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Polymeric nanovesicles as simultaneous delivery platforms with doxorubicin conjugation and elacridar encapsulation for enhanced treatment of multidrug-resistant breast cancer

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Abstract

Multidrug resistance (MDR) is one of the major obstacles hindering the successful chemotherapy of cancer. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is an important factor responsible for MDR. In this study, a novel copolymer methoxy-poly(ethylene glycol)–poly[(N-(6-hydroxyhexyl)-g-doxorubicin-L-aspartamide)-(β-benzyl-L-aspartate)] (mPEG-P[Asp(HPA-g-DOX)-BLA)] was synthesized and utilized to assemble into nanovesicles with hydrophilic P-gp inhibitor elacridar hydrochloride (Ela) encapsulated into the aqueous lumen. Doxorubicin (DOX) was covalently conjugated onto the polymer chain via a pH-cleavable amide linkage, leading to a pH responsive DOX release as well as disintegration of the nanovesicles in the lysosome of tumor cells. In vitro studies demonstrated that the DOX and Ela co-delivered nanovesicles showed superior cytotoxicity and enhanced anti-tumor properties as compared to single DOX-delivery nanosystems in MCF-7/ADR cancer, which was attributed to the P-gp bioactivity inhibition as investigated by a cell immunofluorescence assay. In vivo studies showed that the polymeric nanovesicles effectively accumulated at the tumor site and the co-delivered DOX and Ela effectively suppressed the MCF-7/ADR tumor growth. All the results indicated that the acid-liable nanovesicles had a synergistic effect to enhance antitumor efficacy for multidrug-resistant breast cancer treatment.

Graphical abstract: Polymeric nanovesicles as simultaneous delivery platforms with doxorubicin conjugation and elacridar encapsulation for enhanced treatment of multidrug-resistant breast cancer

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Publication details

The article was received on 13 Jul 2018, accepted on 09 Oct 2018 and first published on 11 Oct 2018


Article type: Paper
DOI: 10.1039/C8TB01829D
Citation: J. Mater. Chem. B, 2018, Advance Article
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    Polymeric nanovesicles as simultaneous delivery platforms with doxorubicin conjugation and elacridar encapsulation for enhanced treatment of multidrug-resistant breast cancer

    H. Xiao, J. He, X. Li, B. Li, L. Zhang, Y. Wang, D. Cheng and X. Shuai, J. Mater. Chem. B, 2018, Advance Article , DOI: 10.1039/C8TB01829D

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