Development of dual acid–visible light-degradable core-crosslinked nanogels with extended conjugate aromatic imines for enhanced drug delivery

The development of stimuli-responsive amphiphilic block copolymers and their nanoassemblies/nanogels integrated with degradable covalent chemistry undergoing chemical transitions has been extensively explored as a promising platform for tumor-targeting controlled/enhanced drug delivery. The conjugate aromatic imine bond is unique in responding to acidic pH through acid-catalyzed hydrolysis and visible light through photo-induced <i>E</i>/<i>Z</i> isomerization, thus allowing for a dual acid-light response <i>via</i> a single conjugate aromatic imine bond. Herein, we report a robust strategy for fabricating well-defined core-crosslinked nanogels bearing extended conjugate aromatic imine linkages that exhibit controlled degradation in response to acidic pH and visible light. This approach utilizes the pre-crosslinking of a poly(ethylene glycol)-based block copolymer bearing reactive imidazole pendants with a diol crosslinker bearing an extended conjugate aromatic imine, followed by the mechanical dispersion of the formed crosslinked polymers in an aqueous solution. The fabricated core-crosslinked nanogels with a hydrodynamic diameter of 119 nm are non-cytotoxic, colloidally stable, and capable of encapsulating cancer drug curcumin. They exhibit controlled/enhanced release of encapsulated curcumin at pH = 5 (acidic) or upon irradiation with visible light (<i>λ</i> = 420 nm) as well as exhibit promisingly accelerated and synergistic release under the combination of the above conditions. Furthermore, curcumin-loaded nanogels reduce cell viability in a controlled manner, unlike free drugs. 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.