Nano Research

, Volume 12, Issue 4, pp 749–757 | Cite as

Infrared fluorescence imaging of infarcted hearts with Ag2S nanodots

  • Dirk H. Ortgies
  • Ángel Luis García-Villalón
  • Miriam Granado
  • Sara Amor
  • Emma Martín Rodríguez
  • Harrisson D. A. Santos
  • Jingke Yao
  • Jorge Rubio-Retama
  • Daniel JaqueEmail author
Research Article


Ag2S nanodots have already been demonstrated as promising near-infrared (NIR-II, 1.0–1.45 μm) emitting nanoprobes with low toxicity, high penetration and high resolution for in vivo imaging of, for example, tumors and vasculature. In this work, we have systematically investigated the potential application of functionalized Ag2S nanodots for accurate imaging of damaged myocardium tissues after a myocardial infarction induced by either partial or global ischemia. Ag2S nanodots surface-functionalized with the angiotensin II peptide (ATII) have shown over 10-fold enhanced binding efficiency to damaged tissues than non-specifically (PEG) functionalized Ag2S nanodots due to their interaction with the upregulated angiotensin II receptor type I (AT1R). It is demonstrated how the NIR-II images generated by ATII-functionalized Ag2S nanodots contain valuable information about the location and extension of damaged tissue in the myocardium allowing for a proper identification of the occluded artery as well as an indirect evaluation of the damage level. The potential application of Ag2S nanodots in the near future for in vivo imaging of myocardial infarction was also corroborated by performing proof of concept whole body imaging experiments.


infrared imaging myocardial infarct Ag2nanodots biological windows Langendorff heart 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This work was partially supported by the Ministerio de Economía y Competitividad de España (MAT2016-75362-C3-1-R) and (MAT2017-83111R), by the Instituto de Salud Carlos III (PI16/ 00812), by the Comunidad Autónoma de Madrid (B2017/BMD-3867RENIMCM), and co-financed by the European Structural and investment fond. Additional funding was provided by the European Commission Horizon 2020 project NanoTBTech, the Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal project IMP18_38 (2018/0265), and also by COST action CM1403. D. H. O. is grateful to the Instituto de Salud Carlos III for a Sara Borrell scholarship (No. CD17/00210).

Supplementary material

12274_2019_2280_MOESM1_ESM.pdf (654 kb)
Infrared fluorescence imaging of infarcted hearts with Ag2S nanodots


