Macrophage targeted theranostic strategy for accurate detection and rapid stabilization of the inflamed high-risk plaque

Abstract

Rationale: Inflammation plays a pivotal role in the pathogenesis of the acute coronary syndrome. Detecting plaques with high inflammatory activity and specifically treating those lesions can be crucial to prevent life-threatening cardiovascular events. Methods: Here, we developed a macrophage mannose receptor (MMR)-targeted theranostic nanodrug (mannose-polyethylene glycol-glycol chitosan-deoxycholic acid-cyanine 7-lobeglitazone; MMR-Lobe-Cy) designed to identify inflammatory activity as well as to deliver peroxisome proliferator-activated gamma (PPARγ) agonist, lobeglitazone, specifically to high-risk plaques based on the high mannose receptor specificity. The MMR-Lobe-Cy was intravenously injected into balloon-injured atheromatous rabbits and serial in vivo optical coherence tomography (OCT)-near-infrared fluorescence (NIRF) structural-molecular imaging was performed. Results: One week after MMR-Lobe-Cy administration, the inflammatory NIRF signals in the plaques notably decreased compared to the baseline whereas the signals in saline controls even increased over time. In accordance with in vivo imaging findings, ex vivo NIRF signals on fluorescence reflectance imaging (FRI) and plaque inflammation by immunostainings significantly decreased compared to oral lobeglitazone group or saline controls. The anti-inflammatory effect of MMR-Lobe-Cy was mediated by inhibition of TLR4/NF-κB pathway. Furthermore, acute resolution of inflammation altered the inflamed plaque into a stable phenotype with less macrophages and collagen-rich matrix. Conclusion: Macrophage targeted PPARγ activator labeled with NIRF rapidly stabilized the inflamed plaques in coronary sized artery, which could be quantitatively assessed using intravascular OCT-NIRF imaging. This novel theranostic approach provides a promising theranostic strategy for high-risk coronary plaques.

Targeted Imaging in Atherosclerosis

“…Therefore, macrophages have been considered a promising target for detection and identification of the atherosclerotic lesions. Some signal receptors, including transmembrane proteins (CD47, CD36, CD44, CD68), a mannose receptor (MMR), folate receptor beta (FR-β), a collagenous structure (MARCO), and transferrin receptor 1 (TfR1), are found to be overexpressed on the surface of macrophages, which have been employed as biological targets for imaging macrophages in atherosclerotic plaques.…”

The Role of Peroxisome Proliferator-Activated Receptor Gamma and Atherosclerosis: Post-translational Modification and Selective Modulators

“…WSF-7 upregulated PPARγ-responsive genes, such as adiponectin and Glut4, inhibits PPARγ phosphorylation at Ser273 by obesity and enhances insulin sensitivity in 3T3-L1 Adipocytes ( Zhang et al, 2020 ). Lobeglitazone inhibits the VSMCs proliferation and migration, reduces the vascular cells adhesion, NF-kB p65 translocation, and improves circulating factors related to atherosclerosis, then reduced neointimal formation significantly in balloon injury rat carotid arteries in ApoE –/– mice ( Lim et al, 2015 ; Song et al, 2021 ). In the presence of pro-inflammatory stimulation, Lobeglitazone effectively inhibited expression of pro-inflammatory gene expression in macrophages and adipocytes ( Sohn et al, 2018 ).…”

“…In the presence of pro-inflammatory stimulation, Lobeglitazone effectively inhibited expression of pro-inflammatory gene expression in macrophages and adipocytes ( Sohn et al, 2018 ). The latest study has found that macrophages targeted PPARγ activator Lobeglitazone could rapidly stabilize a coronary artery-sized inflammatory plaque ( Song et al, 2021 ). Both non-clinical and clinical studies have demonstrated that INT131 have the potential to separate insulin-sensitizing actions and undesirable side effects in Patients With Type 2 Diabetes ( DePaoli et al, 2014 ), and it also has the potential to decrease free fatty acids, increase HDL-C ( Dunn et al, 2011 ).…”

Biofabricated macrophage and fibroblast membranes synergistically promote skin wound healing

“…And then, the inflammation process follows as the decisive phase to combat against bacterial infection and to eliminate damaged cells 3 . During this period, macrophage plays the most important role to present diverse biofunctions such as phagocytosis, promoting inflammation, and producing various cytokines that stimulate new capillary growth, collagen synthesis, and tissue fibrosis 4‐6 . Once the wound is cleaned up by inflammation, the next phase defined as proliferation is demanded for new generated tissues to fill and cover the wound surface 7 .…”

“… 3 During this period, macrophage plays the most important role to present diverse biofunctions such as phagocytosis, promoting inflammation, and producing various cytokines that stimulate new capillary growth, collagen synthesis, and tissue fibrosis. 4 , 5 , 6 Once the wound is cleaned up by inflammation, the next phase defined as proliferation is demanded for new generated tissues to fill and cover the wound surface. 7 As the key reparative cell, fibroblast closely correlates with tissue regeneration due to its immigration along the fibrin network.…”