Room-temperature synthesis of ultrasmall redox-responsive nanogels for tumor-microenvironment-triggered drug release and in vivo tumor growth suppression

This study focuses on the easy and fast synthesis of exceptionally small nanogels. To the best of our knowledge, this is the first report of redox-degradable, multi-stimuli-responsive nanogels with a uniform diameter below 30 nm prepared entirely at room temperature without surfactants or organic solvents. pH- and thermo-responsive and degradable nanogels, with uniform diameters below 30 nm (TEM), were produced entirely at room temperature without surfactants or organic solvents, through a semi-batch radical polymerization of N-isopropylacrylamide (NIPA) with cross-linking achieved using the redox-sensitive linker N,N′-diacryloyl-L-cystine disodium salt (DACS), synthesized in our laboratory. Notably, these nanogels exhibited multifunctional attributes. The incorporation of COO- from DACS provided pH sensitivity, stability, and the capacity to bind the anticancer drug Epirubicin (EPB). Microscopy analysis confirmed that the nanogels degraded, especially in environments simulating cancer cells with high glutathione concentrations, which act as a reductor for -S-S- bridges. EPB release profiles indicated minimal release at pH 7.4, while the highest release occurred at pH 5.0 with cGSH = 40 mM, conditions typical of most cancer cells. The nanogel exhibited relatively high drug loading capacity (approx. 33%). As drug carriers, the EPB loaded nanogels exhibited high toxicity against cancer cells and low toxicity against healthy cells. In vivo analyses revealed variable but overall suppressive effects of the EPB loaded nanogel formulation on tumor growth, accompanied by areas of necrosis and fibrotic tissue remodeling. Our strategy opens a simple and green route toward next-generation stimuli-responsive nanogels for cancer chemotherapy.