title: Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration.
abstract: Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Formiga
authors.affiliation: Hematology, Cardiology and Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pelacho
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Garbayo
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Imbuluzqueta
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Díaz-Herráez
authors.affiliation: Hematology, Cardiology and Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Abizanda
authors.affiliation: Hematology, Cardiology and Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gavira
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Simón-Yarza
authors.affiliation: Hematology, Cardiology and Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Edurne
authors.initials: E
authors.lastname: Albiasu
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Tamayo
authors.affiliation: Hematology, Cardiology and Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain. Electronic address: fprosper@unav.es.
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain. Electronic address: mjblanco@unav.es.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Blanco-Prieto
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000008:administration & dosage* / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D020890:Neuregulin-1 / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012038:Regeneration
chemical_list: D003692:Delayed-Action Preparations; D020890:Neuregulin-1; D011994:Recombinant Proteins; D016220:Fibroblast Growth Factor 1
keywords: Cardiac repair; FGF1; Myocardial infarction; NRG1; PLGA microparticles