Targeted delivery controlled release of hepatic growth factor and insulin-like growth factor-1 improves left ventricular repair in a porcine model of myocardial ischemia reperfusion injury

Abstract Introduction Nanomedicine offers great potential for treatment of cardiovascular disease. We tested whether direct intramyocardial (IM) injection of pro-angiogenic hepatocyte growth factor (HGF) and pro-myogenic insulin-like growth factor (IGF-1) encapsulated in Alginate-Sulfate nanoparticles (AlgS-NP) enhances myocardial retention, controlled release and improves myocardial repair in a porcine ischemia-reperfusion model. Methods Bioactivity of HGF/IGF, released from AlgS-NP, was determined by cell proliferation assays in vitro. Myocardial infarction (MI) was induced by 75min balloon occlusion of the mid-LAD followed by reperfusion. After 1w, pigs (n=12) with marked LV dysfunction (EF<45%) were randomized to fusion imaging-guided IM injections of 8 mg Cy5-labelled AlgS-NP loaded with 200μg HGF and 200μg IGF-1 (GF) or with phosphate-buffered saline (CON) using the MYOSTAR injection catheter. AlgS-NP retention after IM or intracoronary (IC) injection was determined by measuring Cy5 plasma levels. At 8w, treatment effect was evaluated using in vivo magnetic resonance imaging and coronary physiological measurements, and via post-mortem analysis of myocardial fibrosis and cardiomyocyte circumference. Results We confirmed the bioactivity of the AlgS-NP-released GF in C2C12 and HUVEC cell proliferation assays after 72h culture, being similar to the free GF (Fig. A). AlgS-NP retention was tested in a pig model, 1w after MI. Ejection fraction (EF) was 37±5% (range 27–45%) and infarct size (IS)/LVmass 24±6% (range 19–38%). AlgS-NP retention was better after IM delivery than after IC infusion with plasma Cy5 levels at 30 min after treatment indicating 5% systemic leakage for IM vs. 20% for IC. After 8w, IS/LVmass decreased 8% in GF-treated pigs vs. 3% in CON (P=0.03, Fig. B) and was associated with preserved myocardial blood flow during hyperemia in the infarct (P=0.036) and peri-infarct (PI) zones (P=0.008), increased coronary flow reserve (P=0.05) and decreased index of microcirculatory resistance (P=0.02). LVEF significantly increased in GF-treated pigs (+6±2% vs. −1±1% in CON, P=0.02, Fig. C), and was accompanied by significantly reduced fibrosis (P=0.01) and increased hypertrophy of cardiomyocyte (P=0.03) in the PI zone. Conclusions IM injection of AlgS-NP-encapsulated HGF and IGF-1 to the ischemic myocardium significantly improves LV repair, and offers the prospect of innovative treatment for patients with refractory ischemic heart disease. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EuroNanoMed II Figure AFigure B and C