Theranostic Contribution of Extracellular Matrix Metalloprotease Inducer-Paramagnetic Nanoparticles Against Acute Myocardial Infarction in a Pig Model of Coronary Ischemia-Reperfusion

Abstract

Background: Rapid screening and accurate diagnosis of acute myocardial infarction are critical to reduce the progression of myocardial necrosis, in which proteolytic degradation of myocardial extracellular matrix plays a major role. In previous studies, we found that targeting the extracellular matrix metalloprotease inducer (EMMPRIN) by injecting nanoparticles conjugated with the specific EMMPRIN-binding peptide AP9 significantly improved cardiac function in mice subjected to ischemia/reperfusion. Methods: In a porcine model of coronary ischemia/reperfusion, we tested the theragnostic effects of administering 0.1 mg/kg gadolinium-containing nanoparticles conjugated with AP9 (NAP9), a synthetic peptide that targets EMMPRIN or a control nanoparticle (NAPSC). Cardiac magnetic resonance assessment of the infarct progression, ventricular function, and nanoparticle distribution was performed the next 7 days. We also measured the infarcted area of the heart and cardiac remodeling at 7 or 21 days after ischemia/reperfusion. Results: After 21 days of ischemia/reperfusion, NAP9 reduced the extension of cardiac necrosis (14.1±9.7 versus 35.5±1.8) and the levels of collagenolytic activity of MMPs (matrix metalloproteases), along with a significant reduction in collagen deposition (7.5±4.5 versus 41.3±20); including the ratio of type I versus III collagen fibers in the necrotic myocardium. In terms of cardiac function, the response to NAP9 administration resulted in a significant improvement of cardiac performance overtime, as evidenced by the left ventricle ejection fraction (64.0±7.8), when compared with those present in the NAPSC group (47.3±4.7). As shown by magnetic resonance imaging, noninvasive molecular imaging of NAP9 enabled us to find a significant reduction in cardiac necrosis, myocardial edema, hemorrhage, and microvascular obstruction, suggesting that NAP9 may reduce myocardial injury and preserve left ventricular function, at least, by preventing the effect of EMMPRIN on extracellular matrix degradation. Conclusions: Our data point towards NAP9 as a promising theragnostic tool in managing acute myocardial infarction, by inhibiting EMMPRIN-induced extracellular matrix degradation and allowing noninvasive visualization of cardiac necrosis progression over time.

Inflammation and Oxidative Stress Role of S100A12 as a Potential Diagnostic and Therapeutic Biomarker in Acute Myocardial Infarction

“…As a serious heart disease, acute myocardial infarction (AMI) has the characteristics of high mortality and a poor prognosis; and it is easy to induce severe cardiovascular events, such as ventricular remodeling and heart failure, which seriously threaten people's lives and cause great pain and financial burden in patients [1][2][3]. The early diagnosis and treatment of AMI are essential for reducing myocardial injury and malignant consequences, reducing mortality and improving patient prognosis to some extents [4][5][6]. Currently, the levels of myocardial enzyme (CKMB) and cardiac troponin I (cTnI) are still the gold standards for the clinical diagnosis of AMI, but they are not specific for AMI.…”

NIL10: A New IL10-Receptor Binding Nanoparticle That Induces Cardiac Protection in Mice and Pigs Subjected to Acute Myocardial Infarction through STAT3/NF-κB Activation

“…Furthermore, nanoparticles are extremely versatile, as additional components can be incorporated into their composition to enable the acquisition of new functionalities. Such is the case of NAP9 [ 27 , 36 ] and NIL10—both are nanoparticles based on lipid micelles and incorporate a fluorochrome in their composition to gain visualization by fluorescence, conferring specificity.…”

“…NAP9 nanoparticles incorporate a small peptide, AP9, which specifically binds to EMMPRIN, an inflammatory molecule that induces MMP9 expression and activity in response to cardiac ischemia. NAP9 significantly improved cardiac function after IR and, thanks to the presence of gadolinium, NAP9 was visualized by MRI, correlating the extension of cardiac necrosis and healing overtime [ 27 , 36 ].…”

“…Evans blue/TTC staining in pigs was performed as described [ 27 ]. In brief, 7 days after surgery, the LAD was re-occluded through balloon inflation at the same location as day 0.…”

Good Things in Small Packages: Growth and Potential of Theragnostic Platforms in Cardiovascular Medicine

“…In this issue of Circulation: Cardiovascular Imaging, Ramirez-Carracedo et al 3 present an extension of their previous work using a targeted magnetic resonancevisible therapeutic nanoparticle against the extracellular matrix metalloproteinase inducer (EMMPRIN), which has shown spared cardiac function after acute myocardial infarction in mice. 4 Here, the authors apply the therapeutic nanoparticle in a pig model of 45-minute balloon-induced ischemia-reperfusion and report lower severity of necrosis and fibrosis in the left ventricle compared with control nontherapeutic nanoparticles with a modest improvement with a modest improvement in left ventricle ejection fraction at 7 days after injury.…”