Delivery of two-step transcription amplification exendin-4 plasmid system with arginine-grafted bioreducible polymer in type 2 diabetes animal model.
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 β-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 pβ-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.
Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Pyung-Hwan
PH
Kim
Minhyung
M
Lee
Sung Wan
SW
Kim
D000818:Animals; D001120:Arginine / Q000737:chemistry*; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D004337:Drug Carriers / Q000737:chemistry; D000077270:Exenatide; D015870:Gene Expression; D015316:Genetic Therapy; D052216:Glucagon-Like Peptide 1 / Q000819:agonists; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000235:genetics*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D011108:Polymers / Q000737:chemistry; D014158:Transcription, Genetic; D014688:Venoms / Q000235:genetics*
D001786:Blood Glucose; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D011108:Polymers; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D004247:DNA; D001120:Arginine; D000077270:Exenatide