@article{APS9401,
author = {Zhen-zhen Pan and Hui-yuan Wang and Meng Zhang and Ting-ting Lin and Wen-yuan Zhang and Peng-fei Zhao and Yi-si Tang and Yong Xiong and Yuan-er Zeng and Yong-zhuo Huang},
title = {Nuclear-targeting TAT-PEG-Asp8-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer},
journal = {Acta Pharmacologica Sinica},
volume = {37},
number = {8},
year = {2017},
keywords = {},
abstract = {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-Asp8-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-Asp8-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-Asp8-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-Asp8-Dox NPs for 22 d effectively inhibited tumor growth.
Conclusion: TAT-PEG-Asp8-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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/9401}
}