Intramyocardial sustained delivery of placental growth factor using nanoparticles as a vehicle for delivery in the rat infarct model

Abstract

Background Acute myocardial ischemia results in scar formation with ventricular dilatation and eventually heart failure. Placental growth factor (PlGF) is reported to stimulate angiogenesis and improve cardiac function. In this study, it was hypothesized that intramyocardial injection of PlGF contained in nanoparticles can be released at the site of action for an extended time period as a sustained slow-release protective mechanism that accelerates myocardial recovery in a rat model of ischemic cardiomyopathy. Methods PlGF-loaded chitosan-alginate nanoparticles were injected into an acute myocardial infarction model in rats (n = 10 per group). Transthoracic echocardiography was performed at different time intervals. Enzyme-linked immunosorbent assay was used to measure the serum cytokines levels at 8 weeks. Hearts were stained with Masson’s trichrome for scar area analysis. Immunofluorostaining was performed to evaluate the extent of myocardial angiogenesis at the infarction border. PlGF enzyme-linked immunosorbent assay was used to measure the in vitro release kinetics of PlGF-loaded nanoparticles. Results At 8 weeks after coronary ligation, hearts that were treated with PlGF-loaded chitosan-alginate nanoparticles had significant increases in left-ventricular function ( P < 0.01), vascular density ( P < 0.01), and in the serum level of the anti-inflammatory cytokine interleukin-10 ( P < 0.05). There was significant decrease in scar area formation ( P < 0.05) and in serum levels of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 ( P < 0.01). In vitro PlGF-release kinetic studies showed a sustained release of PlGF from the particles over a 120-hour period. Conclusion The use of nanoparticles as a vehicle for PlGF delivery, as opposed to the direct injection of the growth factor after acute myocardial infarction, can provide sustained slow-release PlGF therapy, enhancing the positive effects of the growth factor in the setting of acute myocardial ischemia.

Cardioprotective activity of placental growth factor combined with oral supplementation of L-arginine in a rat model of acute myocardial infarction

“…PlGF induces new vascular formation by two mechanisms:6,20 stimulation of the local proliferation of endothelial cells and smooth muscle cells and recruitment of EPCs to the myocardium tissue. Recent examinations have revealed that exogenous administration of rhPlGF improves cardiac function and enhances anti-inflammatory cytokine expression; it also reduces the infarction area and regulates metalloproteinase-mediated myocardial tissue remodeling 5,21…”

“…Previous studies have focused on dosage, approaches, or time of administration, whereas few of them have concentrated on improving endothelial environment 5,6,7,21,23…”

“…It is a 50-kDa homodimeric glycoprotein sharing 53% sequence homology at the amino acid level with the vascular endothelial growth factor (VEGF) 4. Previous studies showed that VEGF did not reduce infarction size and improved cardiac function despite its strong angiogenic characteristics, while PlGF significantly improved ventricular remodeling by stimulating angiogenesis and arteriogenesis simultaneously, but without any side effects, such as edema, hypotension, and the formation of hemangiomas 5–7…”

<p>Nanoparticle-Mediated Drug Delivery for the Treatment of Cardiovascular Diseases</p>

“…These nanoparticles can protect the growth factor from enzymatic degradation before its delivery to the tissues. 137 Endogenous angiotensin II is vital for the delayed phase of an injury, recruitment of monocytes, and finally, inflammation of myocardium occurs. Thus, intravenous injection of bioabsorbable nanoparticles (PIGA) loaded with irbesartan (antagonist of angiotensin II type 1 receptor) at the time of reperfusion causes the inhibition of monocyte recruitment and then reduces the myocardium infarct through anti-inflammatory mechanisms.…”

The Roles of Nanoparticles in Stem Cell-Based Therapy for Cardiovascular Disease

“…The mechanisms of their internalization are known as endocytic pathways, including clathrin-mediated endocytosis, caveolae-mediated endocytosis, and micropinocytosis and phagocytosis ( Xiang et al, 2012 ; Calin et al, 2013 ). A study used chitosan-alginate NPs to deliver placental growth factors in a targeted manner, which could achieve the goal of continuously releasing placental growth factors and improving cardiac function at the site of acute MI ( Binsalamah et al, 2011 ). Another study transfected MSCs with molecularly organic-inorganic hybrid hollow mesoporous organosilica NPs with surface conjugated polyethyleneimine loaded with the hepatocyte growth factor gene and found that the paracrine activity of the hepatocyte growth factor-transfected MSCs was enhanced, which reduced the myocardial cell apoptosis and promoted angiogenesis in the rat model of MI ( Zhu et al, 2016 ).…”