EphA2 targeting peptide tethered bioreducible poly(cystamine bisacrylamide-diamino hexane) for the delivery of therapeutic pCMV-RAE-1γ to pancreatic islets.
EphA2 targeting peptide tethered bioreducible poly(cystamine bisacrylamide-diamino hexane) for the delivery of therapeutic pCMV-RAE-1γ to pancreatic islets.
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DOI：
10.1016/j.jconrel.2011.10.022
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发表时间：
2012-02-28
期刊：
影响因子：
--
通讯作者：
Kim SW
中科院分区：
文献类型：
--
作者：
Blevins KS;Jeong JH;Ou M;Brumbach JH;Kim SW
1型糖尿病的发病机制复杂，目前尚无明确、单一的发病机制。研究表明，激活受体NKG2D在疾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。为了预防1型糖尿病，开发了一种多聚体基因递送系统，将可溶性RAE-1基因局部递送到胰岛。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))。聚乙二醇单抗用于提高稳定性和组织选择性，而多肽将针对在胰腺微血管中过度表达的EphA2和A4。靶向聚合物Eph-PEG-p(CBA-DAH)显示出对靶细胞的选择性摄取，表明全身给药将看到靶向特性。利用该递送系统，治疗性质粒可被运送到胰腺，减少β细胞与渗透的NKG2D阳性淋巴细胞之间的相互作用，并有效地保护β细胞免受自身免疫破坏，预防1型糖尿病。
The pathogenesis of type-1 diabetes is complicated, and a clear, single mechanism has yet to be identified. Reports have indicated that the activating receptor NKG2D plays an important role in the development of disease. 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 locally to the pancreatic islets for the prevention of type-1 diabetes. 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. The PEG serves to improve stability and tissue selectivity, while the peptide will target EphA2 and A4, overexpressed in the pancreatic microvasculature. The targeting polymer Eph-PEG-p(CBA-DAH) shows selective uptake by the target cell line, indicative of the targeting properties that will be seen in systemic administration. Using the delivery system, the therapeutic plasmid can be delivered to the pancreas, reduce interactions between the beta-cells and infiltrating NKG2D positive lymphocytes, and effectively protect beta-cells from autoimmune destruction and prevent type 1 diabetes.
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DOI：
10.1016/j.jconrel.2011.02.013
发表时间：
2011-05-30
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Kim TI;Rothmund T;Kissel T;Kim SW
通讯作者：
Kim SW
影响因子：
4.7
作者：
Lin, Chao;Zhong, Zhiyuan;Engbersen, Johan F. J.
通讯作者：
Engbersen, Johan F. J.
影响因子：
4.6
作者：
Kim, Sun Hwa;Ou, Mei;Kim, Sung Wan
通讯作者：
Kim, Sung Wan
影响因子：
4.7
作者：
Christensen, Lane V.;Chang, Chien-Wen;Feijen, Jan
通讯作者：
Feijen, Jan
影响因子：
2.7
作者：
Caillat-Zucman, Sophie
通讯作者：
Caillat-Zucman, Sophie