基于巨噬细胞特异吞噬Gd-HMME的动脉粥样硬化斑块高分辨磁共振成像与精准声动力治疗的研究

Acute myocardial infarction and cerebral infarction arising from atherosclerotic plaque rupture is the leading cause of human disability and mortality. Among the multifarious risks macrophages play a pivotal role, yet there is not a macrophage-targeting noninvasive high-resolution imaging and precise treatment approach. Our previous studies demonstrated that (i) porphyrins photosensitizer was prone to aggregate in macrophages, (ii) porphyrins photosensitizer-mediated sonodynamic therapy (SDT) could promote atherosclerotic plaque regression, (iii) novel synthesized photosensitizer gadolinium-hematoprophyrin monomethyl ether (Gd-HMME) could be largely taken in by macrophages, (iv) Gd-HMME obtained both characteristics of paramagnetism and photosensitivity. Thus, we propose that on the basis of selective devour of Gd-HMME by macrophages, we can simultaneously achieve high resolution magnetic resonance imaging (MRI) and precise SDT of atherosclerotic plaque result from paramagnetism of Gd and sonosensitivity of HMME respectively. We are going to study the bio-modification and representation of Gd-HMME, Gd-HMME as contrast enhanced MRI, Gd-HMME-mediated SDT, Gd-HMME-enhanced MRI-guided SDT and its preclinical research. The project is going to lay a foundation of application of Gd-HMME in high resolution imaging and precise treatment of atherosclerotic plaque in the clinical work, and provide seminal perspective of noninvasive diagnosis and treatment integration of atherosclerotic plaque.

动脉粥样硬化（AS）斑块破裂导致的急性心肌梗死和脑梗死是人类致残、致死的主要原因。巨噬细胞（Mφ）在AS斑块破裂中发挥核心作用。目前临床尚无针对AS斑块Mφ无创的高分辨成像和精准治疗方法。我们前期证实：卟啉类光敏剂选择性聚集在AS斑块Mφ中，其介导的声动力治疗（SDT）能促进AS斑块消退；合成的钆-血卟啉单甲醚（Gd-HMME）能被Mφ大量吞噬，且兼具顺磁性及光敏性。我们设想：基于Mφ特异性吞噬Gd-HMME，通过Gd的顺磁性实现AS斑块高分辨磁共振成像（MRI）并在其指导下通过HMME声敏性实现AS斑块SDT精准治疗。拟研究：Gd-HMME的生物修饰及表征、Gd-HMME为对比剂的MRI、Gd-HMME介导的SDT、Gd-HMME为对比剂的MRI指导SDT及其临床前研究。本课题将为Gd-HMME应用于临床AS斑块的高分辨成像及精准诊疗奠定基础，为AS斑块的无创诊疗一体化提供新的思路。

课题组共发表相关SCI收录文章29篇；获得专利授权9项，其中发明专利8项，实用新型专利1项；培养博士研究生13人，硕士研究生20人。.①合成并筛选金属卟啉：发现人血清白蛋白修饰的钆-华卟啉钠具有良好的磁共振成像（MRI）效果，聚乙二醇修饰的锌-原卟啉IX具有良好的水溶性和生物兼容性；②证实金属卟啉的MRI增强作用：其可被巨噬细胞（Mφ）吞噬，使AS（AS）斑块在MRI呈高信号；③证实金属卟啉的声敏性：其可作为针对AS斑块的声动力治疗（SDT）声敏剂；④揭示了SDT治疗AS机理：低强度SDT-凋亡与极低强度SDT-自噬的作用参数、机理、通路以及对斑块的逆转作用；⑤开展2项转化研究：从细胞到小鼠和兔AS动物模型，再到患者中证实SDT对AS斑块治疗的有效性和安全性；⑥开展2项单中心、双盲、平行对照临床注册研究：在下肢动脉闭塞症患者中证实，SDT治疗后患者斑块炎症明显改善，行走功能改善；在颈动脉出血斑块中证实SDT后斑块内出血明显减少。均无不良反应。.本课题基于Mφ吞噬钆卟啉实现AS斑块高分辨MRI并指导AS斑块SDT精准治疗，最终实现诊疗一体化。SDT将部分替代血运重建术，有里程碑意义。