Development of Dual Acid/Visible Light-Degradable Core-Crosslinked Nanogels with Extended Conjugate Aromatic Imines for Enhanced Drug Delivery

Abstract

The development of stimuli-responsive amphiphilic block copolymers and their nanoassemblies/nanogels integrated with degradable covalent chemistry undergoing chemical transition has been extensively explored as a promising platform for tumor-targeting controlled/enhanced drug delivery. Conjugate aromatic imine bond is unique to respond to both acidic pH through acid-catalyzed hydrolysis and visible light through photo-induced E/Z isomerization, thus allowing for dual acid/light response with a single conjugate aromatic imine bond. Herein, we report a robust strategy to fabricate well-defined core-crosslinked nanogels bearing extended conjugate aromatic imine linkages, exhibiting controlled degradation in response to dual acidic pH and visible light. The approach utilizes the pre-crosslinking of a poly(ethylene glycol)-based block copolymer bearing reactive imidazole pendants with a diol crosslinker bearing extended conjugate aromatic imine, followed by the mechanical dispersion of the formed crosslinked polymers in aqueous solution. The fabricated core-crosslinked nanogels are non-cytotoxic, colloidally stable, and able to encapsulate cancer drug curcumin. They exhibit controlled/enhanced release of encapsulated curcumin in acidic pH and upon irradiation with visible light and promisingly accelerated and synergistic release with their combination. Furthermore, curcumin-loaded nanogels reduce cell viability in a controlled manner, unlike the free drug. This simplified yet efficient synthetic approach paves the way for the development of smart nanocarriers with potential applications in controlled drug release and cancer therapy.