Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors

Kim, Ji Bak; Park, Kyeongsoon; Ryu, Ji Heon; Lee, Jae Joong; Lee, Min Woo; Cho, Han Saem; Nam, Hyunwoo; Park, Ok Kyu; Song, Joon Woo; Kim, Tae Shik; Oh, Dong Joo; Gweon, Dae−Gab; Oh, Wang‐Yuhl; Yoo, Hongki; Kim, Jin Won

doi:10.1038/srep22608

Cited by 53 publications

(40 citation statements)

References 36 publications

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“…To address these unmet needs, we developed a novel PPARγ activation strategy targeting plaque macrophages to treat inflamed high-risk atheroma. As mannose receptor is highly expressed in the macrophages within thin-cap fibroatheroma (TCFAs) of human coronary arteries, it has been utilized as a target for PET and optical imaging of plaque inflamemation 28 , 29 . Here, we loaded PPARγ agonist, lobeglitzone, into a macrophage mannose receptor (MMR) targeted nanocarrier based on biocompatible glycol chitosan (GC).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Effects of Targeted PPARɣ Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging In Vivo

et al. 2018

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Rationale: Atherosclerotic plaque is a chronic inflammatory disorder involving lipid accumulation within arterial walls. In particular, macrophages mediate plaque progression and rupture. While PPARγ agonist is known to have favorable pleiotropic effects on atherogenesis, its clinical application has been very limited due to undesirable systemic effects. We hypothesized that the specific delivery of a PPARγ agonist to inflamed plaques could reduce plaque burden and inflammation without systemic adverse effects.Methods: Herein, we newly developed a macrophage mannose receptor (MMR)-targeted biocompatible nanocarrier loaded with lobeglitazone (MMR-Lobe), which is able to specifically activate PPARγ pathways within inflamed high-risk plaques, and investigated its anti-atherogenic and anti-inflammatory effects both in in vitro and in vivo experiments.Results: MMR-Lobe had a high affinity to macrophage foam cells, and it could efficiently promote cholesterol efflux via LXRα-, ABCA1, and ABCG1 dependent pathways, and inhibit plaque protease expression. Using in vivo serial optical imaging of carotid artery, MMR-Lobe markedly reduced both plaque burden and inflammation in atherogenic mice without undesirable systemic effects. Comprehensive analysis of en face aorta by ex vivo imaging and immunostaining well corroborated the in vivo findings.Conclusion: MMR-Lobe was able to activate PPARγ pathways within high-risk plaques and effectively reduce both plaque burden and inflammation. This novel targetable PPARγ activation in macrophages could be a promising therapeutic strategy for high-risk plaques.

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Section: Introductionmentioning

confidence: 99%

Therapeutic Effects of Targeted PPARɣ Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging In Vivo

et al. 2018

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“…Therefore, they have emerged as key target biomarkers for high-risk coronary atheromata [ 58 , 59 , 60 ]. Recently, Kim et al developed a macrophage mannose receptor (MMR)-targeted near-infrared fluorescence (NIRF) nanoprobe to specifically target macrophages in high-risk plaques ( Figure 2 B) [ 61 ]. The MMR-targeting nanoprobe was prepared as follows: GC (Mw = 2.5 × 10 5 , degree of deacetylation = 82.7%) was reacted with NAC ( N -acetylcysteine) in MES (4-morpholineethanesulfonic acid sodium salt) buffer (pH 5.6) containing EDC and NHS to yield thiolated GC (tGC).…”

Section: Versatile Chemical Derivatizations Of Glycol Chitosanmentioning

confidence: 99%

Versatile Chemical Derivatizations to Design Glycol Chitosan-Based Drug Carriers

Kim

Rhee

et al. 2017

Molecules

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Glycol chitosan (GC) and its derivatives have been extensively investigated as safe and effective drug delivery carriers because of their unique physiochemical and biological properties. The reactive functional groups such as the amine and hydroxyl groups on the GC backbone allow for easy chemical modification with various chemical compounds (e.g., hydrophobic molecules, crosslinkers, and acid-sensitive and labile molecules), and the versatility in chemical modifications enables production of a wide range of GC-based drug carriers. This review summarizes the versatile chemical modification methods that can be used to design GC-based drug carriers and describes their recent applications in disease therapy.

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“…Leukocytes are central components of the inflammatory response, and plaque macrophages account for the majority of leukocytes in atherosclerotic plaques 4 – 6 . There is extensive evidence linking local macrophage infiltration with plaque characteristics and vulnerability 7 , and plaque macrophages have emerged as key imaging targets for inflammatory atheroma in animal models 8 – 12 . Consequently, techniques that can detect macrophages in vivo are useful for monitoring the development of atherosclerotic lesions.…”

Section: Introductionmentioning

confidence: 99%

A Novel iRFP-Incorporated in vivo Murine Atherosclerosis Imaging System

Kulathunga

Hamada

Hiraishi

et al. 2018

Sci Rep

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By using near-infrared fluorescent protein (iRFP)-expressing hematopoietic cells, we established a novel, quantitative, in vivo, noninvasive atherosclerosis imaging system. This murine atherosclerosis imaging approach targets macrophages expressing iRFP in plaques. Low-density lipoprotein receptor-deficient (LDLR−/−) mice transplanted with beta-actin promoter-derived iRFP transgenic (TG) mouse bone marrow (BM) cells (iRFP → LDLR−/−) were used. Atherosclerosis was induced by a nonfluorescent 1.25% cholesterol diet (HCD). Atherosclerosis was compared among the three differently induced mouse groups. iRFP → LDLR−/− mice fed a normal diet (ND) and LDLR−/− mice transplanted with wild-type (WT) BM cells were used as controls. The in vivo imaging system (IVIS) detected an enhanced iRFP signal in the thoracic aorta of HCD-fed iRFP → LDLR−/− mice, whereas iRFP signals were not observed in the control mice. Time-course imaging showed a gradual increase in the signal area, which was correlated with atherosclerotic plaque progression. Oil red O (ORO) staining of aortas and histological analysis of plaques confirmed that the detected signal was strictly emitted from plaque-positive areas of the aorta. Our new murine atherosclerosis imaging system can noninvasively image atherosclerotic plaques in the aorta and generate longitudinal data, validating the ability of the system to monitor lesion progression.

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Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors

Cited by 53 publications

References 36 publications

Therapeutic Effects of Targeted PPARɣ Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging In Vivo

Therapeutic Effects of Targeted PPARɣ Activation on Inflamed High-Risk Plaques Assessed by Serial Optical Imaging In Vivo

Versatile Chemical Derivatizations to Design Glycol Chitosan-Based Drug Carriers

A Novel iRFP-Incorporated in vivo Murine Atherosclerosis Imaging System

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