Controlling stimulus sensitivity by tailoring nanoparticle core hydrophobicity

Cancer remains a significant global health challenge, necessitating the development of more effective therapeutic strategies. This work presents a novel glutathione (GSH)-responsive platform designed to enhance the delivery and efficacy of the anticancer drug mertansine (DM1) through the modulation of pendant groups in polycarbonate-drug conjugates. By systematically varying the hydrophobicity of the pendant groups, we investigated their effects on nanostructures, GSH sensitivity, colloidal stability, drug release profiles, and the <i>in vitro</i> anticancer efficacy of these polymeric nanoparticles, revealing that more hydrophobic pendant groups effectively reduce GSH accessibility for the nanoparticle cores, improve colloidal stability, and slow drug release rates. The results underscore the critical importance of polymer structures in optimizing drug delivery systems and offer valuable insights for future research on advanced nanomaterials with enhanced drug delivery for cancer therapies.