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Molecular imaging of advanced atherosclerotic plaques with folate receptor-targeted 2D nanoprobes

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Abstract

Vulnerable atherosclerotic plaques are responsible for most cardiovascular diseases (CVDs). Folate receptor (FR) positive activated macrophages were thought to be a prominent component in the development of vulnerable plaque. The objective of this study is to develop folate conjugated two-dimensional (2D) Pd@Au nanomaterials (Pd@Au-PEG-FA) for targeted multimodal imaging of the FRs in advanced atherosclerotic plaques. Pharmacokinetic and imaging studies (single photon emission computed tomography (SPECT), computed tomography (CT) and photoacoustic (PA) imaging) were performed to confirm the prolonged blood half-life and enrichment of radioactivity in atherosclerotic plaques. Strong signals were detected in vivo with SPECT, CT and PA imaging in heavy atherosclerotic plaques, which were significantly higher than those of the normal aortas after injection of Pd@Au-PEG-FA. Blocking studies with preinjection of excess FA could effectively reduce the targeting ability of Pd@Au-PEG-FA in atherosclerotic plaques, further demonstrating the specific binding of Pd@Au-PEG-FA for plaque lesions. Histopathological characterization revealed that the signal of probe was in accordance with the high-risk plaques. In summary, the Pd@Au-PEG-FA has favorable pharmacokinetic properties and provides a valuable approach for detecting high-risk plaques in the presence of FRs in atherosclerotic plaques.

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References

  1. Williams, J. W.; Giannarelli, C.; Rahman, A.; Randolph, G. J.; Kovacic, J. C. Macrophage biology, classification, and phenotype in cardiovascular disease: JACC macrophage in CVD series (part 1). J. Am. Coll. Cardiol.2018, 72, 2166–2180.

    Article  CAS  Google Scholar 

  2. Schwalm, J. D.; McKee, M.; Huffman, M. D.; Yusuf, S. Resource effective strategies to prevent and treat cardiovascular disease. Circulation2016, 133, 742–755.

    Article  CAS  Google Scholar 

  3. Reimann, C.; Brangsch, J.; Colletini, F.; Walter, T.; Hamm, B.; Botnar, R. M.; Makowski, M. R. Molecular imaging of the extracellular matrix in the context of atherosclerosis. Adv. Drug. Deliver. Rev.2017, 113, 49–60.

    Article  CAS  Google Scholar 

  4. Lewis, D. R.; Petersen, L. K.; York, A. W.; Ahuja, S.; Chae, H.; Joseph, L. B.; Rahimi, S.; Uhrich, K. E.; Haser, P. B.; Moghe, P. V. Nanotherapeutics for inhibition of atherogenesis and modulation of inflammation in atherosclerotic plaques. Cardiovasc. Res.2016, 109, 283–293.

    Article  Google Scholar 

  5. Vancraeynest, D.; Pasquet, A.; Roelants, V.; Gerber, B. L.; Vanoverschelde, J. L. J. Imaging the vulnerable plaque. J. Am. Coll. Cardiol.2011, 57, 1961–1979.

    Article  Google Scholar 

  6. Fiz, F.; Morbelli, S.; Piccardo, A.; Bauckneht, M.; Ferrarazzo, G.; Pestarino, E.; Cabria, M.; Democrito, A.; Riondato, M.; Villavecchia, G et al. 18F-NaF uptake by atherosclerotic plaque on PET/CT imaging: Inverse correlation between calcification density and mineral metabolic activity. J. Nucl. Med.2015, 56, 1019–1023.

    Article  CAS  Google Scholar 

  7. Tahara, N; Mukherjee, J.; de Haas, H. J.; Petrov, A. D.; Tawakol, A.; Haider, N; Tahara, A.; Constantinescu, C. C.; Zhou, J.; Boersma, H. H. et al. 2-Deoxy-2-[18F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat. Med.2014, 20, 215–219.

    Article  CAS  Google Scholar 

  8. Ayala-López, W.; Xia, W.; Varghese, B.; Low, P. S. Imaging of atherosclerosis in apoliprotein e knockout mice: Targeting of a folate-conjugated radiopharmaceutical to activated macrophages. J. Nucl. Med.2010, 57, 768–774.

    Article  Google Scholar 

  9. Joseph, P.; Tawakol, A. Imaging atherosclerosis with positron emission tomography. Eur. Heart. J.2016, 37, 2974–2980.

    Article  Google Scholar 

  10. Tarkin, J. M.; Joshi, F. R.; Evans, N. R.; Chowdhury, M. M.; Figg, N. L.; Shah, A. V.; Starks, L. T.; Martin-Garrido, A.; Manavaki, R.; Yu, E. et al. Detection of atherosclerotic inflammation by 68Ga-DOTATATE PET compared to [18F]FDG PET imaging. J. Am. Coll. Cardiol.2017, 69, 1774–1791.

    Article  CAS  Google Scholar 

  11. Hyafil, R.; Pelisek, J.; Laitinen, I.; Schottelius, M.; Mohring, M.; Döring, Y.; van der Vorst, E. P. C.; Kallmayer, M.; Steiger, K.; Poschenrieder, A. et al. Imaging the cytokine receptor CXCR4 in atherosclerotic plaques with the radiotracer 68Ga-pentixafor for PET. J. Nucl. Med.2017, 58, 499–506.

    Article  CAS  Google Scholar 

  12. Beer, A. J.; Pelisek, J.; Heider, P.; Saraste, A.; Reeps, C.; Metz, S.; Seidl, S.; Kessler, H.; Wester, H. J.; Eckstein, H. H. et al. PET/CT imaging of integrin avβ3 expression in human carotid atherosclerosis. JACC Cardiovasc. Imaging2014, 7, 178–187.

    Article  Google Scholar 

  13. Keliher, E. J.; Ye, Y. X.; Wojtkiewicz, G R.; Aguirre, A. D.; Tricot, B.; Senders, M. L.; Groenen, H; Fay, F.; Perez-Medina, C.; Calcagno, C. et al. Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease. Nat. Commun.2017, 8, 14064.

    Article  CAS  Google Scholar 

  14. Kelderhouse, L. E.; Mahalingam, S.; Low, P. S. Predicting response to therapy for autoimmune and inflammatory diseases using a folate receptor-targeted near-infrared fluorescent imaging agent. Mol. Imaging Biol.2016, 18, 201–208.

    Article  CAS  Google Scholar 

  15. Jager, N. A.; Westra, J; Golestani, R.; van Dam, G M.; Low, P. S.; Tio, R. A.; Slart, R. H. J. A.; Boersma, H. H.; Bijl, M.; Zeebregts, C. J. Folate receptor-β imaging using 99mTc-folate to explore distribution of polarized macrophage populations in human atherosclerotic plaque. J. Nucl. Med.2014, 55, 1945–1951.

    Article  CAS  Google Scholar 

  16. Xia, W.; Hilgenbrink, A. R.; Matteson, E. L.; Lockwood, M. B.; Cheng, J. X.; Low, P. S. A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. Blood2009, 113, 438–446.

    Article  CAS  Google Scholar 

  17. Liang, M. M.; Tan, H.; Zhou, J.; Wang, T.; Duan, D. M.; Fan, K. L.; He, J. Y.; Cheng, D. R.; Shi, H. C.; Choi, H. S. et al. Bioengineered H-ferritin nanocages for quantitative imaging of vulnerable plaques in atherosclerosis. ACS Nano2018, 12, 9300–9308.

    Article  CAS  Google Scholar 

  18. Bejarano, J.; Navarro-Marquez, M.; Morales-Zavala, F.; Morales, J. O.; Garcia-Carvajal, I.; Araya-Fuentes, E.; Flores, Y.; Verdejo, H. E.; Castro, P. F.; Lavandero, S. et al. Nanoparticles for diagnosis and therapy of atherosclerosis and myocardial infarction: Evolution toward prospective theranostic approaches. Theranostics2018, 8, 4710–4732.

    Article  CAS  Google Scholar 

  19. Ma, S.; Motevalli, S. M.; Chen, J. W.; Xu, M. Q.; Wang, Y B.; Feng, J.; Qiu, Y.; Han, D.; Fan, M. M.; Ding, M. L. et al. Precise theranostic nanomedicines for inhibiting vulnerable atherosclerotic plaque progression through regulation of vascular smooth muscle cell phenotype switching. Theranostics2018, 8, 3693–3706.

    Article  CAS  Google Scholar 

  20. Stendahl, J. C.; Sinusas, A. J. Nanoparticles for cardiovascular imaging and therapeutic delivery, part 2: Radiolabeled probes. J. Nucl. Med.2015, 56, 1637–1641.

    Article  CAS  Google Scholar 

  21. Qiao, R R.; Qiao, H. Y.; Zhang, Y.; Wang, Y B.; Chi, C. W.; Tian, J.; Zhang, L. F.; Cao, F; Gao, M. Y Molecular imaging of vulnerable atherosclerotic plaques in vivo with osteopontin-specific upconversion nanoprobes}. ACS Nano 2017, 11, 1816–1825.

