Targeted theranostic photoactivation on atherosclerosis

Abstract

Background Photoactivation 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. Results The 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. Conclusion Imaging-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

Photodynamic Therapy and Cardiovascular Diseases

“…In the arteries, differentiated monocyte-derived macrophages take up lipids, and these foam cells are then presented in the initial stages of atherosclerosis development [ 95 ]. Photoactivation, i.e., the process of activating a photosensitizer using laser irradiation, has proven to be a promising therapeutic strategy in the treatment of atherosclerosis, reducing activated macrophages in atherosclerosis and stabilizing atherosclerotic plaques [ 96 ]. This process involves using a specific wavelength of light to activate photosensitizers, which leads to the conversion of oxygen into reactive oxygen species (ROS), such as singlet oxygen ( 1 O 2 ) [ 97 ].…”

“…Increasing evidence suggests that macrophage apoptosis and the subsequent removal of dead cells play a key role in the treatment of atherosclerosis. The emergence of photoactivation represents a promising alternative for the local treatment of atherosclerosis [ 96 ]. Recent studies have identified several new subtypes, e.g., including Mox, M(Hb), Mhem, M4 and HAMac of macrophages, that can be present in atherosclerotic plaques ( Table 2 ) [ 101 ].…”

Recent Advances for Dynamic-Based Therapy of Atherosclerosis

“…Optical imaging-guided DS-Ce6 photoactivation can detect inflammatory activity in plaques in vivo and simultaneously reduce plaque burden and inflammation by inducing apoptosis, autophagy ( Figure 4A(b )), and efferocytosis. 112 With the triple-helix structure of beta-glucan (Glu), Glu/Ce6 nanocomplexes can be recognized by the dectin-1 receptor of macrophages to mediate efficient membrane destruction and apoptosis of foam cells under irradiation. 113

Figure 4 ( A ) (a) Schematic overview of photoactivation activated by DS-Ce6 targeting macrophage SR-A for autophagy induction and efferocytosis enhancement to regress atherosclerosis.

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“…Copyright 2021, Springer Nature. 112 ( B ) Schematic diagram of UCNPs-Ce6-mediated PDT and the mechanism of autophagy. Reproduced with permission from Han XB, Li HX, Jiang YQ, et al Upconversion nanoparticle-mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage-derived foam cells via ROS generation.…”

Comprehensive view of macrophage autophagy and its application in cardiovascular diseases

“…Mechanistic results show that imaging‐guided DS‐Ce6 light activation dampens plaque burden and inflammation owing to the elevation in apoptotic cell engulfment via increasing autophagy and phagocytic receptor Mer tyrosine kinase (MerTK) expression in foam cells (Figure 7). 142 Moreover, resveratrol enhances SIRT1‐mediated autophagy and improves the defective efferocytosis of ox‐LDL‐induced apoptotic cells 143 . PUFA‐mediated atheroprotection is associated with the arrest of caspase‐1 cleavage, apoptosis, necrosis, and amelioration of efferocytosis, whereas myeloid ATG5 deletion abolishes these protective effects 144 .…”