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Electrostatic interactions between polyglutamic acid and polylysine yields stable polyion complex micelles for deoxypodophyllotoxin delivery

Authors Wang Y, Huang L, Shen Y, Tang L, Sun R, Shi D, Webster TJ, Tu J, Sun C

Received 27 April 2017

Accepted for publication 21 June 2017

Published 30 October 2017 Volume 2017:12 Pages 7963—7977


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Israel (Rudi) Rubinstein

Yutong Wang,1–3,* Liping Huang,1,2,* Yan Shen,1,2,* Lidan Tang,1,2,4 Runing Sun,1,5 Di Shi,6 Thomas J Webster,6 Jiasheng Tu,1,2 Chunmeng Sun1,2

1Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, China Pharmaceutical University, 2State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 3Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 4Changzhou Second People’s Hospital, Changzhou, 5School of Engineering, China Pharmaceutical University, Nanjing, People’s Republic of China; 6Department of Chemical Engineering, Northeastern University, Boston, MA, USA

*These authors contributed equally to this work

Abstract: To achieve enhanced physical stability of poly(ethylene glycol)-poly(D,L-lactide) polymeric micelles (PEG-PDLLA PMs), a mixture of methoxy PEG-PDLLA-polyglutamate (mPEG-PDLLA-PLG) and mPEG-PDLLA-poly(L-lysine) (mPEG-PDLLA-PLL) copolymers was applied to self-assembled stable micelles with polyion-stabilized cores. Prior to micelle preparation, the synthetic copolymers were characterized by 1H-nuclear magnetic resonance (NMR) and infrared spectroscopy (IR), and their molecular weights were calculated by 1H-NMR and gel permeation chromatography (GPC). Dialysis was used to prepare PMs with deoxypodophyllotoxin (DPT). Transmission electron microscopy (TEM) images showed that DPT polyion complex micelles (DPT-PCMs) were spherical, with uniform distribution and particle sizes of 36.3±0.8 nm. In addition, compared with nonpeptide-modified DPT-PMs, the stability of DPT-PCMs was significantly improved under various temperatures. In the meantime, the pH sensitivity induced by charged peptides allowed them to have a stronger antitumor effect and a pH-triggered release profile. As a result, the dynamic characteristic of DPT-PCM was retained, and high biocompatibility of DPT-PCM was observed in an in vivo study. These results indicated that the interaction of anionic and cationic charged polyionic segments could be an effective strategy to control drug release and to improve the stability of polymer-based nanocarriers.

Keywords: polyion complex micelles, electrostatic interaction, oligopeptide, stability, pharmacokinetics

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