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Preparation of poly(β-L-malic acid)-based charge-conversional nanoconjugates for tumor-specific uptake and cellular delivery

Authors Zhou Q, Yang T, Qiao Y, Guo S, Zhu L, Wu H

Received 2 December 2014

Accepted for publication 23 January 2015

Published 10 March 2015 Volume 2015:10(1) Pages 1941—1952


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 5

Editor who approved publication: Dr Lei Yang

Video abstract presented by Qing Zhou

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Qing Zhou,1,* Tiehong Yang,1,* Youbei Qiao,1 Songyan Guo,1 Lin Zhu,2 Hong Wu1

1Department of Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi’an, People’s Republic of China; 2Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Health Science Center, Kingsville, Texas, USA

*These authors contributed equally to this work

Abstract: In this study, a multifunctional poly(β-L-malic acid)-based nanoconjugate with a pH-dependent charge conversional characteristic was developed for tumor-specific drug delivery. The short branched polyethylenimine-modified poly(β-L-malic acid) (PEPM) was first synthesized. Then, the fragment HAb18 F(ab′)2 and 2,3-dimethylmaleic anhydride were covalently attached to the PEPM to form the nanoconjugate, HDPEPM. In this nanoconjugate, the 2,3-dimethylmaleic anhydride, the shielding group, could shield the positive charge of the conjugate at pH 7.4, while it was selectively hydrolyzed in the tumor extracellular space (pH 6.8) to expose the previously-shielded positive charge. To study the anticancer activity, the anticancer drug, doxorubicin, was covalently attached to the nanoconjugate. The doxorubicin-loaded HDPEPM nanoconjugate was able to efficiently undergo a quick charge conversion from -11.62 mV to 9.04 mV in response to the tumor extracellular pH. The electrostatic interaction between the positively charged HDPEPM nanoconjugates and the negatively charged cell membrane significantly enhanced their cellular uptake, resulting in the enhanced anticancer activity. Also, the tumor targetability of the nanoconjugates could be further improved via the fragment HAb18 F(ab′)2 ligand–receptor-mediated tumor cell-specific endocytosis.

Keywords: nanoconjugate, charge-conversional, PMLA, pH-sensitive

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