A networked swellable dextrin nanogels loading Bcl2 siRNA for melanoma tumor therapy
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In this study, a networked swellable dextrin nanogel (DNG) was developed to achieve stimulated responsive small interfering RNA (siRNA) release for melanoma tumor therapy. siRNA was loaded into multidimensional dextrin nanogels by charge condensation with positive arginine residues modified in the dextrin backbone. Moreover, the networked nanogel was destroyed and loosened based on its bioreducible responsive property to control accelerated siRNA release in a bioreducible intracellular environment, while it remained stable under normal physiological conditions. We demonstrated that DNGs had swellable and disassembly properties under reduced buffer condition by transmission electron microscopy evaluation. The DNGs achieved an endosomal escape followed by selective release of the cargo into the cytosol by glutathione-triggered disassembly according to confocal microscopy observation. Thus, this smart nanogel achieved outstanding luciferase gene silencing efficiency and decreased Bcl2 protein expression in vitro and in vivo based on western blot analysis. Moreover, this nanogel exhibited superior anti-tumor activity for B16F10 xenograft tumors in C57BL/6 mice. These results demonstrate that the networked DNGs are effective for gene condensation and controlled intracellular release for tumor therapy. Overall, these findings suggest that this multidimensional swellable stimuli-responsive dextrin nanogel is an innovative strategy with great promise for gene and drug delivery.
Keywordsdextrin nanogels local enrichment reduction-responsive lysosomal escape disulfide cross-linked small interfering RNA (siRNA) delivery
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This work was financially supported by the National Science and Technology Major Project (No. 2017YFA0205400), the National Natural Science Foundation of China (Nos. 81373983 and 81573377), the Jiangsu Fund for Distinguished Youth (No. BK20170028) and the Natural Science Foundation of Jiangsu Province (No. BK20141352). The authors also acknowledged Dr. Maoshen Jie (Roquette Ltd., Shanghai, China) for his kind help in providing dextrin.
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