Enhanced antitumor efficacies of multifunctional nanocomplexes through knocking down the barriers for siRNA delivery |
| |
| Affiliation: | 1. Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan;2. Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan;3. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan;4. Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan;1. Key Laboratory of Eco-Textiles, Ministry of Education (Jiangnan University), Wuxi 214122, China;2. College of Textile & Clothing, Jiangnan University, Wuxi 214122, China;3. Technical University of Denmark, DTU Food, Søltofts plads, B227, 2800 Kgs. Lyngby, Denmark;1. Key Laboratory of Magnetic Materials and Devices & Division of Functional Materials and Nanodevices, Ningbo Institute of Material Technology and Engineering, Ningbo 315201, PR China;2. The School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, PR China;3. Department of Medical Imaging, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, PR China;4. State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China;1. Department of Chemistry, College of Science, Huazhong Agricultural University, Wuhan 430070, PR China;2. School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive Singapore 637459, Singapore;3. Department of Chemistry, National University of Singapore, Science Drive 3 117543, Singapore;4. Institute of Materials Research and Engineering (IMRE), A*STAR, 2 Fusionopolis Way, Innovis #08-03 138634, Singapore;5. Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1 117576, Singapore |
| |
| Abstract: | Multifunctional nanocomplexes (NCs) consisting of urocanic acid-modified galactosylated trimethyl chitosan (UA-GT) conjugates as polymeric vectors, poly(allylamine hydrochloride)-citraconic anhydride (PAH-Cit) as charge-reversible crosslinkers, and vascular endothelial growth factor (VEGF) siRNA as therapeutic genes, were rationally designed to simultaneously overcome the extracellular, cellular, and intracellular barriers for siRNA delivery. The strong physical stability of UA-GT/PAH-Cit/siRNA NCs (UA-GT NCs) at pH 7.4 and 6.5 endowed protection from massive dilution, competitive ions, and ubiquitous nucleases in the blood and tumorous microenvironment. Their internalization into hepato-carcinoma cells was facilitated through the recognition of galactose receptors, followed by effective escape from endosomes/lysosomes owing to the strong buffering capacity of imidazole residues. At the meantime, the endosomal/lysosomal acidity triggered the charge reversal of PAH-Cit in UA-GT NCs, thus evoking their structural disassembly and subsequently accelerated release of siRNA in the cytosol. As a result, robust in vivo performance in terms of both gene silencing and tumor inhibition was achieved by UA-GT NCs at a low siRNA dose. Moreover, neither histological nor hematological toxicity was detected following repeated intravenous administration. Therefore, UA-GT NCs potentially served as an efficient and safe candidate in the treatment of hepatocellular carcinoma through knocking down the overall barriers for siRNA delivery. |
| |
| Keywords: | siRNA delivery Extracellular stability Active targeting Endosomal escape Intracellular release Cancer therapy |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
