Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

Sci Rep. 2016 May 17:6:25932. doi: 10.1038/srep25932.

Abstract

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Animals
  • Cell Line
  • Disease Models, Animal
  • Female
  • Fibroblast Growth Factor 1 / administration & dosage*
  • Heart Function Tests / drug effects
  • Injections
  • Lactic Acid
  • Male
  • Mice
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / physiopathology*
  • Neuregulin-1 / administration & dosage*
  • Polyglycolic Acid
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Swine
  • Swine, Miniature
  • Treatment Outcome

Substances

  • Neuregulin-1
  • Fibroblast Growth Factor 1
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid