The delivery of superoxide dismutase encapsulated in polyketal microparticles to rat myocardium and protection from myocardial ischemia-reperfusion injury.
Oxidative stress is increased in the myocardium following infarction and plays a significant role in death of cardiac myocytes, leading to cardiac dysfunction. Levels of the endogenous antioxidant Cu/Zn-superoxide dismutase (SOD1) decrease following myocardial infarction. While SOD1 gene therapy studies show promise, trials with SOD1 protein have had little success due to poor pharmacokinetics and thus new delivery vehicles are needed. In this work, polyketal particles, a recently developed delivery vehicle, were used to make SOD1-encapsulated-microparticles (PKSOD). Our studies with cultured macrophages demonstrated that PKSOD treatment scavenges both intracellular and extracellular superoxide, suggesting efficient delivery of SOD1 protein to the inside of cells. In a rat model of ischemia/reperfusion (IR) injury, injection of PKSOD, and not free SOD1 or empty particles was able to scavenge IR-induced excess superoxide 3 days following infarction. In addition, only PKSOD treatment significantly reduced myocyte apoptosis. Further, PKSOD treatment was able to improve cardiac function as measured by acute changes in fractional shortening from baseline echocardiography, suggesting that sustained delivery of SOD1 is critical during the early phase of cardiac repair. These data demonstrate that delivery of SOD1 with polyketals is superior to free SOD1 protein therapy and may have potential clinical implications.
Seshadri
Gokulakrishnan
G
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA.
Sy
Jay C
JC
Brown
Milton
M
Dikalov
Sergey
S
Yang
Stephen C
SC
Murthy
Niren
N
Davis
Michael E
ME
D000818:Animals; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000737:chemistry; D008863:Microspheres; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000737:chemistry*; D016896:Treatment Outcome
D004337:Drug Carriers; D016166:Free Radical Scavengers; D013482:Superoxide Dismutase