Synthetic polycations are key components for engineering polyelectrolyte complexes with wide-ranging biomedical potential. However, the high cytotoxicity of fully charged polycations remains a major limitation for clinical applications. To address this challenge, we report on polycations derived from the cationic monomer 2-(N,N-dimethylaminoethyl) acrylate (DMAEA), which gradually loses charge through hydrolysis, thereby reducing their charge density over time. The overall charge fraction (from 100% to 20%) was further controlled through copolymerization with the neutral comonomer 2-hydroxyethyl acrylate (HEA). The selected conditions of reversible addition–fragmentation chain transfer (RAFT) copolymerization, specifically protonation of DMAEA with trifluoroacetic acid to mask its tertiary amino groups, enabled a precise control over the characteristics of the copolymers (termed D/H) up to 75% conversions, with close agreement between theoretical and experimental molecular weights up to 100 000 g/mol, consistently low dispersities (<1.2), and an excellent match between the theoretical and actual copolymer compositions. Hydrolysis studies at pH 7.4 showed that increasing the HEA content in D/H copolymers from 20 to 50 mol % led to only a 10% increase in the hydrolysis over 3 weeks. Isothermal titration calorimetry analysis demonstrated that all copolymers retained their ability to complex with heparin, with binding strength comparable to that of commonly used polycations. Importantly, the cytotoxicity of D/H copolymers toward human umbilical vein endothelial cells (HUVECs) decreased with increasing HEA content, reaching more than 80% cell viability at a relatively high concentration of 30 μg/mL. These findings demonstrate that D/H copolymers combine precise structural control with reduced cytotoxicity, making them promising candidates for biomedical polyelectrolyte platforms.
Sivkova et al. (Sun,) studied this question.