A Novel PEGylation Method for Improving the Pharmacokinetic Properties of Anti-Interleukin-17A RNA Aptamers
| Autor: | Hiroaki Yamazaki, Kazuhiko Haruta, Kuniyoshi Hota, Masayuki Takahashi, Hideaki Sato, Natsuki Otaki, Shinsuke Hiramoto, Asako Sasaki, Tomoyoshi Kayo, Masakazu Nagamine |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Aptamer 02 engineering and technology Polyethylene glycol Pharmacology interleukin-17A Biochemistry Polyethylene Glycols Inhibitory Concentration 50 Mice 03 medical and health sciences chemistry.chemical_compound RNA Aptamers Pharmacokinetics Drug Discovery PEG ratio Genetics Animals Humans Molecular Biology Nuclease biology Interleukin-6 Interleukin-17 PEGylation aptamer Original Articles Aptamers Nucleotide 021001 nanoscience & nanotechnology Mice Inbred C57BL Macaca fascicularis 030104 developmental biology chemistry NIH 3T3 Cells biology.protein Molecular Medicine Interleukin 17 0210 nano-technology pharmacokinetics Blood Chemical Analysis Injections Intraperitoneal |
| Zdroj: | Nucleic Acid Therapeutics |
| ISSN: | 2159-3345 2159-3337 |
| DOI: | 10.1089/nat.2016.0627 |
| Popis: | The obstacles to the development of therapeutic aptamers for systemic inflammatory diseases, such as nuclease degradation and renal clearance, have not been fully overcome. Here, we report a novel PEGylation method, sbC-PEGylation, which improves the pharmacokinetic properties of RNA aptamers that act against interleukin-17A (IL-17A) in mice and monkeys. sbC-PEGylated aptamers were synthesized by coupling the symmetrical branching molecule 2-cyanoethyl-N,N-diisopropyl phosphoroamidite to the 5' end of the aptamer, before conjugating two polyethylene glycol (PEG) molecules to the aptamer. Pharmacokinetic studies showed that compared with conventionally PEGylated aptamers, the sbC-PEGylated aptamer exhibited excellent stability in the blood circulation of mice and monkeys. In addition, one of the sbC-PEGylated aptamers, 17M-382, inhibited the interleukin-6 (IL-6) production induced by IL-17A in NIH3T3 cells in a concentration-dependent manner, and the half-maximal inhibitory concentration of sbC-PEGylated 17M-382 was two times lower than that of non-PEGylated 17M-382. Furthermore, the intraperitoneal administration of sbC-PEGylated 17M-382 significantly inhibited the IL-6 production induced by IL-17A in a mouse air pouch model. Our findings suggest that the novel PEGylation method described in this study, sbC-PEGylation, could be used to develop anti-IL-17A aptamers as a therapeutic option for systemic inflammatory disease. |
| Databáze: | OpenAIRE |
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