Poly (l-γ-glutamylglutamine) Polymer Enhances Doxorubicin Accumulation in Multidrug Resistant Breast Cancer Cells

Ting Peng; Kai Liu; Liefang Gao; Lipeng Gao; Jing Chen; Jing Wang; Yu Liu; Yiting Wang; Zhiqiang Yan; Lei Yu

doi:10.3390/molecules21060720

Poly (l-γ-glutamylglutamine) Polymer Enhances Doxorubicin Accumulation in Multidrug Resistant Breast Cancer Cells

Molecules. 2016 Jun 2;21(6):720. doi: 10.3390/molecules21060720.

Authors

Ting Peng¹, Kai Liu², Liefang Gao³, Lipeng Gao⁴, Jing Chen⁵, Jing Wang⁶, Yu Liu⁷, Yiting Wang⁸, Zhiqiang Yan⁹, Lei Yu¹⁰

Affiliations

¹ Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. pengtingcpu@163.com.
² Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. adamlilith-lilin@163.com.
³ Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. gaoliefang@163.com.
⁴ Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. glp229@163.com.
⁵ Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. jing.chen@sibcb.ac.cn.
⁶ Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. jwang@nbic.ecnu.edu.cn.
⁷ Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China. liuyu0726@foxmail.com.
⁸ Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. ytwang@nbic.ecnu.edu.cn.
⁹ Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. zqyan@sat.ecnu.edu.cn.
¹⁰ Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. yulei@nbic.ecnu.edu.cn.

Abstract

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.

Keywords: PGG; conjugate; doxorubicin; multidrug resistance; polymer nanomedicines.

MeSH terms

Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / chemistry
Breast Neoplasms / drug therapy*
Cell Line, Tumor
Dipeptides / administration & dosage*
Dipeptides / chemistry
Doxorubicin / administration & dosage*
Doxorubicin / chemistry
Drug Delivery Systems
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects
Female
Humans
Polymers / administration & dosage
Polymers / chemistry

Substances

Antineoplastic Agents
Dipeptides
Polymers
gamma-glutamylglutamine
Doxorubicin