Journal
NANOMATERIALS
Volume 11, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/nano11102745
Keywords
docetaxel; prodrug; polymeric micelle; prostate cancer
Categories
Funding
- University of Wisconsin Madison Graduate School Fall Competition - VCRGE [AAG9354]
- NIH [1R01 CA257837-01A1]
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This study aimed to improve the stability of micelles by synthesizing an ester prodrug, successfully loading it within the micelle, solubilizing it in aqueous media, and delaying drug release. The prodrug rapidly converted to the parent drug post-release, showing efficacy and reduced toxicity compared to the traditional drug in a preclinical mouse model of prostate cancer.
Docetaxel (DTX) is among the most frequently prescribed chemotherapy drugs and has recently been shown to extend survival in advanced prostate cancer patients. However, the poor water solubility of DTX prevents full exploitation of this potent anticancer drug. The current marketed formulation, Taxotere(R), contains a toxic co-solvent that induces adverse reactions following intravenous injection. Nano-sized polymeric micelles have been proposed to create safer, water-soluble carriers for DTX, but many have failed to reach the clinic due to poor carrier stability in vivo. In this study, we aimed to improve micelle stability by synthesizing an ester prodrug of DTX, oligo(lactic acid)(8)-docetaxel (o(LA)(8)-DTX), for augmented compatibility with the core of poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) micelles. Due to the enhancement of drug-carrier compatibility, we were able to load 50% (w/w) prodrug within the micelle, solubilize 20 mg/mL o(LA)(8)-DTX (similar to 12 mg/mL DTX-equivalent) in aqueous media, and delay payload release. While the micelle core prohibited premature degradation, o(LA)(8)-DTX was rapidly converted to parent drug DTX through intramolecular backbiting (t(1/2) = 6.3 h) or esterase-mediated degradation (t(1/2) = 2.5 h) following release. Most importantly, o(LA)(8)-DTX micelles proved to be as efficacious but less toxic than Taxotere(R) in a preclinical mouse model of prostate cancer.
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