Dexamethasone-loaded peptide micelles for delivery of the heme oxygenase-1 gene to ischemic brain

• Published in: Journal of controlled release Vol. 158; no. 1; pp. 131 - 138
• Main Authors: Lee, Jiyoung, Hyun, Hyesun, Kim, Jinyoung, Ryu, Jae Hwan, Kim, Hyun Ah, Park, Ji Hwan, Lee, Minhyung
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 28-02-2012; Elsevier
• Subjects: Animals; aqueous solutions; Biological and medical sciences; brain; Brain - metabolism; Brain Ischemia - genetics; Brain Ischemia - metabolism; Cell Line; Cell Line, Tumor; dexamethasone; Dexamethasone - administration & dosage; Disease Models, Animal; fluorescence; Gene delivery; Gene therapy; Gene Transfer Techniques; General pharmacology; genes; Genetic Therapy; HEK293 Cells; heme oxygenase (biliverdin-producing); Heme Oxygenase-1 - administration & dosage; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - pharmacokinetics; Humans; hydrophobicity; Immunosuppressive Agents - administration & dosage; infarction; interleukin-6; Interleukin-6 - metabolism; kidneys; lipopolysaccharides; Male; Medical sciences; Mice; Micelle; Micelles; Oligopeptides - administration & dosage; Peptide; peptides; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; plasmids; Rats; Rats, Sprague-Dawley; Stroke; transfection; Micelle; Gene delivery; Stroke; Gene therapy; Peptide; Peptides; Cardiovascular disease; Encephalon; Vascular disease; Gene; Ischemia; Genetics; Cerebrovascular disease; Corticosteroid; Nervous system diseases; Dexamethasone; Pharmaceutical technology; Enzyme; Steroid hormone; Antiinflammatory agent; Heme oxygenase (decyclizing); Cerebral disorder; Genetic transfer; Central nervous system disease; Oxidoreductases
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2011.11.001

The R3V6 peptides, which are composed of a 3-arginine block and a 6-valine block, formed self-assembled micelles in aqueous solution. Dye quenching assays showed that a hydrophobic fluorescent dye, 5-dodecanoylaminofluorescein (DAF), interacted with and was loaded into the hydrophobic core of the micelles. In this study, dexamethasone-loaded R3V6 peptide micelles (R3V6-Dexa) were evaluated as a gene carrier. R3V6-Dexa had higher gene delivery efficiency in human embryonic kidney 293 cells compared to those of the R3V6 peptides and poly-l-lysine (PLL). Dexamethasone might stabilize the micelle structure of the R3V6 peptides by forming strong hydrophobic cores and enhanced the transfection efficiency. Furthermore, R3V6-Dexa reduced the expression of an inflammatory cytokine, interleukin-6 (IL-6), more efficiently in lipopolysaccharide (LPS)-induced Raw264.7 cells than did dexamethasone, suggesting that R3V6-Dexa is also a useful carrier for dexamethasone delivery. A focal brain ischemia-reperfusion model was produced by middle cerebral artery occlusion (MCAO). A heme oxygenase-1 (HO-1) expression plasmid DNA, pSV-HO-1, was delivered into the brain using R3V6-Dexa as a carrier. The pSV-HO-1/R3V6-Dexa complex was injected into the brain 1hr prior to MCAO. Twenty-four hours later, the HO-1 expression of the pSV-HO-1/R3V6-Dexa injection group was higher than those of the MCAO control, pβ-Luc/R3V6-Dexa, and pSV-HO-1/PEI25k injection groups. In addition, the infarct size was reduced due to the delivery of pSV-HO-1/R3V6-Dexa complex. Therefore, R3V6-Dexa may be a useful carrier for HO-1 gene delivery and stroke gene therapy.
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