The delivery of superoxide dismutase encapsulated in polyketal microparticles to rat myocardium and protection from myocardial ischemia-reperfusion injury

Abstract

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.

Antioxidant-based therapies for angiotensin II-associated cardiovascular diseases

“…In other studies, poly(cyclohexane-1,4-diyl acetone dimethylene ketal) polymer was used to deliver CuZnSOD to the heart. These CuZnSOD polyketal particle-encapsulated microparticles (PKSOD) injected into the perimeter of the cyanotic ischemic zone scavenged excess O 2˙Ϫ , prevented myocyte apoptosis, and improved cardiac function in a rat model of myocardial I/R injury (125). Although these PKSOD microparticles were not in the nanometer-size range, they could potentially be reformulated to afford the benefits of nanomedicine, including a more clinically relevant and noninvasive route of administration than direct myocardial injection.…”

Acute Preconditioning of Cardiac Progenitor Cells with Hydrogen Peroxide Enhances Angiogenic Pathways Following Ischemia-Reperfusion Injury

“…The animals were anesthetized with isoflurane and, after tracheal intubation, MI was induced by occlusion of the left anterior descending artery for 30 min followed by reperfusion [22]. Immediately following reperfusion, three injections of Luc + GFP + CPCs in self-assembling peptides were made in the border zone of the left ventricular free wall, while the heart was beating.…”

Nano- and Microscale Delivery Systems for Cardiovascular Therapy

“…AcDex microparticles that were 40-70 μm released basic fi broblast growth factor (bFGF) into the myocardium for over 28 days and despite acute infl ammatory response showed biocompatibility. In another rat model of myocardial ischemia/reperfusion injury, polyketal microparticles (12 μm) delivering an antioxidant superoxide dismutase reduced oxidative stress by sustainably scavenging superoxide early during injury and enhanced cardiac function [ 79 ]. A recent study demonstrated a PLGA microparticles formulation optimized for intramyocardial injection and host response [ 80 ].…”