Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes

JOURNAL OF CONTROLLED RELEASE

卷:162

Article

Jeong, Ji Hoon²  Salama, Mohamed E.³  Kim, Sung Wan¹ 

[1] Univ Utah, Ctr Controlled Chem Delivery, Dept Pharmaceut & Pharmaceut Chem, BPRB, Salt Lake City, UT 84112 USA

[2] Sungkyunkwan Univ, Sch Pharm, Suwon 440746, South Korea

[3] Univ Utah, ARUP Reference Lab Res Inst, Dept Pathol, Salt Lake City, UT 84112 USA

关键词: Gene therapy;    Drug delivery;    Retinoic acid early inducible gene-1 (RAE-1);    Type 1 diabetes;   

DOI  :  10.1016/j.jconrel.2012.08.008

来源: Elsevier

【 摘 要 】

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-1.) was isolated and engineered into a plasmid expression system. A polymeric gene delivery systemwas 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 suggests that the therapy of the Eph-PEG-p (CBA-DAH) delivering therapeutic sRAE-1 gene may be used to protect beta-cells from autoimmune destruction and prevent type-1 diabetes. (C) 2012 Elsevier B. V. All rights reserved.

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