TY - JOUR
T1 - Polymeric micellar delivery of novel microtubule destabilizer and hedgehog signaling inhibitor for treating chemoresistant prostate cancer
AU - Yang, Ruinan
AU - Chen, Hao
AU - Guo, Dawei
AU - Dong, Yuxiang
AU - Miller, Duane D.
AU - Li, Wei
AU - Mahato, Ram I.
N1 - Funding Information:
This work was supported by Fred and Pamela Buffet Cancer Center and the faculty start-up fund from the University of Nebraska Medical center (UNMC) (to R.I.M.), and the National Institutes of Health National Cancer Institute [Grant R01CA148706] (to W.L. and D.D.M.) and grant 1R01GM113166 (to R.I.M.). D.G. was supported by the China Scholarship Council.
Funding Information:
This work was supported by Fred and Pamela Buffet Cancer Center and the faculty start-up fund from the University of Nebraska Medical center (UNMC) (to R.I.M.), and the National Institutes of Health National Cancer Institute [Grant R01CA148706] (to W.L. and D.D.M.) and grant 1R01GM113166 (to R.I.M.). D.G. was supported by the China Scholarship Council. 1R.Y. and H.C. contributed equally to this work as first authors. 2Current affiliation: Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jingsu, Peoples Republic of China. https://doi.org/10.1124/jpet.119.256628. s This article has supplemental material available at jpet.aspetjournals.org.
Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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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U2 - 10.1124/jpet.119.256628
DO - 10.1124/jpet.119.256628
M3 - Article
C2 - 30996033
AN - SCOPUS:85070086935
VL - 370
SP - 864
EP - 875
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -