Reactive Oxygen Species-Responsive Polymeric Chloroquine Nanogel for Targeted Oral Therapy of Ulcerative Colitis

Targeted drug delivery remains a critical challenge in the treatment of ulcerative colitis, as the side effects of current systemic therapies often outweigh their therapeutic benefits. In this study, we developed a reactive oxygen species (ROS)-responsive nanogel system that releases polymeric chloroquine (PCQ), a macromolecular derivative of hydroxychloroquine (HCQ), for localized treatment of ulcerative colitis. The initial nanogel formulation, measuring 183 nm in size with a surface charge of +13 mV, was synthesized via RAFT polymerization using a thioketal dimethacrylate cross-linker to demonstrate ROS-triggered degradation, physicochemical stability in simulated gastrointestinal fluids, favorable biocompatibility, and preferential accumulation in inflamed colonic tissue. To assess how variations in size and surface charge impact in vivo therapeutic efficacy, additional formulations were synthesized, resulting in a series of nanogels (T1-T4) with hydrodynamic diameters ranging from 180 to 680 nm and surface charges from +13 to +24 mV and tested in a Citrobacter rodentium-induced model of colitis. The nanogels delivered superior therapeutic benefits, including histological recovery, restoration of epithelial architecture, reduced immune cell infiltration, and attenuation of STAT3 activation as compared to the parent drug HCQ. Cytokine and eicosanoid profiling further revealed robust local and partial systemic immunomodulatory effects, with T1 showing the greatest local efficacy but relatively limited systemic eicosanoid suppression. These findings underscore the importance of optimizing nanogel size and surface properties to balance local and systemic therapeutic outcomes. Overall, this inflammation-responsive PCQ nanogel platform represents a promising strategy for targeted ulcerative colitis therapy with potentially no side effects.