Multi-responsive nanogels with tunable orthogonal reversible covalent (TORC) core-crosslinks for AND-gate controlled release

Smart, multi-stimuli-responsive nanogels that possess dynamic covalent bonds (DCBs) exhibit reversibility under equilibrium conditions allowing for controlled disassembly and release of cargo. These nanomaterials have innumerable applications in areas including drug delivery, sensors, soft actuators, smart surfaces, and environmental remediation. In this work, we implement one-pot, photo-controlled atom transfer radical polymerization-induced self-assembly (PhotoATR-PISA), mediated by UV light (λ = 365 nm) and parts per million (ppm) levels (ca. <20 ppm) of a copper(II) bromide catalyst, to fabricate dual crosslinked, polymeric nanogels with tunable orthogonal reversible covalent (TORC-NGs) core-crosslinks (CCLs). These TORC-NGs were crosslinked efficiently via coumarin photodimerization which occured simultaneously during polymerization using coumarin-functionalized methacrylate crosslinkers (CouMA). At the same time, crosslinking of nanocarriers with N,N-cystamine bismethacrylamide (CBMA) introduced orthogonal, redox-responsive, disulfide CCLs. Furthermore, incoproration of poly(glycidyl methacrylate) (PGMA) core-forming segments provided a simple handle for switchable solubility through acid-catalyzed ring-opening hydrolysis of pendant epoxide groups. In this way, the kinetics of release were tailored by the pH of the surrounding media. Thus, these TORC-NG systems showed coupled pH-, redox- and photo-responsive controlled release and disassembly behavior with full release of cargo only observed in the right sequence of stimuli and only when all three are utilized. The multi-stimuli-responsive nature of these TORC-NGs was successfully utilized herein for the controlled encapsulation and on-demand AND-gate release of hydrophobic Nile Red fluorescent reporters used as drug simulants. Various TORC-NG morphologies were synthesized in this report including nanosphere, worm-like and tubesome NGs showing variable release characteristics.