1. Targeting and modulating infarct macrophages with hemin formulated in designed lipid-based particles improves cardiac remodeling and function.
- Author
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Ben-Mordechai T, Kain D, Holbova R, Landa N, Levin LP, Elron-Gross I, Glucksam-Galnoy Y, Feinberg MS, Margalit R, and Leor J
- Subjects
- Animals, Anti-Inflammatory Agents administration & dosage, Drug Carriers chemistry, Female, Heart drug effects, Heart physiopathology, Hemin administration & dosage, Lipids chemistry, Macrophages immunology, Macrophages pathology, Mice, Mice, Inbred BALB C, Myocardial Infarction immunology, Myocardial Infarction physiopathology, Anti-Inflammatory Agents therapeutic use, Drug Delivery Systems, Hemin therapeutic use, Macrophages drug effects, Myocardial Infarction drug therapy, Ventricular Remodeling drug effects
- 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., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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