title: Tracking the in vivo release of bioactive NRG from PLGA and PEG-PLGA microparticles in infarcted hearts.
abstract: The growth factor neuregulin (NRG) is one of the most promising candidates in protein therapy as potential treatment for myocardial infarction (MI). In the last few years, biomaterial based delivery systems, such as polymeric microparticles (MPs) made of poly(lactic co glycolic acid) and polyethylene glycol (PLGA and PEG-PLGA MPs), have improved the efficacy of protein therapy in preclinical studies. However, no cardiac treatment based on MPs has yet been commercialized since this is a relatively new field and total characterization of polymeric MPs remains mandatory before they reach the clinical arena. Therefore, the objective of this study was to characterize the in vivo release, bioactivity and biodegradation of PLGA and PEG-PLGA MPs loaded with biotinylated NRG in a rat model of MI. The effect of PEGylation in the clearance of the particles from the cardiac tissue was also evaluated. Interestingly, MPs were detected in the cardiac tissue for up to 12 weeks after administration. In vivo release analysis showed that bNRG was released in a controlled manner throughout the twelve week study. Moreover, the biological cardiomyocyte receptor (ErbB4) for NRG was detected in its activated form only in those animals treated with bNRG loaded MPs. On the other hand, the PEGylation strategy was effective in diminishing phagocytosis of these MPs compared to noncoated MPs in the long term (12 weeks after injection). Taking all this together, we report new evidence in favor of the use of polymeric PLGA and PEG-PLGA MPs as delivery systems for treating MI, which could be soon included in clinical trials.
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, University of Navarra, Pamplona 31080, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Pascual-Gil
authors.affiliation: Porous Solids Group, Institut Lavoisier-CNRS UMR 8180, Université de Versailles-St-Quentin-en-Yvelines, Versailles 78000, France.
authors.forename: T
authors.initials: T
authors.lastname: Simón-Yarza
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, University of Navarra, Pamplona 31080, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Garbayo
authors.affiliation: Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona 31080, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Prosper
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, University of Navarra, Pamplona 31080, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain. Electronic address: mjblanco@unav.es.
authors.forename: M J
authors.initials: MJ
authors.lastname: Blanco-Prieto
mesh_terms: D000818:Animals; D001682:Biological Availability; D019921:Biotinylation; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008264:Macrophages / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020890:Neuregulin-1 / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010316:Particle Size; D010587:Phagocytosis; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4 / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000493:pharmacokinetics
chemical_list: D002317:Cardiovascular Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; C094131:NRG1 protein, human; D020890:Neuregulin-1; D011091:Polyesters; D011994:Recombinant Proteins; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4
keywords: Bioactivity; Biotinylation; Microparticles; Myocardial infarction; Phagocytosis; Protein therapy