the NCI, NIH, under contract no 75N91019D00024 and R01 CA257837.
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Repp, L., Skoczen, S.L., Rasoulianboroujeni, M. et al. Plasma Stability and Plasma Metabolite Concentration–Time Profiles of Oligo(Lactic Acid)8-Paclitaxel Prodrug Loaded Polymeric Micelles. AAPS J 25, 39 (2023). https://doi.org/10.1208/s12248-023-00807-4
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DOI: https://doi.org/10.1208/s12248-023-00807-4