张茜,叶豪奕,崔思美,王威,高磊

• 1:中国人民解放军总医院第六医学中心心血管病医学部
• 2:中国人民解放军医学院

摘要(Abstract)：

动脉粥样硬化是心血管病的主要病理基础，其并发症如心肌梗死和脑卒中的主要诱因是动脉粥样硬化易损斑块（VASPs）的破裂。传统影像技术依赖解剖结构变化，难以在早期评估斑块易损性。近年来，分子影像结合纳米探针技术通过靶向斑块的病理特征（如脂质核心、炎症、薄纤维帽等），实现了细胞和分子水平的精准可视化。本文综述了VASPs的病理特征、现有影像技术的局限性，以及分子影像探针的设计原则与应用进展，探讨其临床转化面临的挑战与未来方向。

关键词(KeyWords)： 动脉粥样硬化;易损斑块;分子影像

Abstract:

Keywords:

基金项目(Foundation): 北京市自然科学基金项目（7242138）;; 中国人民解放军总医院第六医学中心创新培育基金项目（CXPY202202）;; 首都卫生发展科研专项项目（首发2024-2-5072）

作者(Author): 张茜,叶豪奕,崔思美,王威,高磊

参考文献(References)：

• [1] Wang H, Liddell CA, Coates MM, et al. Global, regional,and national levels of neonatal, infant, and under-5 mortality during 1990-2013:a systematic analysis for the Global Burden of Disease Study 2013[J]. Lancet, 2014, 384(9947):957-979. DOI:10.1016/S0140-6736(14)60497-9.
• [2] Song P, Fang Z, Wang H, et al. Global and regional prevalence,burden, and risk factors for carotid atherosclerosis:a systematic review, meta-analysis, and modelling study[J]. Lancet Glob Health, 2020, 8(5):e721-e729. DOI:10.1016/S2214-109X(20)30117-0.
• [3] Weissleder R. Molecular imaging:exploring the next frontier[J]. Radiology,1999,212(3):609-614. DOI:10.1148/radiology.212.3.r99se18609.
• [4]郭炳辰，涂应锋，于波.分子成像和非分子成像识别动脉粥样硬化血栓形成的研究进展[J].中国介入心脏病学杂志，2021, 29(11):642-647. DOI:10. 3969/j. issn. 1004-8812.2021. 11. 008.
• [5] Dweck MR, Doris MK, Motwani M, et al. Imaging o f coronary atherosclerosis-evolution towards new treatment strategies[J]. Nat Rev Cardiol, 2016, 13(9):533-548.DOI:10.1038/nrcardio.2016.79.
• [6] Libby P. Infl ammation during the life cycle of the atherosclerotic plaque[J]. Cardiovasc Res, 2021, 117(13):2525-2536. DOI:10.1093/cvr/cvab303.
• [7] Johnson JL. Metalloproteinases in atherosclerosis[J].Eur J Pharmacol, 2017, 816:93-106. DOI:10.1016/j.ejphar.2017.09.007.
• [8] Gonzalez L, Trigatti BL. Macrophage apoptosis and necrotic core development in atherosclerosis:a rapidly advancing field with clinical relevance to imaging and therapy[J].Can J Cardiol, 2017, 33(3):303-312. DOI:10.1016/j.cjca.2016.12.010.
• [9] Henein MY, Vancheri S, Longo G, et al. The role of infl ammation in cardiovascular disease[J]. Int J Mol Sci,2022, 23(21):12906. DOI:10.3390/ijms232112906.
• [10] Kong P, Cui ZY, Huang XF, et al. Inflammation and atherosclerosis:signaling pathways and therapeutic intervention[J]. Signal Transduct Target Ther, 2022, 7(1):131.DOI:10.1038/s41392-022-00955-7.
• [11]刘博清，余再新.连续冠状动脉CT血管造影评估动脉粥样硬化斑块逆转治疗的研究进展[J].中国介入心脏病学杂志，2023, 31(10):775-780. DOI:10. 3969/j. issn. 1004-8812.2023. 10. 009.
• [12] van Veelen A, van der Sangen NMR, Henriques JPS, et al. Identifi cation and treatment of the vulnerable coronary plaque[J]. Rev Cardiovasc Med, 2022, 23(1):39. DOI:10.31083/j.rcm2301039.
• [13]折振兴，于波.易损斑块成像进展[J].中国介入心脏病学杂志，2022, 30(3):208-213. DOI:10. 3969/j. issn. 1004-8812. 2022. 03. 009.
• [14] Yao Y, Zhang P. Novel ultrasound techniques in the identifi cation of vulnerable plaques-an updated review of the literature[J].Front Cardiovasc Med, 2023, 10:1069745. DOI:10.3389/fcvm.2023.1069745.
• [15] Wang X, Mu D, Liang J, et al. Emerging nanoprobes for the features visualization of vulnerable atherosclerotic plaques[J].Smart Med, 2024, 3(4):e20240033. DOI:10.1002/SMMD.20240033.
• [16] Kerwin WS, Miller Z, Yuan C. Imaging of the highr i s k carotid plaque:magnetic resonance imaging[J].Semin Vasc Surg, 2017, 30(1):54-61. DOI:10.1053/j.semvascsurg.2017.04.009.
