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Enhancing Membrane-Disruptive Activity via Hydrophobic Phenylalanine and Lysine Tethered to Poly(aspartic acid)

Author:
Liu, Bo, Zhang, Qifa, Zhou, Fang, Ren, Lixia, Zhao, Yunhui, Yuan, Xiaoyan
Source:
ACS applied materials & interfaces 2019 v.11 no.16 pp. 14538-14547
ISSN:
1944-8252
Subject:
aspartic acid, bioactive compounds, carboxylic acids, cell membranes, human cell lines, hydrophobicity, lysine, moieties, pH, phenylalanine, polymers
Abstract:
Amphiphilic polymers with pH-responsive abilities have been widely used as carriers for intracellular delivery of bioactive substances, while their membrane-disruptive activity exerted on cells is a critical characteristic that determines delivery efficiency. Herein, we present a novel method to prepare amphiphilic and pH-responsive polymers by chemically tethering l-phenylalanine methyl ester and followed by Nε-carbobenzyloxy-l-lysine benzyl ester to the side carboxylic acid groups of poly(aspartic acid). The obtained phenylalanine- and lysine-grafted polymer (PAsp-g-Phe)-g-Lys demonstrated enhanced membrane-disruptive activity at pH 7.4 in comparison with that of PAsp-g-Phe. Moreover, the pH-responsive behavior of the grafted polymers caused by the significantly intensified hydrophobicity could be modulated by the tethered amount of hydrophobic amino acids with phenyl groups. The prepared amphiphilic (PAsp-g-Phe)-g-Lys could facilitate entry of calcein into NIH/3T3 and HeLa cells at physiological pH values, possibly due to local chemical destabilization of cell membranes by the interaction between the polymer and membrane bilayers. Therefore, we have provided a feasible approach to prepare pH-responsive polymers with enhanced membrane-disruptive activity, and the phenylalanine- and lysine-grafted polymers could be a potential candidate for intracellular delivery of bioactive molecules in biomedical applications.
Agid:
6377163