TY - JOUR
T1 - Targeting and modulating infarct macrophages with hemin formulated in designed lipid-based particles improves cardiac remodeling and function
AU - Ben-Mordechai, Tamar
AU - Kain, David
AU - Holbova, Radka
AU - Landa, Natalie
AU - Levin, La Paz
AU - Elron-Gross, Inbar
AU - Glucksam-Galnoy, Yifat
AU - Feinberg, Micha S.
AU - Margalit, Rimona
AU - Leor, Jonathan
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/7/10
Y1 - 2017/7/10
N2 - 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 (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 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.
AB - 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 (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 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.
KW - Heme oxygenase 1
KW - Hemin
KW - Inflammation
KW - Macrophage
KW - Myocardial infarction
KW - Targeted carrier
UR - http://www.scopus.com/inward/record.url?scp=85009802413&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2017.01.001
DO - 10.1016/j.jconrel.2017.01.001
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:85009802413
SN - 0168-3659
VL - 257
SP - 21
EP - 31
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -
