Liposomal delivery of azithromycin enhances its immunotherapeutic efficacy and reduces toxicity in myocardial infarction

Ahmed Al-Darraji,Dalia Haydar,Lakshman Chelvarajan,Renée R Donahue,Bryana M Levitan,David J Feola,John C Gensel,Hsuan Peng,Vincent J Venditto,Himi Tripathi,Ahmed Abdel-Latif,Erhe Gao,David Henson

doi:10.1038/s41598-020-73593-0

Abstract

A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). We have previously shown that oral azithromycin (AZM), initiated prior to MI, reduces inflammation and its negative sequelae on the myocardium. Here, we investigated the immunomodulatory role of a liposomal AZM formulation (L-AZM) in a clinically relevant model to enhance its therapeutic potency and avoid off-target effects. L-AZM (40 or 10 mg/kg, IV) was administered immediately post-MI and compared to free AZM (F-AZM). L-AZM reduced cardiac toxicity and associated mortality by 50% in mice. We observed a significant shift favoring reparatory/anti-inflammatory macrophages with L-AZM formulation. L-AZM use resulted in a remarkable decrease in cardiac inflammatory neutrophils and the infiltration of inflammatory monocytes. Immune cell modulation was associated with the downregulation of pro-inflammatory genes and the upregulation of anti-inflammatory genes. The immunomodulatory effects of L-AZM were associated with a reduction in cardiac cell death and scar size as well as enhanced angiogenesis. Overall, L-AZM use enhanced cardiac recovery and survival after MI. Importantly, L-AZM was protective from F-AZM cardiac off-target effects. We demonstrate that the liposomal formulation of AZM enhances the drug’s efficacy and safety in an animal model of acute myocardial injury. This is the first study to establish the immunomodulatory properties of liposomal AZM formulations. Our findings strongly support clinical trials using L-AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.

Highlights

A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI)
Neutrophils are the first line of immune cells arriving in the myocardium after injury and they play an important role in the development of adverse remodeling as well as healing of the m yocardium[8,9]
Neutrophils are followed by two waves of monocytes, pro- and anti-inflammatory monocytes which convert to tissue macrophages that play a crucial role in the healing myocardium[10]

Summary

Introduction

A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). Previous research from our lab suggests that azithromycin (AZM), a commonly used antibiotic with immunomodulatory effects, alters post-MI inflammation through repolarization of macrophages to a reparative phenotype. These immunomodulatory effects were associated with protection against adverse cardiac remodeling and heart failure[22]. These findings have limited clinical translation given the pre-MI initiation of therapy and the relatively high dose (160 mg/kg/day, orally), which were dictated by our non-targeted delivery of A ZM22. The goal of this translational study is to determine the efficacy and safety of encapsulated AZM as immunotherapeutic agent for MI, using a clinically relevant experimental design

Results

Discussion

Conclusion