Polymeric Micellar Delivery of Novel Microtubule Destabilizer and Hedgehog Signaling Inhibitor for Treating Chemoresistant Prostate Cancer

Castration-resistant prostate cancer that has become resistant to docetaxel (DTX) represents one of the greatest clinical challenges in the management of this malignancy. Therefore, there is an urgent need to develop novel therapeutic agents, which can overcome chemoresistance and improve overall survival of patients. Herein, we designed a novel microtubule destabilizer (2-(4-hydroxy-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) methanone (QW-296) and combined with a newly synthesized hedgehog (Hh) signaling pathway inhibitor 2-chloro-N1-[4-chloro-3-(2-pyridinyl)phenyl]-N4,N4- bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) to treat taxane resistant (TXR) prostate cancer. The combination of QW-296 and MDB5 exhibited stronger anticancer activity towards DU145-TXR and PC3-TXR cells and suppressed tumor colony formation, compared to single drug treatment. Since these drugs are hydrophobic, we synthesized mPEG-p(TMC-MBC) copolymer, which could self-assemble into micelles with loading capacities of 8.13 ± 0.75% and 9.12± 0.69% for QW-296 and MDB5, respectively. Further, these micelles provided controlled drug release of 58% and 42% release of QW-296 and MDB5 within 24 hours when dialyzed against PBS (pH 7.4). We established an orthotopic prostate tumor in nude mice using stably luciferase expressing PC3-TXR cells. There was maximum tumor growth inhibition in the group treated with the combination therapy of QW-296 and MDB5 in micelles compared to their monotherapies or combination therapy formulated in co-solvent. The overall findings suggest that combination therapy of QW-296 and MDB5 have great clinical potential to treat TXR prostate cancer and copolymer mPEG-p(TMC-MBC) could serve as an effective delivery vehicle to boost therapeutic efficacy in vivo. SIGNIFICANCE STATEMENT We are submitting our revised manuscript.