title: Targeting and modulating infarct macrophages with hemin formulated in designed lipid-based particles improves cardiac remodeling and function.
abstract: Uncontrolled activation of pro-inflammatory macrophages after myocardial infarction (MI) accelerates adverse left ventricular (LV) remodeling and dysfunction. Hemin, an iron-containing porphyrin, activates heme oxygenase-1 (HO-1), an enzyme with anti-inflammatory and cytoprotective properties. We sought to determine the effects of hemin formulated in a macrophage-targeted lipid-based carrier (denoted HA-LP) on LV remodeling and function after MI. Hemin encapsulation efficiency was ~100% at therapeutic dose levels. In vitro, hemin/HA-LP abolished TNF-α secretion from macrophages, whereas the same doses of free hemin and drug free HA-LP had no effect. Hemin/HA-LP polarized peritoneal and splenic macrophages toward M2 anti-inflammatory phenotype. We next induced MI in mice and allocated them to IV treatment with hemin/HA-LP (10mg/kg), drug free HA-LP, free hemin (10mg/kg) or saline, one day after MI. Active in vivo targeting to infarct macrophages was confirmed with HA-LP doped with PE-rhodamine. LV remodeling and function were assessed by echocardiography before, 7, and 30days after treatment. Significantly, hemin/HA-LP effectively and specifically targets infarct macrophages, switches infarct macrophages toward M2 anti-inflammatory phenotype, improves angiogenesis, reduces scar expansion and improves infarct-related regional function. In conclusion, macrophage-targeted lipid-based drug carriers with hemin switch macrophages into an anti-inflammatory phenotype, and improve infarct healing and repair. Our approach presents a novel strategy to modulate inflammation and improve infarct repair.
authors.affiliation: Sackler Faculty of Medicine, Neufeld Cardiac Research Institute, Tel Aviv University, Tel Aviv, Israel; Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel-hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel-Hashomer, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Ben-Mordechai
authors.affiliation: Sackler Faculty of Medicine, Neufeld Cardiac Research Institute, Tel Aviv University, Tel Aviv, Israel; Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel-hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel-Hashomer, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Kain
authors.affiliation: Sackler Faculty of Medicine, Neufeld Cardiac Research Institute, Tel Aviv University, Tel Aviv, Israel; Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel-hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel-Hashomer, Israel.
authors.forename: Radka
authors.initials: R
authors.lastname: Holbova
authors.affiliation: Sackler Faculty of Medicine, Neufeld Cardiac Research Institute, Tel Aviv University, Tel Aviv, Israel; Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel-hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel-Hashomer, Israel.
authors.forename: Natalie
authors.initials: N
authors.lastname: Landa
authors.affiliation: Sackler Faculty of Medicine, Neufeld Cardiac Research Institute, Tel Aviv University, Tel Aviv, Israel; Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel-hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel-Hashomer, Israel.
authors.forename: La-Paz
authors.initials: LP
authors.lastname: Levin
authors.affiliation: Department of Biochemistry and Molecular Biology, The George S. Wise, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Inbar
authors.initials: I
authors.lastname: Elron-Gross
authors.affiliation: Department of Biochemistry and Molecular Biology, The George S. Wise, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Glucksam-Galnoy
authors.affiliation: Sackler Faculty of Medicine, Neufeld Cardiac Research Institute, Tel Aviv University, Tel Aviv, Israel; Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel-hashomer, Israel.
authors.forename: Micha S
authors.initials: MS
authors.lastname: Feinberg
authors.affiliation: Department of Biochemistry and Molecular Biology, The George S. Wise, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rimona
authors.initials: R
authors.lastname: Margalit
authors.affiliation: Sackler Faculty of Medicine, Neufeld Cardiac Research Institute, Tel Aviv University, Tel Aviv, Israel; Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel-hashomer, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel-Hashomer, Israel. Electronic address: leorj@post.tau.ac.il.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Leor
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006427:Hemin / Q000008:administration & dosage / Q000627:therapeutic use*; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D008055:Lipids; D006427:Hemin
keywords: Heme oxygenase 1; Hemin; Inflammation; Macrophage; Myocardial infarction; Targeted carrier