Preparetion And Characteration Of Combinational Stimuli-responsive Magnetic Nanogel With Parallel Structure For Controlled Drug Delivery

It’s known that, there are many differences between the tumor and normal tissue. And it has developed variety of different responsive carriers. However, in complex environment of body, the limitations of single responsive has gradually exposed. In this paper, according to the different pH and GSH concentration between the tumor and normal tissue, two kinds of nanogel which have pH/GSH dual parameter-stimulated release mode were presented with magnetic nanoparticles. The nanogel features the targeting release under combinational stimuli by acid and reduction environment with low release level in healthy tissues.First, a superparamagnetic DOX-loaded nanogel-D with the typical logic “and”-type dual parameter-stimulated release mode was presented. Dextran was first modified to involve both thiol groups and carboxyl groups. The dextran derivative was then covalently coupled with previously thiolated/aminated magnetic iron oxide nanoparticles(SH-MION-NH2) through both the linkage of disulfide bond and electrostatic interaction. Upon the optimal conditions, a nanogel was fabricated via the dual crosslinking. The nanogel features the targeting release under combinational stimuli by acid and reduction environment with low release level in healthy tissues. In vitro release profiles revealed these release modes as expected. Cytotoxicity assay exhibited a much lower toxicity of the DOX-loaded nanogel-D to African green monkey kidney fibroblast-like cell line(COS-7) cells than free DOX. Prussian blue staining and Confocal laser scanning microscopy observation revealed the cellular uptake and subcellular release in nuclei of the nanogel. Hematoxylin-eosin(H & E) staining indicated remarkable necrosis in the tumor area. In vivo study exhibited that the nanogel presented inhibition rate of 67.3% on tumor and a stable growth in body weight and a healthy appearance.In order to simplify the preparation of nanogel based on dextran, a new nanogel was presented. The disulfide bond and electrostatic interaction between thiolated alginate(SA-SH) and SH-MION-NH2 were employed to achieve the mechanism. The obtained DOX-loaded magnetic nanogel-A is 122.7±20.3 nm in size with superparamagnetism. In vitro release profiles can also revealed the typical logic “and”-type dual parameter-stimulated release mode. In vitro cytotoxicity tests clearly illustrated the effective selectivity of killing the human cervial cancer cells(HeLa) with IC50 of 1.01 μg/mL and the human hepatoma cells(HepG2) with IC50 of 1.57 μg/mL but significantly low cytotoxicity to the cercopithecus aethiops kidney cells(Vero). CLSM presented the internationalization of the nanogel into cytoplasm and nuclei with time. In vivo investigation revealed that the selective intratumoral accumulation and antitumor efficacy were significantly advantageous over free DOX whereas low systemic toxicity exhibited up-regulated security as compared to free DOX. Comparing with DOX-loaded magnetic nanogel-D, DOX-loaded magnetic nanogel-A also have the typical logic “and”-type dual parameter-stimulated release mode, but simple preparation.