Growth factor loaded-microparticles as a tool for cardiac repair

Resumen

Myocardial infarction (MI) is a major health concern worldwide. Over the years extensive research has been conducted to find new treatments. Growth factor (GF)-based therapy has emerged as a promising strategy to treat patients with MI. However, the therapeutic value of GF has important limitations in vivo, related to their short-lived effect and high instability after systemic administration. In this work, we evaluated the therapeutic potential of GF encapsulated in Poly(lactic-co-glycolic acid) (PLGA) microparticles (MP) to repair the myocardium after a MI. First, we developed PLGA-MP by Total Recirculation One-Machine System (TROMS). MP with a diameter of 5 µm were found to be compatible for intramyocardial administration in terms of injectability and tissue response. Next, we prepared vascular endothelial growth factor (VEGF)-loaded PLGA-MP, which released bioactive VEGF in a sustained manner in vitro. In a rat model of ischemia-reperfusion, an increase in vascularization was observed in animals treated with VEGF-MP (p<0.05), but not in the non-loaded MP (NL-MP) or free VEGF groups at 30 days follow-up. Correlating with this data, a positive remodeling of the heart was also detected in the VEGF-MP group with a significantly greater left ventricle wall thickness (p<0.01). Next, we sought to explore further mechanisms of cardiac repair that could be therapeutically induced by GF. For that, we prepared PLGA-MP loaded with acidic fibroblast growth factor (FGF-1) and neuregulin-1 (NRG-1), two factors involved in distinct mechanisms of cardiac repair after MI. FGF-1 and NRG-1 were successfully encapsulated into PLGA-MP, which released the bioactive factors in a controlled manner for up to 28 days in vitro. Also, we have demonstrated that PLGA-MP remained in the heart tissue for up to 90 days. The ability of FGF-1 and/or NRG-1 MP to promote cardiac regeneration was evaluated in a rat model of MI (permanent ligation). Three months after treatment, a cardiac function improvement was detected in the rats treated with FGF1-MP (16.7 ± 4.9%, P<0.05), NRG1-MP (18.0 ± 5.7%, P<0.05) or FGF1/NRG1-MP (13.0 ± 1.9%, P<0.05) in comparison with the NL-MP control group (1.1 ± 3.6%). In addition, a positive cardiac remodeling with a smaller infarct size and a significant tissue revascularization were detected. Also, recruitment of c-Kit+ progenitor cells towards the ischemic myocardium under stimulation of FGF-1 and NRG-1 delivered from the MP was identified. Taken together, these findings support the feasibility of PLGA-MP to enhance the efficacy of VEGF, FGF-1 and NRG-1 by triggering various mechanisms of cardiac repair, paving the way for therapeutic application of these factors in the setting of MI.