    Article  CAS  Google Scholar 

  22. Li, X.; Wang, C.; Tan, H; Cheng, L. L.; Liu, G B.; Yang, Y.; Zhao, Y Z.; Zhang, Y Q.; Li, Y L.; Zhang, C. F. et al. Gold nanoparticles-based SPECT/CT imaging probe targeting for vulnerable atherosclerosis plaques. Biomaterials2016, 108, 71–80.

    Article  Google Scholar 

  23. Chen, M.; Tang, S. H.; Guo, Z. D.; Wang, X. Y.; Mo, S. G.; Huang, X. Q.; Liu, G.; Zheng, N. F. Core-shell Pd@Au nanoplates as theranostic agents for in-vivo photoacoustic imaging, CT imaging, and photothermal therapy. Adv. Mater.2014, 26, 8210–8216.

    Article  CAS  Google Scholar 

  24. Chen, M.; Guo, Z. D.; Chen, Q. H.; Wei, J. P.; Li, J. C.; Shi, C. R.; Xu, D.; Zhou, D. W.; Zhang, X. Z.; Zheng, N. F. Pd nanosheets with their surface coordinated by radioactive iodide as a high-performance theranostic nanoagent for orthotopic hepatocellular carcinoma imaging and cancer therapy. Chem. Sci.2018, 9, 426Z–A214.

    Google Scholar 

  25. Guo, Z. D.; Chen, M.; Peng, C. Y.; Mo, S. G.; Shi, C. R.; Fu, G F.; Wen, X. J.; Zhuang, R. Q.; Su, X. H.; Liu, T. et al. pH-sensitive radiolabeled and superfluorinated ultra-small palladium nanosheet as a high-performance multimodal platform for tumor theranostics. Biomaterials2018, 779, 134–143.

    Article  Google Scholar 

  26. Lüscher, T. F. Frontiers of interventional cardiology: Plaque imaging, thrombus load, and bifurcation lesions. Eur. Heart J.2016, 37, 1861–1864.

    Article  Google Scholar 

  27. Solomon, S. B.; Cornells, F Interventional molecular imaging}. J. Nucl. Med.2016, 57, 493–496.

    Article  CAS  Google Scholar 

  28. Pavlin-Premrl, D.; Sharma, R.; Campbell, B. C. V.; Mocco, J.; Opie, N. L.; Oxley, T. J. Advanced imaging of intracranial atherosclerosis: Lessons from interventional cardiology. Front. Neurol.2017, 8, 387.

    Article  Google Scholar 

  29. Gao, W.; Sun, Y H.; Cai, M.; Zhao, Y. J.; Cao, W. H.; Liu, Z. H.; Cui, G W.; Tang, B. Copper sulfide nanoparticles as a photothermal switch for TRPV1 signaling to attenuate atherosclerosis}. Nat. Commun.2018, 9, 231–240.

    Article  Google Scholar 

  30. Libby, P.; Ridker, P. M.; Hansson, G K. Progress and challenges in translating the biology of atherosclerosis}. Nature2011, 473, 317–325.

    Article  CAS  Google Scholar 

  31. Qiao, H. Y.; Wang, Y B.; Zhang, R. H.; Gao, Q. S.; Liang, X.; Gao, L.; Jiang, Z. H.; Qiao, R. R.; Han, D.; Zhang, Y et al. MRI/optical dual-modality imaging of vulnerable atherosclerotic plaque with an osteopontin-targeted probe based on Fe3O4 nanoparticles. Biomaterials2017, 772, 336–345.

    Article  Google Scholar 

  32. Guo, Z. D.; Gao, M. N.; Song, M. L.; Shi, C. R.; Zhang, P.; Xu, D.; You, L. Y.; Zhuang, R. Q.; Su, X. H.; Liu, T. et al. Synthesis and evaluation of 99mTc-labeled dimeric folic acid for FR-targeting. Molecules2016, 21, 817.

    Article  Google Scholar 

  33. Guo, Z. D.; You, L. Y.; Shi, C. R.; Song, M. L.; Gao, M. N.; Xu, D.; Peng, C. Y.; Zhuang, R. Q.; Liu, T.; Su, X. H. et al. Development of a new FR-targeting agent 99mTc-HYNFA with improved imaging contrast and comparison of multimerization and/or PEGylation strategies for radio-folate modification. Mol. Pharmaceutics2017, 14, 3780–3788.

