Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
J Control Release. 2012 Aug 20;162(1):9-18. doi: 10.1016/j.jconrel.2012.06.010. Epub 2012 Jun 15.
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.
Exendin-4，胰高血糖素样肽 1（GLP-1）受体激动剂，是一种外分泌激素，具有类似于 GLP-1 的强大胰岛素促分泌作用，如刺激胰岛素生物合成、促进葡萄糖浓度依赖的胰岛素分泌、减缓胃排空、减少食物摄入和刺激β细胞增殖。Exendin-4 由于其对二肽基肽酶-IV（DPP-IV）的降解具有抗性，因此半衰期比 GLP-1 更长。尽管它作为糖尿病治疗剂具有许多优点，但它的临床应用仍然受到限制。因此，为了提高 exendin-4 在体内的活性，开发了基因治疗系统作为替代方法。使用两步转录扩增（TSTA）系统构建了 exendin-4 表达系统，该系统由 pβ-Gal4-p65 和 pUAS-SP-exendin-4 组成，结合了信号肽（SP）的优点，以促进其在异位细胞或组织中的分泌。精氨酸接枝环丁烷双丙烯酰胺-二氨基己烷聚合物（ABP）被用作基因载体。在体外，用 ABP/TSTA-SP-exendin-4 转染后，评估了 NIT-1 胰岛素瘤细胞中 exendin-4 的表达增加、葡萄糖依赖性胰岛素分泌以及存在 DPP-IV 时的高胰岛素表达。在单次静脉注射 ABP/TSTA-SP-exendin-4 后的实验期间，糖尿病小鼠的血糖水平从第 3 天开始显著降低。与其他组相比，在注射后第 3 天，ABP/TSTA/SP-exendin-4 治疗组也观察到 exendin-4 的最大胰岛素促分泌作用。带有 SP 和 ABP 聚合物的 TSTA exendin-4 表达系统具有治疗 2 型糖尿病的潜在基因治疗作用。
