Abstract 5867: Reversal of drug resistance in prostate cancer using PBM nanoparticle

Abstract

Abstract Multidrug-resistance (MDR) is the major reason behind the failure of prostate cancer (PCa) therapy. ATP-binding cassette (ABC) transporters contribute to drug resistance via ATP-dependent drug efflux. P-glycoprotein (Pgp), which is encoded by MDR1 gene, confers resistance to certain anticancer agents. The development of agents able to modulate MDR mediated by Pgp and other ABC transporters remained a major goal for PCa therapy. The proposed study evaluated a novel method for targeted delivery of resveratrol alone or in combination with docetaxel at desired rates for reversal of drug resistance. We described a proprietary planetary ball milling approach (PBM) that uses a natural polysaccharide (starch; FDA approved) to create a drug-polysaccharide nanoparticle as a core that is subsequently coated with novel folate-conjugated poly (ϵ-caprolactone) / poly (ethylene glycol) co-polymer, which allows binding to high-affinity folate receptors presents on PCa cells. The resulting PBM nanoparticles were shown to be rapidly internalized and induce significant cancer cell apoptosis at lower doses compared to unformulated resveratrol and/or docetaxel. Our data showed that resveratrol potently synergizes with docetaxel to inhibit proliferation and induce cell death in resistance PCa cells. The up-regulation of pro-apoptotic (BAX, BID, BAK), p53 and down regulation of anti-apoptotic (BCL-2, MCL-1), Pgp and NF-κB protein confirmed that a synergistic combination of resveratrol-docetaxel with targeted delivery to tumor cells could provide a more potent therapeutic effect at lower drug concentrations and improve the therapeutic index. These results suggested that the co-delivery of resveratrol, and a cytotoxic agent in a PBM nanoparticle might potentially improve the treatment of drug-resistant tumors. [This work is supported from Grant # 5SC1CA193758-03] Citation Format: Santosh K. Singh, James W. Lillard, Rajesh Singh. Reversal of drug resistance in prostate cancer using PBM nanoparticle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5867. doi:10.1158/1538-7445.AM2017-5867