Poly (l-γ-glutamylglutamine) Polymer Enhances Doxorubicin Accumulation in Multidrug Resistant Breast Cancer Cells.
BACKGROUND
Drug resistance is one of the bottlenecks of cancer chemotherapy in the clinic. Polymeric nanomedicine is one of the most promising strategies for overcoming poor chemotherapy responses due to the multidrug resistance (MDR).


METHODS
In this study, a new polymer-based drug delivery system, poly (l-γ-glutamylglutamine)-doxorubicin (PGG-Dox) conjugate, was studied in both drug-induced resistant human breast cancer MDA-MB-231/MDR cells and their parent human breast cancer MDA-MB-231 cells. The effect of PGG on facilitating the growth inhibition of Dox against multidrug resistant cells were investigated by evaluating the cytotoxicity of PGG-Dox conjugate, PGG/Dox unconjugated complex and free Dox on both cells. The underlying mechanisms in resistant cells were further studied via the intracellular traffic studies.


RESULTS
Both conjugated and unconjugated PGG significantly increased Dox uptake, prolonged Dox retention and reduced Dox efflux in the MDA-MB-231/MDR cells. The PGG-Dox conjugate is taken up by tumor cells mainly by pinocytosis pathway, in which PGG-Dox conjugate-containing vesicles are formed and enter the cells.


CONCLUSIONS
This study indicated that both polymer-drug conjugate and unconjugated complex are promising strategies of overcoming resistance of anti-tumor drugs.
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. pengtingcpu@163.com.
Ting
T
Peng
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. adamlilith-lilin@163.com.
Kai
K
Liu
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. gaoliefang@163.com.
Liefang
L
Gao
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. glp229@163.com.
Lipeng
L
Gao
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. jing.chen@sibcb.ac.cn.
Jing
J
Chen
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. jwang@nbic.ecnu.edu.cn.
Jing
J
Wang
Key Laboratory of Smart Drug Delivery, Ministry of Education &amp; PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China. liuyu0726@foxmail.com.
Yu
Y
Liu
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. ytwang@nbic.ecnu.edu.cn.
Yiting
Y
Wang
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. zqyan@sat.ecnu.edu.cn.
Zhiqiang
Z
Yan
Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. yulei@nbic.ecnu.edu.cn.
Lei
L
Yu
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000008:administration & dosage* / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry
D000970:Antineoplastic Agents; D004151:Dipeptides; D011108:Polymers; C047442:gamma-glutamylglutamine; D004317:Doxorubicin
PGG; conjugate; doxorubicin; multidrug resistance; polymer nanomedicines