Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes.
Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes.
复制标题
DOI：
10.1016/j.jconrel.2012.08.008
复制
发表时间：
2012-09-28
期刊：
影响因子：
--
通讯作者：
Kim SW
中科院分区：
文献类型：
--
作者：
Joo WS;Jeong JH;Nam K;Blevins KS;Salama ME;Kim SW
激活受体NKG2D在1型糖尿病的发生发展中起重要作用。利用在肿瘤中观察到的一种自然现象，提取了编码NKG2D可溶性配体的质粒DNA(sRAE-1γ)，并将其构建成表达系统。建立了一种多聚体基因递送系统，将可溶性RAE-1基因递送到胰岛。用聚乙二醇(PEG)和靶向EphA2和EphA4受体的多肽CHVLWSTRC修饰了生物可还原阳离子聚合物聚(半胱胺双丙烯酰胺-二氨基己烷)(p(CBA-DAH))。我们观察到与非靶向对照组相比，NOD小鼠胰腺对靶向聚合物Eph-PEG-p(CBA-DAH)的摄取更高。为评价Eph-PEG-p(CBA-DAH)/RAE-1复合体(Polyplex)对6周龄NOD雌性小鼠预防糖尿病的效果。在17周内，注射Polyplex的动物的血糖水平稳定下来，而那些没有接受治疗质粒治疗的动物出现了进行性高血糖。此外，复合治疗组的胰岛素炎症程度和CD8+T细胞的浸润程度也比单纯靶向聚合物治疗组有所改善。目前的研究表明，携带治疗性sRAE-1基因的EPH-PEGp(CBA-DAH)的治疗可能用于保护β细胞免受自身免疫破坏，预防1型糖尿病。
The activating receptor NKG2D plays an important role in the development of type-1 diabetes. Exploiting a natural phenomenon observed in tumors, plasmid DNA encoding for a soluble ligand to NKG2D (sRAE-1γ) was isolated and engineered into a plasmid expression system. A polymeric gene delivery system was developed to deliver the soluble RAE-1 plasmid to the pancreatic islets. The bioreducible cationic polymer poly(cystamine bisacrylamide–diamino hexane) (p(CBA-DAH)) was modified with poly(ethylene glycol) (PEG) and the targeting peptide CHVLWSTRC, known to target the EphA2 and EphA4 receptors. We observed a higher uptake of the targeting polymer Eph-PEG-p(CBA-DAH) in the pancreas of NOD mice compared to non-targeting controls. To evaluate the efficacy of preventing diabetes, the Eph-PEG-p(CBA-DAH)/RAE-1 complex (polyplex) was intravenously injected into 6-week-old female NOD mice. Within 17 weeks blood glucose levels were stabilized in animals injected with polyplex, while those treated without therapeutic plasmid developed progressive hyperglycemia. Additionally, the degree of insulitis and the infiltration of CD8+ T-cells in the polyplex treated group were improved over the targeting polymer only treated group. The current study suggest that the therapy of the Eph-PEG-p(CBA-DAH) delivering therapeutic sRAE-1 gene may be used to protect β-cells from autoimmune destruction and prevent type-1 diabetes.
登录
查看更多内容
DOI：
10.1016/j.jconrel.2011.10.022
发表时间：
2012-02-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Blevins KS;Jeong JH;Ou M;Brumbach JH;Kim SW
通讯作者：
Kim SW
影响因子：
4.7
作者：
Jeong, Ji Hoon;Kim, Sun Hwa;Christensen, Lane V.;Feijen, Jan;Kim, Sung Wan
通讯作者：
Kim, Sung Wan
影响因子：
4
作者：
Mudali, Shiyama V.;Fu, Baojin;Iacobuzio-Donahue, Christine A.
通讯作者：
Iacobuzio-Donahue, Christine A.
影响因子：
7.7
作者：
Gonzalez, C;de Murcia, JM;Lévi-Strauss, M
通讯作者：
Lévi-Strauss, M
影响因子：
5.9
作者：
Kim SW
通讯作者：
Kim SW