Nuclear-targeting TAT-PEG-Asp8-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer.
OBJECTIVE
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.


CONCLUSIONS
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.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Zhen-Zhen
ZZ
Pan
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Hui-Yuan
HY
Wang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Meng
M
Zhang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Ting-Ting
TT
Lin
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Wen-Yuan
WY
Zhang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Peng-Fei
PF
Zhao
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Yi-Si
YS
Tang
Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Yong
Y
Xiong
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Yuan-Er
YE
Zeng
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Yong-Zhuo
YZ
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry; D004247:DNA / Q000096:biosynthesis; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D010455:Peptides; C017645:polyaspartate; D011092:Polyethylene Glycols; D004317:Doxorubicin; D004247:DNA