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Nuclear-targeting TAT-PEG-Asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer

AIM: Drug efflux-associated multidrug resistance (MDR) is a main obstacle to effective cancer chemotherapy. Large molecule drugs are not the substrates of P-glycoprotein, and can circumvent drug efflux and be retained inside cells. In this article we report a polymer-drug conjugate nanoparticulate s...

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Autores principales: Pan, Zhen-zhen, Wang, Hui-yuan, Zhang, Meng, Lin, Ting-ting, Zhang, Wen-yuan, Zhao, Peng-fei, Tang, Yi-si, Xiong, Yong, Zeng, Yuan-er, Huang, Yong-zhuo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973383/
https://www.ncbi.nlm.nih.gov/pubmed/27292613
http://dx.doi.org/10.1038/aps.2016.48
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author Pan, Zhen-zhen
Wang, Hui-yuan
Zhang, Meng
Lin, Ting-ting
Zhang, Wen-yuan
Zhao, Peng-fei
Tang, Yi-si
Xiong, Yong
Zeng, Yuan-er
Huang, Yong-zhuo
author_facet Pan, Zhen-zhen
Wang, Hui-yuan
Zhang, Meng
Lin, Ting-ting
Zhang, Wen-yuan
Zhao, Peng-fei
Tang, Yi-si
Xiong, Yong
Zeng, Yuan-er
Huang, Yong-zhuo
author_sort Pan, Zhen-zhen
collection PubMed
description AIM: Drug efflux-associated multidrug resistance (MDR) is a main obstacle to effective cancer chemotherapy. Large molecule drugs are not the substrates of P-glycoprotein, and can circumvent drug efflux and be retained inside cells. In this article we report a polymer-drug conjugate nanoparticulate system that can overcome MDR based on size-related exclusion effect. METHODS: Doxorubicin was coupled with the triblock polymeric material cell-penetrating TAT-PEG-poly(aspartic acid). The amphiphilic macromolecules (termed TAT-PEG-Asp(8)-Dox) could self-assemble into nanoparticles (NPs) in water. The antitumor activity was evaluated in drug-resistant human colon cancer HCT8/ADR cells in vitro and in nude mice bearing HCT8/ADR tumor. RESULTS: The self-assembling TAT-PEG-Asp(8)-Dox NPs were approximately 150 nm with a narrow particle size distribution, which not only increased the cellular uptake efficiency, but also bypassed P-glycoprotein-mediated drug efflux and improved the intracellular drug retention, thus yielding an enhanced efficacy for killing drug-resistant HCT8/ADR colon cancer cells in vitro. Importantly, the TAT-PEG-Asp(8)-Dox NPs enhanced the intranuclear disposition of drugs for grater inhibition of DNA/RNA biosynthesis. In nude mice bearing xenografted HCT8/ADR colon cancers, intravenous or peritumoral injection of TAT-PEG-Asp(8)-Dox NPs for 22 d effectively inhibited tumor growth. CONCLUSION: TAT-PEG-Asp(8)-Dox NPs can increase cellular drug uptake and intranuclear drug delivery and retain effective drug accumulation inside the cells, thus exhibiting enhanced anticancer activity toward the drug-resistant human colon cancer HCT8/ADR cells.
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spelling pubmed-49733832016-08-17 Nuclear-targeting TAT-PEG-Asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer Pan, Zhen-zhen Wang, Hui-yuan Zhang, Meng Lin, Ting-ting Zhang, Wen-yuan Zhao, Peng-fei Tang, Yi-si Xiong, Yong Zeng, Yuan-er Huang, Yong-zhuo Acta Pharmacol Sin Original Article AIM: Drug efflux-associated multidrug resistance (MDR) is a main obstacle to effective cancer chemotherapy. Large molecule drugs are not the substrates of P-glycoprotein, and can circumvent drug efflux and be retained inside cells. In this article we report a polymer-drug conjugate nanoparticulate system that can overcome MDR based on size-related exclusion effect. METHODS: Doxorubicin was coupled with the triblock polymeric material cell-penetrating TAT-PEG-poly(aspartic acid). The amphiphilic macromolecules (termed TAT-PEG-Asp(8)-Dox) could self-assemble into nanoparticles (NPs) in water. The antitumor activity was evaluated in drug-resistant human colon cancer HCT8/ADR cells in vitro and in nude mice bearing HCT8/ADR tumor. RESULTS: The self-assembling TAT-PEG-Asp(8)-Dox NPs were approximately 150 nm with a narrow particle size distribution, which not only increased the cellular uptake efficiency, but also bypassed P-glycoprotein-mediated drug efflux and improved the intracellular drug retention, thus yielding an enhanced efficacy for killing drug-resistant HCT8/ADR colon cancer cells in vitro. Importantly, the TAT-PEG-Asp(8)-Dox NPs enhanced the intranuclear disposition of drugs for grater inhibition of DNA/RNA biosynthesis. In nude mice bearing xenografted HCT8/ADR colon cancers, intravenous or peritumoral injection of TAT-PEG-Asp(8)-Dox NPs for 22 d effectively inhibited tumor growth. CONCLUSION: TAT-PEG-Asp(8)-Dox NPs can increase cellular drug uptake and intranuclear drug delivery and retain effective drug accumulation inside the cells, thus exhibiting enhanced anticancer activity toward the drug-resistant human colon cancer HCT8/ADR cells. Nature Publishing Group 2016-08 2016-06-13 /pmc/articles/PMC4973383/ /pubmed/27292613 http://dx.doi.org/10.1038/aps.2016.48 Text en Copyright © 2016 CPS and SIMM http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Pan, Zhen-zhen
Wang, Hui-yuan
Zhang, Meng
Lin, Ting-ting
Zhang, Wen-yuan
Zhao, Peng-fei
Tang, Yi-si
Xiong, Yong
Zeng, Yuan-er
Huang, Yong-zhuo
Nuclear-targeting TAT-PEG-Asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer
title Nuclear-targeting TAT-PEG-Asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer
title_full Nuclear-targeting TAT-PEG-Asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer
title_fullStr Nuclear-targeting TAT-PEG-Asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer
title_full_unstemmed Nuclear-targeting TAT-PEG-Asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer
title_short Nuclear-targeting TAT-PEG-Asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer
title_sort nuclear-targeting tat-peg-asp(8)-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973383/
https://www.ncbi.nlm.nih.gov/pubmed/27292613
http://dx.doi.org/10.1038/aps.2016.48
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