Xu Mengqi, Mao Cong, Chen Haoting, Liu Lu, Wang Yabin, Hussain Abid, Li Sulei, Zhang Xu, Tuguntaev Ruslan G, Liang Xing-Jie, Guo Weisheng, Cao Feng
Department of Cardiology, National Clinical Research Center for Geriatric Diseases & Second Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
Department of Minimally Invasive Interventional Radiology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.
Acta Pharm Sin B. 2022 Apr;12(4):2014-2028. doi: 10.1016/j.apsb.2021.12.020. Epub 2021 Dec 31.
Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great clinical significance, yet remain a major challenge. Photodynamic therapy (PDT) realizes potent ablation efficacy under precise manipulation of laser irradiation. In this study, we constructed theranostic nanoprobes (NPs), which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging. The NPs were formulated from human serum albumin (HSA) conjugated with a high affinity-peptide targeting osteopontin (OPN) and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine (TPZ). After intravenous injection into atherosclerotic mice, the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery. Under the visible guidance of fluorescence and MR dual-model imaging, the precise near-infrared (NIR) laser irradiation generated massive reactive oxygen species (ROS), which resulted in efficient plaque ablation and amplified hypoxia within VASPs. In response to the elevated hypoxia, the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages. After therapeutic administration of the NPs for 2 weeks, the plaque area and the degree of carotid artery stenosis were markedly reduced. Furthermore, the formulated NPs displayed excellent biocompatibility. In conclusion, the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.
易损性动脉粥样硬化斑块（VASPs）是急性心血管事件的主要病理原因。VASPs的早期检测和精准干预具有重要的临床意义，但仍然是一项重大挑战。光动力疗法（PDT）在激光照射的精确操控下可实现强大的消融效果。在本研究中，我们构建了诊疗纳米探针（NPs），其可在荧光/磁共振成像引导下，通过局部激光照射引发的一系列协同事件精确消退VASPs。这些NPs由与人血清白蛋白（HSA）偶联的靶向骨桥蛋白（OPN）的高亲和力肽制成，并包裹有光敏剂IR780和低氧激活的替拉扎明（TPZ）。将其静脉注射到动脉粥样硬化小鼠体内后，由于颈动脉中活化的泡沫巨噬细胞中OPN的过表达，OPN靶向的NPs在VASPs中表现出高度特异性积累。在荧光和磁共振双模态成像的可视引导下，精确的近红外（NIR）激光照射产生大量活性氧（ROS），这导致了有效的斑块消融并放大了VASPs内的低氧状态。针对升高的低氧状态，最初无活性的TPZ被相继激活，从而对泡沫巨噬细胞产生强大的生物学抑制作用。在给予NPs进行治疗2周后，斑块面积和颈动脉狭窄程度显著减小。此外，所制备的NPs表现出优异的生物相容性。总之，所开发的基于HSA的NPs表现出对VASPs可观的特异性识别能力，并实现了动脉粥样硬化的精确协同消退。