  1. [1]
    WHO; World Heart Federation; World Stroke Organization. Global Atlas on Cardiovascular Disease Prevention and Control; World Health Organization in Collaboration with the World Heart Federation and the World Stroke Organization: Geneva, 2011; pp 155Google Scholar
  2. [2]
    Luengo-Fernández, R.; Leal, J.; Gray, A.; Petersen, S.; Rayner, M. Cost of cardiovascular diseases in the United Kingdom. Heart 2006, 92, 1384–1389.CrossRefGoogle Scholar
  3. [3]
    Mahmoudi, M.; Yu, M.; Serpooshan, V.; Wu, J. C.; Langer, R.; Lee, R. T.; Karp, J. M.; Farokhzad, O. C. Multiscale technologies for treatment of ischemic cardiomyopathy. Nat. Nanotechnol. 2017, 12, 845–855.CrossRefGoogle Scholar
  4. [4]
    Ximendes, E. C.; Rocha, U.; del Rosal, B.; Vaquero, A.; Sanz-Rodríguez, F.; Monge, L.; Ren, F. Q.; Vetrone, F.; Ma, D. L.; García-Solé, J. et al. In vivo ischemia detection by luminescent nanothermometers. Adv. Health. Mater. 2017, 6, 1601195.CrossRefGoogle Scholar
  5. [5]
    Ruvinov, E.; Dvir, T.; Leor, J.; Cohen, S. Myocardial repair: From salvage to tissue reconstruction. Expert Rev. Cardiovasc. Ther. 2008, 6, 669–686.CrossRefGoogle Scholar
  6. [6]
    Flachskampf, F. A.; Schmid, M.; Rost, C.; Achenbach, S.; DeMaria, A. N.; Daniel, W. G. Cardiac imaging after myocardial infarction. Eur. Heart J. 2011, 32, 272–283.CrossRefGoogle Scholar
  7. [7]
    Mulder, W. J.; Griffioen, A. W.; Strijkers, G. J.; Cormode, D. P.; Nicolay, K.; Fayad, Z. A. Magnetic and fluorescent nanoparticles for multimodality imaging. Nanomedicine 2007, 2, 307–324.CrossRefGoogle Scholar
  8. [8]
    Lozano, O.; Torres-Quintanilla, A.; García-Rivas, G. Nanomedicine for the cardiac myocyte: Where are we? J. Control. Release 2018, 271, 149–165.CrossRefGoogle Scholar
  9. [9]
    Hu, J.; Ortgies, D. H.; Martín Rodríguez, E.; Rivero, F.; Aguilar Torres, R.; Alfonso, F.; Fernández, N.; Carreño-Tarragona, G.; Monge, L.; Sanz-Rodriguez, F. et al. Optical nanoparticles for cardiovascular imaging. Adv. Opt. Mater. 2018, 6, 1800626.CrossRefGoogle Scholar
  10. [10]
    Dvir, T.; Bauer, M.; Schroeder, A.; Tsui, J. H.; Anderson, D. G.; Langer, R.; Liao, R.; Kohane, D. S. Nanoparticles targeting the infarcted heart. Nano Lett. 2011, 11, 4411–4414.CrossRefGoogle Scholar
  11. [11]
    Jiang, W. S.; Rutherford, D.; Vuong, T.; Liu, H. N. Nanomaterials for treating cardiovascular diseases: A review. Bioact. Mater. 2017, 2, 185–198.CrossRefGoogle Scholar
  12. [12]
    Stendahl, J. C.; Sinusas, A. J. Nanoparticles for cardiovascular imaging and therapeutic delivery, Part 1: Compositions and features. J. Nucl. Med. 2015, 56, 1469–1475.CrossRefGoogle Scholar
  13. [13]
    Sharma, R.; Kwon, S. New applications of nanoparticles in cardiovascular imaging. J. Exp. Nanosci. 2007, 2, 115–126.CrossRefGoogle Scholar
  14. [14]
    Taillefer, R.; Tamaki, N. New Radiotracers in Cardiac Imaging: Principles and Applications; Appleton & Lange: Stamford, Connecticut, 1999.Google Scholar
  15. [15]
    Sosnovik, D. E.; Schellenberger, E. A.; Nahrendorf, M.; Novikov, M. S.; Matsui, T.; Dai, G.; Reynolds, F.; Grazette, L.; Rosenzweig, A.; Weissleder, R. et al. Magnetic resonance imaging of cardiomyocyte apoptosis with a novel magneto-optical nanoparticle. Magn. Reson. Med. 2005, 54, 718–724.CrossRefGoogle Scholar
  16. [16]
    Ruan, S. B.; Wan, J. Y.; Fu, Y.; Han, K.; Li, X.; Chen, J. T.; Zhang, Q. Y.; Shen, S.; He, Q.; Gao, H. L. PEGylated fluorescent carbon nanoparticles for noninvasive heart imaging. Bioconjug. Chem. 2014, 25, 1061–1068.CrossRefGoogle Scholar
  17. [17]
    Lundy, D. J.; Chen, K. H.; Toh, E. K. W.; Hsieh, P. C. H. Distribution of systemically administered nanoparticles reveals a size-dependent effect immediately following cardiac ischaemia-reperfusion injury. Sci. Rep. 2016, 6, 25613.CrossRefGoogle Scholar
  18. [18]
