Impact of the polymer side chain chemistry on interactions of amino-acid-derived polyelectrolytes with cells

Abstract

Polyelectrolytes have gained significant attention for their unique, potentially specific association with living cells. Particularly, amino-acid-derived polyzwitterions feature specificity to cancer cells, highlighting their potential for biomedical applications. Here, the synthesis of lysine- and phenylalanine-derived polyelectrolytes via post-polymerisation modification is presented. The amidation of activated ester prepolymers with protected basic amino acids and their subsequent deprotection yield tailored amino acid-functionalised polyzwitterions comprising side chain chirality. Similarly, the use of achiral neutral amino acids results in polyanionic analogues of these polyzwitterions. Via this strategy, a small library of five polymers was created, which enables the careful evaluation of structure–property relationships of polyelectrolytes and their interactions with cells. In particular, we study the influence of side chain motifs: (i) aliphatic vs. aromatic side chains, (ii) permanent vs. non-permanent charge, and (iii) zwitterionic vs. anionic patterns. High-performance liquid chromatography measurements are performed to investigate the influence of both the charge character and aromaticity on the hydrophilicity of the polyelectrolytes. Response to changes in the pH value is studied by dynamic light scattering (DLS) and electrophoretic light scattering at different pH values. Furthermore, polyelectrolyte stability under biologically relevant conditions, i.e. in the presence of model proteins and more complex protein mixtures from foetal bovine serum, is assessed by DLS. Association with cells from different cancer and non-cancer cell lines provides information regarding structural driving forces for association efficiency and specificity. Furthermore, fluorescence imaging shows fast uptake of polyanions into targeted cells, making them interesting candidates for drug-delivery applications.