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.

中文翻译：

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巨噬细胞靶向治疗诊断策略可准确检测并快速稳定发炎的高风险斑块。


理由：炎症在急性冠状动脉综合征的发病机制中起着关键作用。检测具有高炎症活性的斑块并专门治疗这些病变对于预防危及生命的心血管事件至关重要。方法：在这里，我们开发了一种针对巨噬细胞甘露糖受体 (MMR) 的治疗诊断纳米药物（甘露糖-聚乙二醇-乙二醇壳聚糖-脱氧胆酸-花青 7-洛格列酮；MMR-Lobe-Cy），旨在识别炎症活动并释放炎症活性。过氧化物酶体增殖物激活γ（PPARγ）激动剂洛格列酮，基于高甘露糖受体特异性，专门针对高风险斑块。将 MMR-Lobe-Cy 静脉注射到球囊损伤的动脉粥样硬化兔子中，并进行连续体内光学相干断层扫描 (OCT)-近红外荧光 (NIRF) 结构分子成像。结果：MMR-Lobe-Cy 给药一周后，斑块中的炎症 NIRF 信号与基线相比显着下降，而盐水对照中的信号甚至随着时间的推移而增加。根据体内成像结果，与口服洛格列酮组或盐水对照组相比，荧光反射成像 (FRI) 上的离体 NIRF 信号和免疫染色的斑块炎症显着降低。 MMR-Lobe-Cy 的抗炎作用是通过抑制 TLR4/NF-κB 通路介导的。此外，炎症的急性消退将发炎斑块转变为具有较少巨噬细胞和富含胶原蛋白基质的稳定表型。结论：NIRF 标记的巨噬细胞靶向 PPARγ 激活剂可快速稳定冠状动脉中的炎症斑块，并可使用血管内 OCT-NIRF 成像进行定量评估。 这种新颖的治疗诊断方法为高风险冠状动脉斑块提供了一种有前途的治疗诊断策略。