Issue 39, 2022

pH-Responsive, two-in-one doxorubicin and Bcl-2 siRNA-loaded micelleplexes for triple-negative breast cancer therapy

Abstract

The combination of chemotherapy and gene therapy is a versatile strategy for treating multi-drug-resistant cancer. Accordingly, we developed a pH-responsive triblock copolymeric carrier for delivering chemotherapeutic and genetic drugs simultaneously. We synthesized a series of block and random copolymers with the same monomer composition, namely poly(ethylene glycol)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-(diisopropylamino)ethyl methacrylate) (PEG-b-PDMAEMA-b-PDPA) and poly(ethylene glycol)-b-poly[(2-(dimethylamino)ethyl methacrylate)-r-(2-(diisopropylamino)ethyl methacrylate)] (PEG-b-(PDMAEMA-r-PDPA)), by using atom transfer radical polymerization (ATRP) and then used them to encapsulate and release doxorubicin (Dox) and Bcl-2 siRNA. Compared with the random copolymers, the block copolymers exhibited a higher Dox-loading efficiency and Dox-loading capacity and higher Bcl-2 siRNA condensation efficiency. The siRNA condensation efficiency could be increased by increasing the length of the PDMAEMA segment in either the block copolymers or random copolymers. PEG-b-PDMAEMA-b-PDPA encapsulated Dox and Bcl-2 siRNA to form Dox/Bcl-2 siRNA-loaded micelleplexes with 87% and 90% loading efficiency, respectively. Changing the pH value from 7.4 to 5.0 engendered a burst release of Dox and Bcl-2 siRNA from the Dox/Bcl-2 siRNA-loaded micelleplexes, thus enhancing the cumulative release efficiency of Dox from 24% to 69% and that of Bcl-2 siRNA from 15% to 59% within 24 h. Our in vitro study revealed that the Dox/Bcl-2 siRNA-loaded micelleplexes downregulated Bcl-2 mRNA expression (51% expression) and further inhibited antiapoptotic mechanisms to sensitize drug-resistant triple-negative breast cancer (TNBC) cells to Dox (36% cell viability); this thus demonstrates the benefits of combining chemotherapy and gene therapy.

Graphical abstract: pH-Responsive, two-in-one doxorubicin and Bcl-2 siRNA-loaded micelleplexes for triple-negative breast cancer therapy

Supplementary files

Article information

Article type
Paper
Submitted
23 பிப்ரவரி 2022
Accepted
30 ஆகஸ்ட் 2022
First published
31 ஆகஸ்ட் 2022

Polym. Chem., 2022,13, 5568-5578

pH-Responsive, two-in-one doxorubicin and Bcl-2 siRNA-loaded micelleplexes for triple-negative breast cancer therapy

H. Lu, H. W. Liu, T. K. Dinh, C. Huang, H. Huang, Y. Tseng, M. Ku, F. Wang, Y. Chen and C. Peng, Polym. Chem., 2022, 13, 5568 DOI: 10.1039/D2PY00246A

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