期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
卷 104, 期 -, 页码 157-164出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijbiomac.2017.06.020
关键词
Chitosan nanogels; pH/redox sensitivities; Stepwise response; Intracellular delivery kinetics; Drug delivery
资金
- National Natural Science Foundation of China [31670972, 31300786]
- Taishan Scholar Program, China
Chitosan based nanogels with pH/redox sensitivities tunable to stepwise response to intracellular delivery kinetics were developed. The nanogels were simply constructed by ionic gelation first, between O-Carboxymethyl-chitosan (CMCS) and thiolated chitosan (TCS), and then oxidation to form disulfide bonds for CMCS-TCS nanogels (CTNGs). Doxorubicin loaded nanogels (DOX/CTNGs) exhibited desirable stability under physiological pH with a mean size of 150.5 nm, and quickly aggregated at pH 5.5 (mimic endo/lysosomes) due to protonation of the carboxyl groups on CMCS. DOX/CFNGs would maintain their TCS skeleton in acidic pH and compromised as treated with 10 mM glutathione (mimic cytosol). In agreement with the structural variation, release of DOX was dramatically enhanced by the synergetic effects of acidic pH and reductive potential. Stepwise responses to intracellular delivery kinetics were evidenced by laser confocal images showing that DOX/CTNGs underwent efficient cellular internalization through endocytosis, endo/lysomse escape via self-precipitation, cleavage of disulfide linkage in cytosol and disintegration in nucleus, achieving enhanced nuclear delivery and rapid release of doxorubicin. DOX/CTNGs exerted comparable or higher anticancer efficacies than that of free DOX against hela cells. The simple construction of the nanogels and their capacity of enhancing anticancer activities of DOX are potential for translational applications in cancer chemotherapy. 2017 Elsevier B.V. All rights reserved.
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