• [17] Robson PM, Dweck MR, Trivieri MG, et al. Coronary artery PET/MR imaging:feasibility, limitations, and solutions[J]. JACC Cardiovasc Imaging, 2017, 10(10 Pt A):1103-1112. DOI:10.1016/j.jcmg.2016.09.029.
• [18]张迪瑞，何路平，于波.腔内影像学对冠状动脉易损斑块的识别与治疗最新进展[J].中国介入心脏病学杂志，2021,29(9):520-522. DOI:10. 3969/j. issn. 1004-8812. 2021.09. 008.
• [19] Lenz T, Nicol P, Castellanos MI, et al. Small dimension-big impact! Nanoparticle-enhanced non-invasive and intravascular molecular imaging of atherosclerosis in vivo[J]. Molecules,2020, 25(5):1029. DOI:10.3390/molecules25051029.
• [20] Jiang S, Fang C, Xu X, et al. Identification of high-risk coronary lesions by 3-vessel optical coherence tomography[J].J Am Coll Cardiol, 2023, 81(13):1217-1230. DOI:10.1016/j.jacc.2023.01.030.
• [21] Ali J, Cody J, Maldonado Y, et al. Near-infrared spectroscopy(NIRS)for cerebral and tissue oximetry:analysis of evolving applications[J]. J Cardiothorac Vasc Anesth, 2022, 36(8 Pt A):2758-2766. DOI:10.1053/j.jvca.2021.07.015.
• [22] Kim JB, Park K, Ryu J, et al. Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors[J]. Sci Rep, 2016, 6:22608. DOI:10.1038/srep22608.
• [23] Seguchi M, Aytekin A, Lenz T, et al. Intravascular molecular imaging:translating pathophysiology of atherosclerosis into human disease conditions[J]. Eur Heart J Cardiovasc Imaging, 2022, 24(1):e1-e16. DOI:10.1093/ehjci/jeac163.
• [24] Verjans JW, Osborn EA, Ughi GJ, et al. Targeted nearinfrared fluorescence imaging of atherosclerosis:clinical and intracoronary evaluation of indocyanine green[J]. JACC Cardiovasc Imaging, 2016, 9(9):1087-1095. DOI:10.1016/j.jcmg.2016.01.034.
• [25] Zhu S, Yung BC, Chandra S, et al. Near-infrared-Ⅱ（NIR-Ⅱ） bioimaging via off-peak NIR-Ⅰfluorescence emission[J]. Theranostics, 2018, 8(15):4141-4151. DOI:10.7150/thno.27995.
• [26] Jansen K, van der Steen AF, van Beusekom HM,e t al. Intravascular photoacoustic imaging of human coronary atherosclerosis[J]. Opt Lett, 2011, 36(5):597-599.DOI:10.1364/OL.36.000597.
• [27] M a B, X u H, Wa n g Y, e t a l. B i o m i m e t i cc o a t e d nanoplatform with lipid-specific imaging and ros responsiveness for atherosclerosis-targeted theranostics[J].ACS Appl Mater Interfaces, 2021, 13(30):35410-35421.DOI:10.1021/acsami.1c08552.
• [28] van Tilborg GA, Vucic E, Strijkers GJ, et al. Annexin A5-functionalized bimodal nanoparticles for MRI and fluorescence imaging of atherosclerotic plaques[J]. Bioconjug Chem,2010, 21(10):1794-1803. DOI:10.1021/bc100091q.
• [29] Logtenberg MEW, Scheeren FA, Schumacher TN. The CD47-SIRPα immune checkpoint[J]. Immunity, 2020, 52(5):742-752. DOI:10.1016/j.immuni.2020.04.011.
• [30] Wang K, Gao H, Zhang Y, et al. Highly bright A I E nanoparticles by regulating the substituent of rhodanine for precise early detection of atherosclerosis and drug screening[J].Adv Mater, 2022, 34(9):e2106994. DOI:10.1002/adma.202106994.
• [31] Qin H, Zhao Y, Zhang J, et al. Infl ammation-targeted gold nanorods for intravascular photoacoustic imaging detection of matrix metalloproteinase-2(MMP 2)in atherosclerotic plaques[J]. Nanomedicine, 2016, 12(7):1765-1774. DOI:10.1016/j.nano.2016.02.016.
• [32] Tu Y, Ma X, Chen H, et al. Molecular imaging of matrix metalloproteinase-2 in atherosclerosis using a smart multifunctional PET/MRI nanoparticle[J]. Int J Nanomedicine, 2022, 17:6773-6789. DOI:10.2147/IJN.S385679.
