Engineering the Hydrophilic–Hydrophobic Interface of Polymeric Micelles by Cationic Blocks for Enhanced Chemotherapy

The cationic surface charge critically influences the biological functions and therapeutic outcomes of the cancer nanomedicines. However, the basic correlation between the cationic group categories and their therapeutic efficacy has not been elucidated. In this study, cationic polymeric nanoparticles with amino groups (primary, tertiary, and quaternary amines) as the single variable were leveraged to investigate the various effects of amino species for enhanced antitumor chemotherapy. The nanoparticles were constructed from a series of triblock polymers with varying cationic repeating units at the hydrophilic-hydrophobic interface. Our results suggested that quaternary ammonium outperforms its primary and tertiary counterparts in destroying mitochondrial membranes to induce apoptosis, penetrating deep inside the tumor tissue, and damaging tumor vasculatures. As a result, we were able to effectively inhibit tumor growth in mice by a quaternary ammonium conjugate without causing significant toxicity. Our work demonstrated that the chemical structures played vital roles in regulating their biological functions and provided valuable information for designing cationic drug delivery systems.