Polymeric micellar delivery of novel microtubule destabilizer and hedgehog signaling inhibitor for treating chemoresistant prostate cancer

Ruinan Yang, Hao Chen, Dawei Guo, Yuxiang Dong, Duane D. Miller, Wei Li, Ram I. Mahato

Research output: Contribution to journalArticle

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-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 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% 6 0.75% and 9.12% 6 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.

Original languageEnglish (US)
Pages (from-to)864-875
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume370
Issue number3
DOIs
StatePublished - Jan 1 2019

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Microtubules
Prostatic Neoplasms
Micelles
docetaxel
Neoplasms
Therapeutics
Hedgehogs
Ethylene Glycol
Castration
Luciferases
Nude Mice
Pharmaceutical Preparations
Prostate
taxane
Survival
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Polymeric micellar delivery of novel microtubule destabilizer and hedgehog signaling inhibitor for treating chemoresistant prostate cancer. / Yang, Ruinan; Chen, Hao; Guo, Dawei; Dong, Yuxiang; Miller, Duane D.; Li, Wei; Mahato, Ram I.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 370, No. 3, 01.01.2019, p. 864-875.

Research output: Contribution to journalArticle

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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-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 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{\%} 6 0.75{\%} and 9.12{\%} 6 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.",
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AU - Yang, Ruinan

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AU - Miller, Duane D.

AU - Li, Wei

AU - Mahato, Ram I.

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