Abstract
BackgroundPhotoactivation targeting macrophages has emerged as a therapeutic strategy for atherosclerosis, but limited targetable ability of photosensitizers to the lesions hinders its applications. Moreover, the molecular mechanistic insight to its phototherapeutic effects on atheroma is still lacking. Herein, we developed a macrophage targetable near-infrared fluorescence (NIRF) emitting phototheranostic agent by conjugating dextran sulfate (DS) to chlorin e6 (Ce6) and estimated its phototherapeutic feasibility in murine atheroma. Also, the phototherapeutic mechanisms of DS-Ce6 on atherosclerosis were investigated.ResultsThe phototheranostic agent DS-Ce6 efficiently internalized into the activated macrophages and foam cells via scavenger receptor-A (SR-A) mediated endocytosis. Customized serial optical imaging-guided photoactivation of DS-Ce6 by light illumination reduced both atheroma burden and inflammation in murine models. Immuno-fluorescence and -histochemical analyses revealed that the photoactivation of DS-Ce6 produced a prominent increase in macrophage-associated apoptotic bodies 1 week after laser irradiation and induced autophagy with Mer tyrosine-protein kinase expression as early as day 1, indicative of an enhanced efferocytosis in atheroma.ConclusionImaging-guided DS-Ce6 photoactivation was able to in vivo detect inflammatory activity in atheroma as well as to simultaneously reduce both plaque burden and inflammation by harmonic contribution of apoptosis, autophagy, and lesional efferocytosis. These results suggest that macrophage targetable phototheranostic nanoagents will be a promising theranostic strategy for high-risk atheroma.Graphical abstract
Highlights
Photoactivation targeting macrophages has emerged as a therapeutic strategy for atherosclerosis, but limited targetable ability of photosensitizers to the lesions hinders its applications
Macrophage-targetable phototheranostic agent dextran sulfate (DS)-chlorin e6 (Ce6) internalizes into the plaque macrophages through scavenger receptor-A (SR-A)-mediated endocytosis
Transmission electron microscopy (TEM) images revealed that DS-Ce6 had a spherical shape with an average size of 50.1 ± 1.1 nm in dried condition (Fig. 1b, inset)
Summary
Photoactivation targeting macrophages has emerged as a therapeutic strategy for atherosclerosis, but limited targetable ability of photosensitizers to the lesions hinders its applications. While lipid lowering strategies facilitating a stabilization of high-risk atheroma have been developed, the residual risk of ASCVD is still substantial [2]. The differentiated macrophages from monocytes take up the lipid These macrophage-derived foam cells are presented at initial stages in the development of atherosclerosis [6, 7]. Photoactivation, the process of activating a photosensitizer by means of laser irradiation, has emerged as a promising therapeutic strategy for atherosclerosis therapy because this approach reduces activated macrophages in atheroma and stabilizes atherosclerotic plaques [8,9,10]. A novel photoactivatable agent with a specific targeting affinity to macrophage needs to be developed
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