    Lipinski, M. J.; Albelda, M. T.; Frias, J. C.; Anderson, S. A.; Luger, D.; Westman, P. C.; Escarcega, R. O.; Hellinga, D. G.; Waksman, R.; Arai, A. E. et al. Multimodality imaging demonstrates trafficking of liposomes preferentially to ischemic myocardium. Cardiovasc. Revasc. Med. 2016, 17, 106–112.CrossRefGoogle Scholar
  19. [19]
    Sosnovik, D. E.; Nahrendorf, M.; Deliolanis, N.; Novikov, M.; Aikawa, E.; Josephson, L.; Rosenzweig, A.; Weissleder, R.; Ntziachristos, V. Fluorescence tomography and magnetic resonance imaging of myocardial macrophage infiltration in infarcted myocardium in vivo. Circulation 2007, 115, 1384–1391.CrossRefGoogle Scholar
  20. [20]
    Nahrendorf, M.; Sosnovik, D. E.; Waterman, P.; Swirski, F. K.; Pande, A. N.; Aikawa, E.; Figueiredo, J. L.; Pittet, M. J.; Weissleder, R. Dual channel optical tomographic imaging of leukocyte recruitment and protease activity in the healing myocardial infarct. Circ. Res. 2007, 100, 1218–1225.CrossRefGoogle Scholar
  21. [21]
    Ferreira, M. P. A.; Ranjan, S.; Kinnunen, S.; Correia, A.; Talman, V.; Mäkilä, E.; Barrios-Lopez, B.; Kemell, M.; Balasubramanian, V.; Salonen, J. et al. Drug-loaded multifunctional nanoparticles targeted to the endocardial layer of the injured heart modulate hypertrophic signaling. Small 2017, 13, 1701276.CrossRefGoogle Scholar
  22. [22]
    Sosnovik, D. E.; Garanger, E.; Aikawa, E.; Nahrendorf, M.; Figuiredo, J. L.; Dai, G. P.; Reynolds, F.; Rosenzweig, A.; Weissleder, R.; Josephson, L. Molecular MRI of cardiomyocyte apoptosis with simultaneous delayedenhancement MRI distinguishes apoptotic and necrotic myocytes in vivo: Potential for midmyocardial salvage in acute ischemia. Circ. Cardiovasc. Imaging 2009, 2, 460–467.CrossRefGoogle Scholar
  23. [23]
    Bashkatov, A. N.; Genina, E. A.; Tuchin, V. V. Optical properties of skin, subcutaneous, and muscle tissues: A review. J. Innov. Opt. Health Sci. 2011, 4, 9–38.CrossRefGoogle Scholar
  24. [24]
    Smith, A. M.; Mancini, M. C.; Nie, S. M. Second window for in vivo imaging. Nat. Nanotechnol. 2009, 4, 710–711.CrossRefGoogle Scholar
  25. [25]
    Jaque, D.; Richard, C.; Viana, B.; Soga, K.; Liu, X. G.; García Solé, J. Inorganic nanoparticles for optical bioimaging. Adv. Opt. Photonics 2016, 8, 1–103.CrossRefGoogle Scholar
  26. [26]
    Welsher, K.; Sherlock, S. P.; Dai, H. J. Deep-tissue anatomical imaging of mice using carbon nanotube fluorophores in the second near-infrared window. Proc. Natl. Acad. Sci. USA 2011, 108, 8943–8948.CrossRefGoogle Scholar
  27. [27]
    Villa, I.; Vedda, A.; Cantarelli, I. X.; Pedroni, M.; Piccinelli, F.; Bettinelli, M.; Speghini, A.; Quintanilla, M.; Vetrone, F.; Rocha, U. et al. 1.3 μm emitting SrF2:Nd3+ nanoparticles for high contrast in vivo imaging in the second biological window. Nano Res. 2015, 8, 649–665.CrossRefGoogle Scholar
  28. [28]
    del Rosal, B.; Villa, I.; Jaque, D.; Sanz-Rodríguez, F. In vivo autofluorescence in the biological windows: The role of pigmentation. J. Biophotonics 2016, 9, 1059–1067.CrossRefGoogle Scholar
  29. [29]
    Zhang, Y. J.; Liu, Y. S.; Li, C. Y.; Chen, X. Y.; Wang, Q. B. Controlled synthesis of Ag2S quantum dots and experimental determination of the exciton Bohr radius. J. Phys. Chem. C 2014, 118, 4918–4923.CrossRefGoogle Scholar
  30. [30]
    Sadovnikov, S. I.; Gusev, A. I. Recent progress in nanostructured silver sulfide: From synthesis and nonstoichiometry to properties. J. Mater. Chem. A 2017, 5, 17676–17704.CrossRefGoogle Scholar
  31. [31]
    Hu, F.; Li, C. Y.; Zhang, Y. J.; Wang, M.; Wu, D. M.; Wang, Q. B. Real-time in vivo visualization of tumor therapy by a near-infrared-II Ag2S quantum dot-based theranostic nanoplatform. Nano Res. 2015, 8, 1637–1647.CrossRefGoogle Scholar
  32. [32]
