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Enhancing Membrane-Disruptive Activity via Hydrophobic Phenylalanine and Lysine Tethered to Poly(aspartic acid)
Bo Liu1, Qifa Zhang1, Fang Zhou1
1School of Materials Science and Engineering, and Tianjin Key Laboratory of Composite and Functional Materials , Tianjin University , Tianjin 300350 , China.
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.
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