Delivery of two-step transcription amplification exendin-4 plasmid system with arginine-grafted bioreducible polymer in type 2 diabetes animal model
- Authors
- Kim, Pyung-Hwan; Lee, Minhyung; Kim, Sung Wan
- Issue Date
- Aug-2012
- Publisher
- ELSEVIER
- Keywords
- Diabetes; Exendin-4 polyplex; TSTA system; Gene delivery
- Citation
- JOURNAL OF CONTROLLED RELEASE, v.162, no.1, pp.9 - 18
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF CONTROLLED RELEASE
- Volume
- 162
- Number
- 1
- Start Page
- 9
- End Page
- 18
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/165019
- DOI
- 10.1016/j.jconrel.2012.06.010
- ISSN
- 0168-3659
- Abstract
- Exendin-4, glucagon-like peptide 1 (GLP-1) receptor agonist, is an exocrine hormone, which has potent insulinotropic actions similar to GLP-1 such as stimulating insulin biosynthesis, facilitating glucose concentration dependent insulin secretion, slowing gastric emptying, reducing food intake and stimulating beta-cell proliferation. Exendin-4, also, has a longer half-life than GLP-1, due to its resistance to degradation by dipeptidyl peptidase-IV (DPP-IV). In spite of its many advantages as a therapeutic agent for diabetes, its clinical application is still restricted. Thus, to improve the activity of exendin-4 in vivo, gene therapy system was developed as an alternative method. An exendin-4 expression system was constructed using the two-step transcription amplification (TSTA) system, which is composed of p beta-Gal4-p65 and pUAS-SP-exendin-4 with combining the advantages of signal peptide (SP) in order to facilitate its secretion in ectopic cells or tissue. Arginine-grafted cyctaminebisacrylamide-diaminohexane polymer (ABP) was used as a gene carrier. Increased expression of exendin-4, glucose dependent insulin secretion in NIT-1 insulinoma cells, and high insulin expression in the presence of DPP-IV were evaluated in vitro after delivery of ABP/TSTA-SP-exendin-4. Blood glucose levels in diabetic mice were decreased dramatically from the third day for experimental period after single intravenous administration with ABP/TSTA-SP-exendin-4. The highest insulinotropic effect of exendin-4 was also observed in the ABP/TSTA/SP-exendin-4-treated mice groups, compared with the others groups from the 3rd day after injection. TSTA exendin-4 expression system with SP and ABP polymer has a potential gene therapy for the treatment of type 2 diabetes.
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