Synthesis and preparation of nanoparticles composed of amphiphilic poly(γ-glutamic acid) with different hydrophobic side chains and their potential of membrane disruptive activity

Abstract

In the development of nanoparticle-based vaccine adjuvants, the interaction between nanoparticles (NPs) and the cells is a key factor. To control them, we focused on the relationship between the hydrophobicity of the side chains and the cell membrane. In this study, amphiphilic poly(γ-glutamic acid) (γ-PGA), using various types of hydrophobic side chains, was synthesized and used to prepare NPs for evaluating the membrane disruptive activity. When leucine ethyl ester (Leu), methionine ethyl ester (Met), or tryptophan ethyl ester (Trp) was grafted, each polymer formed monodispersed NPs at physiological conditions. Significantly, NPs composed of Leu and Trp showed a membrane disruptive activity at the endosomal environment (pH 5-6.5), while NPs composed of Met did not show. This might be due to the weak hydrophobicity of Met compared to that of Leu and Trp, which demonstrated that the interaction between NPs and cells could be controlled by designing the polymer compositions.

Small Wonders—The Use of Nanoparticles for Delivering Antigen

“…The author suggested that the high level of cross-presentation induced by nanoparticles might be due to the amphiphilic nature of nanoparticles, aiding the antigen with endo-lysosomal escape into cytosol. This finding was supported with the observation made when hydrophobic amino acid side chains were grafted onto the same particles, and a significant increase in the membrane disruption was observed at endosomal pH (measured by the haemolytic activity on blood cell membrane) [ 89 ]. Furthermore, cationic nanoparticles comprised of PLGA can induce disruption of endosomal membranes due to cationisation from gradual acidification [ 90 , 91 ].…”

Effects of cholesterol on the binding of the precursor neurotransmitter tryptophan to zwitterionic membranes

“…15 Recently, some studies indicated promising antibacterial properties of tryptophan when synthesized at polyionic membranes 16 and its major role in the preparation of nanoparticles able to control membrane disruption. 17 So, given the importance of tryptophan, we have explored its interactions with a typical zwitterionic phospholipid membrane formed by DPPC and cholesterol in an aqueous solution of sodium chloride, analyzing its mechanical properties, the local structure, and some relevant dynamical properties such as diffusion and vibrational spectra. However, we do not state that the particular properties and data reported for tryptophan in the present work can be considered as general for a wide variety of small probes.…”

pH-Responsive Amphiphilic Carboxylate Polymers: Design and Potential for Endosomal Escape

“…These polypeptides are considered to be more biocompatible and biodegradable than their vinyl polymer counterparts (Akagi et al, 2006 ; Liu et al, 2019 ). A systematically investigated example is poly(γ-glutamic acid) (γPGA) and its derivatives grafted by different amino acids as pedant groups (Shima et al, 2014a ). The protonation/deprotonation of glutamic acid units of PGA enabled the pH-dependent conformation changes, while the hydrophobic amino acids (e.g., leucine, methionine, phenylalanine, valine, and tryptophan) enhanced the hydrophobicity and interaction with membranes.…”

“…The protonation/deprotonation of glutamic acid units of PGA enabled the pH-dependent conformation changes, while the hydrophobic amino acids (e.g., leucine, methionine, phenylalanine, valine, and tryptophan) enhanced the hydrophobicity and interaction with membranes. Unlike PPAA, γPGA with sufficient hydrophobic amino acid group grafting (53% phenylalanine, 71% tryptophan, and 87% leucine) formed stable nanoparticle in PBS buffer, and the nanoparticles maintained pH-responsive hemolytic activity similar to polymers (Akagi et al, 2010 ; Shima et al, 2014a ). Furthermore, phenylalanine modified γPGA could encapsulate protein during its self-assembly and delivered protein payload to antigen presenting cells efficiently both in vitro and in vivo (Yoshikawa et al, 2008 ; Akagi et al, 2011 ).…”