Efficient reduction and pH co-triggered DOX-loaded magnetic nanogel carrier using disulfide crosslinking

To reduce leakage on the drug-delivery pathway to minimize side effect of reduction or pH sensitive drug delivery systems, we designed a glutathione (GSH)/pH co-triggered magnetic nanogel drug delivery system for doxorubicin (DOX) based on the GSH concentration and pH difference between intracellular and extracellular environments. The introduction of superparamagnetic iron oxide nanoparticles (SPION) was intended for magnetic targeting. The magnetic DOX-loaded nanogel was then prepared by the oxidation of thiolated alginate with thiolated SPION in the presence of DOX. The nanogel size can be readily regulated in a range of 120-320 nm upon preparation conditions, with a negative surface charge of around -40 mV. Saturation magnetization was estimated at 27.4 emu/g Fe by VSM. In vitro release was conducted in simulated cancerous environment conditions such as a high GSH concentration and mild acidity. As a result, the nanogel expressed, upon dual stimuli of pH 5/10 mM GSH, significantly higher accumulative release than upon single stimulus of pH 5 without GSH or pH 7.4/10 mM GSH. In vitro cytotoxicity against HeLa cells clearly illustrated that the nanogel could effectively inhibit cell growth, and the IC50 was figured out to be 2.3 μg/mL of the nanogel, while the nanogel exclusive of DOX was nontoxic. Confocal laser scanning microscopy observation, combined with the result of Prussian blue staining, indicated that DOX was efficiently internalized into HeLa cells through endocytosis, released into the cytoplasm, and then principally entered the nuclei. The quantitative examination of the iron content revealed an exponential increase in the cellular uptake and an exponential decrease in the uptake efficiency with the fed nanogel. This drug-loaded nanogel could be a promising drug carrier for effective tumor-targeted chemotherapy.