Abstract
Backgrounds: Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture and its key aspect is a failure to resolve inflammation. We hypothesized that macrophage targeted near-infrared fluorescence (NIRF) emitting photoactivation could simultaneously in vivo assess the inflamed high-risk plaques and facilitate the inflammation resolution. Method and results: We newly synthesized a Dectin-1 targeted photoactivatable theranostic agent by the chemical conjugation of photosensitizer chlorin e6 (Ce6) and Dectin-1 ligand laminarin (LAM-Ce6). Intravascular photoactivation through a customized fiber-based diffuser effectively reduced inflammation in the targeted plaques 4 weeks after LAM-Ce6 administration as serially assessed by dual-modal optical coherence tomography (OCT)-NIRF catheter imaging. The number of TUNEL-positive apoptotic macrophages peaked at 1 day after laser irradiation, and then resolved until 4 weeks. One hour after the light therapy, autophagy was strongly augmented with the formation of autophagolysosomes revealed by co-localization of enhanced microtubule-associated protein light-chain 3 (LC3) and lysosome-associated membrane protein 2 (LAMP2) expressions in the plaques (Figure). LAM-Ce6 photoactivation increased the TUNEL/RAM11- and MerTK-positive cells in the plaques, suggestive of enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden with collagen-rich fibrotic replacement via TGF-β pathway confirmed by corroborative immunostainings ( p <0.01). Conclusions: OCT-NIRF imaging-guided macrophage Dectin-1 targetable photoactivation could stabilize the inflamed high-risk plaques by autophagy-mediated inflammation resolution and TGF-β dependent fibrotic replacement. This novel targeted photoactivation will offer new opportunity for the catheter based theranostic strategy.
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