Therapeutic effects of a reducible poly (oligo-D-arginine) carrier with the heme oxygenase-1 gene in the treatment of hypoxic-ischemic brain injury.
Non-viral carriers for gene therapy have been developed to minimize carrier cytotoxicity and to enhance transfection efficiency. Previously, we synthesized a 9-arginine-based reducible high molecular weight peptide for gene delivery. For the reducible poly(oligo-D-arginines) (rPOA), 9-arginine oligopeptides are connected by internal disulfide linkages to produce a high molecular weight peptide. In this study, rPOA was evaluated as a carrier of the heme oxygenase-1 (HO-1) gene for the treatment of ischemia/reperfusion (I/R) -induced brain stroke. An in vitro transfection assay showed that rPOA had higher transfection efficiency and lower toxicity than polyethylenimine (PEI). For in vivo evaluation, I/R rat models were produced by middle cerebral artery occlusion (MCAO). rPOA/HO-1 expression plasmid (pHO-1) polyplexes were injected into the brain at 1 h before MCAO, and HO-1 expression levels in the brain were then measured by ELISA. The results indicated that rPOA/pHO-1 polyplexes had higher transfection efficiencies than PEI/pHO-1 polyplexes. The rPOA/pHO-1 polyplexes significantly reduced infarct volumes. In addition, tumor necrosis factor-alpha (TNF-α) was reduced in the rPOA/pHO-1 polyplex injection group, suggesting that HO-1 had an anti-inflammatory effect, while the PEI/pHO-1 polyplex did not show this effect. These results suggest that rPOA is a potential non-viral vector for HO-1 gene therapy to protect brain cells from I/R-related neuronal injury including stroke.
Hyun
Hyesun
H
Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
Won
Young-Wook
YW
Kim
Kyung-Min
KM
Lee
Jiyoung
J
Lee
Minhyung
M
Kim
Yong-Hee
YH
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D020520:Brain Infarction / Q000150:complications / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry*; D024202:Electrophoretic Mobility Shift Assay; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000627:therapeutic use*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000473:pathology / Q000628:therapy*; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D051379:Mice; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D010957:Plasmids / Q000235:genetics; D011506:Proteins / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D004337:Drug Carriers; D010455:Peptides; D011506:Proteins; C015462:polyarginine; D051547:Heme Oxygenase-1