Targeting and modulating infarct macrophages with hemin formulated in designed lipid-based particles improves cardiac remodeling and function

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 oxygen- ase-1 (HO-1), an enzymewith anti-inflammatory and cytoprotective properties.We sought to determine the ef- fects of hemin formulated in amacrophage-targeted lipid-based carrier (denoted HA-LP) on LV remodeling and function afterMI. Hemin encapsulation efficiencywas ~100% at therapeutic dose levels. In vitro, hemin/HA-LP abolished TNF-αse- cretion frommacrophages,whereas the same doses of free hemin and drug freeHA-LP had no effect.Hemin/HA- LP polarized peritoneal and splenicmacrophages towardM2anti-inflammatory phenotype.Wenext inducedMI in mice and allocated them to IV treatment with hemin/HA-LP (10 mg/kg), drug free HA-LP, free hemin (10 mg/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 30 days after treatment. Significantly, hemin/HA-LP effectively and specifically targets infarctmacrophages, switches infarctmacrophages towardM2anti-inflammatoryphenotype,improves angiogenesis, reduces scar ex- pansion and improves infarct-related regional function. In conclusion, macrophage-targeted lipid-based drug carriers with hemin switch macrophages into an anti-in- flammatory phenotype, and improve infarct healing and repair. Our approach presents a novel strategy tomod- ulate inflammation and improve infarct repair.