A redox stimuli-responsive superparamagnetic nanogel with chemically anchored DOX for enhanced anticancer efficacy and low systemic adverse effects

Abstract

A reduction-triggered superparamagnetic nanogel was designed for enhancing targeting release but minimizing leakage of drug in the drug-transportation pathway. Doxorubicin (DOX) was first conjugated onto sodium alginate (SA) with a disulfide linker (SA-SS-DOX). SA-SS-DOX was then electrostatically assembled with aminated superparamagnetic iron oxide nanoparticles for the preparation of nanogel. The nanogel was estimated with a size of 122 ± 15 nm, a polydispersity index of 0.178, a surface charge of around −36.0 mV, a DOX loading of 7.2 wt%, and a saturation magnetization of 40.0 emu g⁻¹ Fe. In vitro release profiles showed a significantly high accumulative release at pH 5.5/10 mM Glutathione (GSH) but pretty low release at pH 7.4/pH 5.5 without GSH, exhibiting apparent reduction responsiveness. In vitro cytotoxicity tests clearly illustrated that the effective selectivity of killing the human cervical cancer cells (HeLa) with a IC₅₀ of 0.30 μg mL⁻¹, significantly enhanced the cytotoxicity of the African green monkey Sv40-transformed kidney fibroblast cells (COS-7). Prussian blue staining and quantification of cellular iron and protein concentration revealed apparent iron uptake by HeLa cells. Confocal laser scanning microscopy observation demonstrated that DOX was efficiently internalized into HeLa cells, released into the cytoplasm, and then principally entered the nuclei. In vivo investigation exhibited that nanogel treatment induced obvious shrinkage in tumor volume but a stable growth in body weight and a healthy appearance. Hematoxylin-eosin (H&E) staining indicated remarkable necrosis in the tumor area and histologic examination revealed lower toxicity in vital organs. Thus this kind of nanogel expressed high targeted release but low systemic toxicity. It is thus believed that this nanogel will offer a promising candidate for highly effective cancer therapy.