Abstract 14558: Macrophage Targeted Theranostic Photoactivation Attenuates Plaque Inflammation and Regresses the Atheroma via Autophagy-Induced Cholesterol Efflux Assessed by Serial in vivo Imaging

Introduction and HypothesisMacrophages are associated with progression and destabilization of the atherosclerosis. Photoactivation has emerged as a therapeutic strategy for atherosclerosis but its mechanism has not been clarified. We hypothesized that macrophage scavenger receptor targeted photoactivatable theranostic strategy could 1) selectively image active inflammation in atheroma and 2) reduce plaque burden and inflammation via activation of autophagy within macrophage foam cells.Methods and ResultsWe synthesized the novel photoactivatable theranostic agent by the chemical reaction of dextran sulfate (scavenger receptor-A ligand) and chlorin e6 (photosensitizer) [DS-Ce6]. DS-Ce6 had a high affinity to macrophage foam cells and induced apoptosis under laser irradiation. Using in vivo serial optical imaging of carotid artery, administration of DS-Ce6 with irradiation markedly reduced both plaque burden (p < 0.05) and inflammation (p < 0.05) in atherogenic mice (Figure A). Comprehensive analysis of FM and immunostainings well corroborated the in vivo findings. Mechanistically, in vitro studies demonstrated that therapeutic laser irradiation resulted in autophagic degradation of p62 and increase of autophagosome marker LC3-II in macrophage foam cells (Figure B), implying the induction of autophagy which promotes cell cholesterol efflux.ConclusionsPhotoactivatable therapy with DS-Ce6 was able to selectively target plaque macrophages, and effectively reduce both plaque burden and inflammation in vivo. This therapeutic effect of plaque regression was mediated through autophagy activation, which could enhance cholesterol efflux and efferocytosis of macrophage foam cells. We suggest targeted theranostic photoactivation could be a promising strategy for the high-risk atheroma.