title: EphA2 targeting peptide tethered bioreducible poly(cystamine bisacrylamide-diamino hexane) for the delivery of therapeutic pCMV-RAE-1γ to pancreatic islets.
abstract: 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.
authors: Department of Bioengineering, University of Utah, 20 South 2030 East, Salt Lake City, UT 84112-5820, USA.
authors: Katherine S
authors: KS
authors: Blevins
authors: Ji Hoon
authors: JH
authors: Jeong
authors: Mei
authors: M
authors: Ou
authors: Jonathan H
authors: JH
authors: Brumbach
authors: Sung Wan
authors: SW
authors: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry; D018014:Gene Transfer Techniques; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000235:genetics; D051379:Mice; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D010957:Plasmids; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D036104:Receptor, EphA2 / Q000737:chemistry*
chemical_list: D008565:Membrane Proteins; D009842:Oligopeptides; D011108:Polymers; C491217:Raet1c protein, mouse; D004247:DNA; D036104:Receptor, EphA2