• [33] Narita Y, Shimizu K, Ikemoto K, et al. Macrophagetargeted, enzyme-triggered fluorescence switch-on system for detection of embolism-vulnerable atherosclerotic plaques[J].J Control Release, 2019, 302:105-115. DOI:10.1016/j.jconrel.2019.03.025.
• [34] Liu Z, Nian L, Cai X, et al. A robust collagen-targeting MRI peptide contrast agent for in vivo imaging of hepatic fi brosis[J].Chem Commun(Camb), 2023, 59(40):6068-6071.DOI:10.1039/d3cc01096a.
• [35] Ye M, Zhou J, Zhong Y, et al. SR-A-Targeted phase-transition nanoparticles for the detection and treatment of atherosclerotic vulnerable plaques[J]. ACS Appl Mater Interfaces, 2019, 11(10):9702-9715. DOI:10.1021/acsami.8b18190.
• [36] Guo Z, Yang L, Chen M, et al. Molecular imaging of advanced atherosclerotic plaques with folate receptor-targeted 2D nanoprobes[J]. Nano Research, 2020, 13(1):173-182.DOI:10.1007/s12274-019-2592-4.
• [37] Lee G Y, Kim JH, Choi KY, et al. Hyaluroni c a c i d nanoparticles for active targeting atherosclerosis[J].Biomaterials, 2015, 53:341-348. DOI:10.1016/j.biomaterials.2015.02.089.
• [38] Sun Y, Gao W, Liu Z, et al. Luminescence-resonanceenergy-transfer-based luminescence nanoprobe for in situ imaging of CD36 activation and CD36-oxLDL binding in atherogenesis[J]. Anal Chem, 2019, 91(15):9770-9776. DOI:10.1021/acs.analchem.9b01398.
• [39] Wang Y, Zhang Y, Wang Z, et al. Optical/MRI dual-modality imaging of M1 macrophage polarization in atherosclerotic plaque with MARCO-targeted upconversion luminescence probe[J]. Biomaterials, 2019, 219:119378. DOI:10.1016/j.biomaterials.2019.119378.
• [40] Tong W, Hui H, Shang W, et al. Highly sensitive magnetic particle imaging of vulnerable atherosclerotic plaque with active myeloperoxidase-targeted nanoparticles[J]. Theranostics,2021, 11(2):506-521. DOI:10.7150/thno.49812.
• [41] Kim M, Sahu A, Kim GB, et al. Comparison of i n vivo targeting ability between cRGD and collagen-targeting peptide conjugated nano-carriers for atherosclerosis[J]. J Control Release, 2018, 269:337-346. DOI:10.1016/j.jconrel.2017.11.033.
• [42] Chen H, Chen L, Liang R, et al. Ultrasound and magnetic resonance molecular imaging of atherosclerotic neovasculature with perfluorocarbon magnetic nanocapsules targeted against vascular endothelial growth factor receptor 2 in rats[J]. Mol Med Rep, 2017, 16(5):5986-5996. DOI:10.3892/mmr.2017.7314.
• [43] Su T, Wang YB, Han D, et al. Multimodality imaging of angiogenesis in a rabbit atherosclerotic model by GEBP11peptide targeted nanoparticles[J]. Theranostics, 2017, 7(19):4791-4804. DOI:10.7150/thno.20767.
• [44] Martínez-Parra L, Pi?ol-Cancer M, Sanchez-Cano C, e t al. A comparative study of ultrasmall calcium carbonate nanoparticles for targeting and imaging atherosclerotic plaque[J]. ACS Nano, 2023, 17(14):13811-13825. DOI:10.1021/acsnano.3c03523.
• [45] Nakahara T, Narula J, Strauss HW. NaF uptake in unstable plaque:what does fl uoride uptake mean?[J]. Eur J Nucl Med Mol Imaging, 2018, 45(13):2250-2252. DOI:10.1007/s00259-018-4177-y.
• [46] Ma Y, Shang J, Liu L, et al. Rational design of a doublelocked photoacoustic probe for precise in vivo imaging of cathepsin B in atherosclerotic plaques[J]. J Am Chem Soc, 2023, 145(32):17881-17891. DOI:10.1021/jacs.3c04981.
• [47] Kennedy GT, Azari FS, Chang A, et al. A phase 2 multicenter clinical trial of intraoperative molecular imaging of lung cancer with a pH-activatable nanoprobe[J]. Mol Imaging Biol, 2024, 26(4):585-592. DOI:10.1007/s11307-024-01933-x.