Injectable and degradable hydrogel: in vitro drug release behavior and evaluation in a brain repair context

Injectable hydrogels are attractive for tissue engineering due to their minimally invasive administration and their ability to provide localized and controlled drug delivery. In this study, we investigated an amphiphilic PNIPAAm-b-PLA-b-PEG-b-PLA-b-PNIPAAm pentablock copolymer hydrogel, previously developed as a thermoresponsive system forming via intermicellar bridging at physiological temperature. Its capacity to load and release neuroprotective drugs with distinct physicochemical properties was evaluated. Hydrophobic (riluzole) and hydrophilic (minocycline, apelin-13) model drugs were incorporated, and in vitro release profiles were monitored under physiological conditions. Drug release behavior depended on drug hydrophobicity: hydrophilic compounds exhibited rapid, diffusion-driven release with a pronounced burst effect, whereas the hydrophobic drug showed a slower and more sustained release, correlated with hydrogel degradation (mass loss) at low drug loadings. The hydrogel showed no detectable cytotoxicity toward neuronal cells in vitro. In addition, hydrogel-mediated drug delivery modulated cellular responses depending on the compound, reducing the cytotoxic effects of minocycline and enhancing neuronal survival in the presence of apelin. Importantly, hydrogel-mediated delivery enabled modulation of drug exposure kinetics, thereby influencing the resulting cellular responses. Altogether, these results highlight the ability of this thermoresponsive hydrogel to accommodate drugs with diverse physicochemical properties and to modulate their release and associated biological effects, supporting its relevance as a platform for controlled delivery of neuroactive compounds.