title: Targeted gene delivery to ischemic myocardium by homing peptide-guided polymeric carrier.
abstract: Myocardial ischemia needs an alternative treatment such as gene therapy for the direct protection of cardiomyocytes against necrosis or apoptosis and to prevent the development of myocardial fibrosis and cardiac dysfunction. Despite the utility of gene therapy, its therapeutic use is limited due to inadequate transfection in cardiomyocytes and difficulty in directing to ischemic myocardium. Here, we present a polymeric gene carrier that is capable of targeting ischemic myocardium, resulting in high localization within the ischemic zone of the left ventricle (LV) of an ischemia/reperfusion (I/R) rat model upon systemic administration. Cystamine bisacrylamide-diamino hexane (CD) polymer was modified with the ischemic myocardium-targeted peptide (IMTP) and D-9-arginine (9R) for dual effects of the homing to ischemic myocardium and enhanced transfection efficiency with minimized polymer use. Conjugation of IMTP and 9R to CD led to an increase in transfection under hypoxia and significantly reduced the amount of polymer required for high transfection. Finally, we confirmed targeting of IMTP-CD-9R/DNA polyplex to ischemic myocardium and enhanced gene expression in LV of the I/R rat after tail vein injection. This study provides a clue that gene therapy for the treatment of myocardial ischemia can be achieved by using homing peptide-guided gene delivery systems.
authors.affiliation: Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Young-Wook
authors.initials: YW
authors.lastname: Won
authors.forename: Arlo N
authors.initials: AN
authors.lastname: McGinn
authors.forename: Minhyung
authors.initials: M
authors.lastname: Lee
authors.forename: David A
authors.initials: DA
authors.lastname: Bull
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D004337:Drug Carriers / Q000008:administration & dosage; D015870:Gene Expression / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy / Q000235:genetics; D008297:Male; D017202:Myocardial Ischemia / Q000235:genetics* / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000235:genetics; D011108:Polymers / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000235:genetics; D014162:Transfection / Q000379:methods
chemical_list: D004337:Drug Carriers; D010455:Peptides; D011108:Polymers; D004247:DNA