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

Abstract

Castration-resistant prostate cancer that has become resistant to docetaxel (DTX) represents one of the greatest clinical challenges in the management of this malignancy. There is an urgent need to develop novel therapeutic agents to overcome chemoresistance and improve the overall survival of patients. We have 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 it with a newly synthesized hedgehog (Hh) signaling pathway inhibitor 2-chloro-N 1-[4-chloro-3-(2-pyridinyl)phenyl]-N 4,N 4- 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 toward DU145-TXR and PC3-TXR cells and suppressed tumor colony formation when compared with single-drug treatment. Because these drugs are hydrophobic, we synthesized the mPEG-p(TMC-MBC) [methoxy-poly(ethylene glycol)-block-poly(trimethylene carbonate-co-2-methyl-2-benzoxycarbonyl-propylene carbonate)] 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 the respective 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 with their monotherapies or combination therapy formulated in cosolvent. The overall findings suggest that combination therapy with QW-296 and MDB5 has 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.

• Authors: Ruinan Yang, Hao Chen, Dawei Guo, Yuxiang Dong, Duane D Miller, Wei Li, Ram I Mahato
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 370 Issue 3 Pg. 864-875 (09 2019) ISSN: 1521-0103 [Electronic] United States
• PMID: 30996033 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Antineoplastic Agents
• Benzene Derivatives
• Hedgehog Proteins
• Imidazoles
• Indoles
• MDB5
• Micelles
• Pyridines
• QW-296
• Taxoids

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzene Derivatives (pharmacology, therapeutic use)
• Cell Line, Tumor
• Drug Delivery Systems
• Drug Resistance, Neoplasm
• Hedgehog Proteins (antagonists & inhibitors)
• Humans
• Imidazoles (pharmacology, therapeutic use)
• Indoles (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Nude
• Micelles
• Microtubules (chemistry)
• Molecular Docking Simulation
• Prostatic Neoplasms (drug therapy)
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Pyridines (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Taxoids (therapeutic use)