    Article  CAS  Google Scholar 

  34. Müller, A.; Beck, K.; Rancic, Z.; Müller, C.; Fischer, C. R.; Betzel, T.; Kaufmann, P. A.; Schibli, R.; Krämer, S. D.; Ametamey, S. M. Imaging atherosclerotic plaque inflammation via folate receptor targeting using a novel 18F-folate radiotracer. Mol. Imaging2014, 13, DOI: 10.2310/7290.2013.00074}.

    Article  Google Scholar 

  35. Winkel, L. C. J.; Groen, H. C.; van Thiel, B. S.; Müller, C.; van der Steen, A. F. W.; Wentzel, J. J.; de Jong, M.; van der Heiden, K. Folate receptor-targeted single-photon emission computed tomography/computed tomography to detect activated macrophages in atherosclerosis: Can it distinguish vulnerable from stable atherosclerotic plaques? Mol. Imaging2014, 13, DOI: https://doi.org/10.2310/7290.2013.00061.

    Article  Google Scholar 

  36. Chen, H. J.; Jacobson, O.; Niu, G.; Weiss, I. D.; Kiesewetter, D. O.; Liu, Y.; Ma, Y.; Wu, H; Chen, X. Y Novel “add-on” molecule based on Evans Blue confers superior pharmacokinetics and transforms drugs to theranostic agents}. J. Nucl. Med.2017, 58, 590–597.

    Article  CAS  Google Scholar 

  37. Chen, H. J.; Wang, G H.; Lang, L. X.; Jacobson, O.; Kiesewetter, D. O.; Liu, Y.; Ma, Y.; Zhang, X. Z.; Wu, H.; Zhu, L. et al. Chemical conjugation of Evans Blue derivative: A strategy to develop long-acting therapeutics through albumin binding. Theranostics2016, 6, 243–253.

    Article  Google Scholar 

  38. Wen, X. J.; Shi, C. R.; Xu, D.; Zhang, P.; Li, Z. Z.; Li, J. D.; Su, X. H.; Zhuang, R. Q.; Liu, T.; Guo, Z. D. et al. Radioiodinated portable albumin binder as a versatile agent for in vivo imaging with single-photon emission computed tomography. Mol. Pharmaceutics2019, 16, 816–824.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was financially supported by the National Postdoctoral Program for Innovative Talents (No. BX201700142), Postdoctoral Science Foundation of China (No. 2018M630732), the National Natural Science Foundation of China (Nos. 81901805, 21906135, 81471707, 21705037, and 91539126), Hunan Provincial Natural Science Foundation of China (No. 2018JJ3092), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS 2016-I2M-1-009), and Drug Innovation Major Project (2018ZX09711001-003-011).

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  1. Zhide Guo, Liu Yang and Mei Chen contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China

    Zhide Guo, Xuejun Wen, Huanhuan Liu, Jingchao Li, Duo Xu, Changrong Shi, Jindian Li, Zijing Li, Ting Liu, Rongqiang Zhuang & Xianzhong Zhang

  2. State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Liu Yang, Yuanyuan An & Haibo Zhu

  3. College of Materials Science and Engineering, Hunan University, Changsha, 410082, China

    Mei Chen

  4. The State Key Laboratory for Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, Department of Chemistry, Xiamen University, Xiamen, 361005, China

    Mei Chen & Nanfeng Zheng

  5. Zhongshan Hospital Affiliated to Xiamen University, Xiamen, 361004, China

    Xinhui Su

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  1. Zhide Guo
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  2. Liu Yang
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Contributions

X. Z. Z., H. B. Z., and N. F. Z. were responsible for the conception and design of the study, the drafting of the manuscript, and final approval of the version to be published. Z. D. G., L. Y., and M. C. were responsible for the the acquisition, analysis and interpretation of the data, and the drafting of the manuscript. R. Q. Z., T. L., and Z. J. L. contributed to critical revision for important intellectual content, and final approval of the version to be published. X. H. S. contributed to critical revision of the manuscript for important intellectual content and material support. X. J. W., J. C. L., and D. X. assisted in the synthesis of probes. US and PA imaging was done by H. H. L., Y. Y. A., C. R. S., and J. D. L. directed the histopathological characterization of animal models.

Corresponding authors

Correspondence to Nanfeng Zheng, Haibo Zhu or Xianzhong Zhang.

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The authors declare no competing financial interest.

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Guo, Z., Yang, L., Chen, M. et al. Molecular imaging of advanced atherosclerotic plaques with folate receptor-targeted 2D nanoprobes. Nano Res. 13, 173–182 (2020). https://doi.org/10.1007/s12274-019-2592-4

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  • DOI: https://doi.org/10.1007/s12274-019-2592-4

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