Chemoresistance remains a significant problem in prostate cancer therapy. Repeated treatment with docetaxel (DTX) often develops chemoresistance due to cancer stem cell (CSC) proliferation. As a key negative regulator of CD44+ prostate CSCs, miRNA-34a has been proved to inhibit tumor growth and metastasis. However, the poor intracellular delivery and rapid in vivo degradation have hampered the clinical application of miR-34a. In this study, we propose to use a small molecule termed rubone for the treatment of DTX resistant prostate cancer by restoring miR-34a expression to reverse chemoresistance. We rationally designed a multi-functional micellar system by integrating drug delivery as well as pH and reduction responsive properties in an amphiphilic copolymer named poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate-graft-diisopropanolamino ethanol-graft-rubone). At physiological pH 7.4, the copolymer formed micelles in aqueous solution with a particle size around 48 nm and specifically dissociated in the acidic endocytic vesicles of tumor cells due to protonation and ionic bond breakup in the micellar core. Dissociation of micelles would lead to quick release of encapsulated DTX and facilitate cleavage of disulfide bond by exposure to glutathione. Compared to DTX alone, the combination of DTX and rubone showed enhanced tumor cytotoxicity in vitro. Formulated DTX and rubone exhibited similar inhibition efficacy in resistant prostate cancer cells. Finally, we aims to determine the therapeutic efficacy, biodistribution and toxicity of this micellar delivery system in orthotopic prostate tumor bearing mice.

Multi-functional nanocarrier of docetaxel and miRNA-34a modulator for treating prostate cancer

254th National Meeting (2017)

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