    Kubie, L.; King, L. A.; Kern, M. E.; Murphy, J. R.; Kattel, S.; Yang, Q.; Stecher, J. T.; Rice, W. D.; Parkinson, B. A. Synthesis and characterization of ultrathin silver sulfide nanoplatelets. ACS Nano 2017, 11, 8471–8477.CrossRefGoogle Scholar
  33. [33]
    Li, C. Y.; Li, F.; Zhang, Y. J.; Zhang, W. J.; Zhang, X. E.; Wang, Q. B. Real-time monitoring surface chemistry-dependent in vivo behaviors of protein nanocages via encapsulating an NIR-II Ag2S quantum dot. ACS Nano 2015, 9, 12255–12263.CrossRefGoogle Scholar
  34. [34]
    Zhang, Y.; Hong, G. S.; Zhang, Y. J.; Chen, G. C.; Li, F.; Dai, H. J.; Wang, Q. B. Ag2S Quantum dot: A bright and biocompatible fluorescent nanoprobe in the second near-infrared window. ACS Nano 2012, 6, 3695–3702.CrossRefGoogle Scholar
  35. [35]
    Hong, G. S.; Robinson, J. T.; Zhang, Y. J.; Diao, S.; Antaris, A. L.; Wang, Q. B.; Dai, H. J. In vivo fluorescence imaging with Ag2S quantum dots in the second near-infrared region. Angew. Chem., Int. Ed. 2012, 51, 9818–9821.CrossRefGoogle Scholar
  36. [36]
    Wu, C. X.; Zhang, Y. J.; Li, Z.; Li, C. Y.; Wang, Q. B. A novel photoacoustic nanoprobe of ICG@PEG-Ag2S for atherosclerosis targeting and imaging in vivo. Nanoscale 2016, 8, 12531–12539.CrossRefGoogle Scholar
  37. [37]
    Zhang, Y.; Zhang, Y. J.; Hong, G. S.; He, W.; Zhou, K.; Yang, K.; Li, F.; Chen, G. C.; Liu, Z.; Dai, H. J. et al. Biodistribution, pharmacokinetics and toxicology of Ag2S near-infrared quantum dots in mice. Biomaterials 2013, 34, 3639–3646.CrossRefGoogle Scholar
  38. [38]
    Li, C. Y.; Zhang, Y. J.; Wang, M.; Zhang, Y.; Chen, G. C.; Li, L.; Wu, D. M.; Wang, Q. B. In vivo real-time visualization of tissue blood flow and angiogenesis using Ag2S quantum dots in the NIR-II window. Biomaterials 2014, 35, 393–400.CrossRefGoogle Scholar
  39. [39]
    Santos, H. D. A.; Ruiz, D.; Lifante, G.; Jacinto, C.; Juarez, B. H.; Jaque, D. Time resolved spectroscopy of infrared emitting Ag2S nanocrystals for subcutaneous thermometry. Nanoscale 2017, 9, 2505–2513.CrossRefGoogle Scholar
  40. [40]
    Santos, H. D. A.; Ximendes, E. C.; del Carmen Iglesias-de la Cruz, M.; Chaves-Coira, I.; del Rosal, B.; Jacinto, C.; Monge, L.; Rubia-Rodríguez, I.; Ortega, D.; Mateos, S. et al. In vivo early tumor detection and diagnosis by infrared luminescence transient nanothermometry. Adv. Funct. Mater. 2018, 28, 1803924.CrossRefGoogle Scholar
  41. [41]
    Chang, P. J.; Cheng, H. Y.; Lin, W. W.; Li, X. R.; Zhao, F. Y. A stable and active AgxS crystal preparation and its performance as photocatalyst. Chin. J. Catal. 2015, 36, 564–571.CrossRefGoogle Scholar
  42. [42]
    Yang, T.; Tang, Y. A.; Liu, L.; Lv, X. Y.; Wang, Q. L.; Ke, H. T.; Deng, Y. B.; Yang, H.; Yang, X. L.; Liu, G. et al. Size-dependent Ag2S nanodots for second near-infrared fluorescence/photoacoustics imaging and simultaneous photothermal therapy. ACS Nano 2017, 11, 1848–1857.CrossRefGoogle Scholar
  43. [43]
    Hong, G. S.; Lee, J. C.; Jha, A.; Diao, S.; Nakayama, K. H.; Hou, L. Q.; Doyle, T. C.; Robinson, J. T.; Antaris, A. L.; Dai, H. J. et al. Near-infrared II fluorescence for imaging hindlimb vessel regeneration with dynamic tissue perfusion measurement. Circ. Cardiovasc. Imaging 2014, 7, 517–525.CrossRefGoogle Scholar
  44. [44]
    Hennig, R.; Pollinger, K.; Tessmar, J.; Goepferich, A. Multivalent targeting of AT1 receptors with angiotensin II-functionalized nanoparticles. J. Drug Target. 2015, 23, 681–689.CrossRefGoogle Scholar
  45. [45]
    Molavi, B.; Chen, J. W.; Mehta, J. L. Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK. Am. J. Physiol. Heart. Circ. Physiol. 2006, 291, H687–H693.CrossRefGoogle Scholar
  46. [46]
    Nio, Y.; Matsubara, H.; Murasawa, S.; Kanasaki, M.; Inada, M. Regulation of gene transcription of angiotensin II receptor subtypes in myocardial infarction. J. Clin. Invest. 1995, 95, 46–54.CrossRefGoogle Scholar
  47. [47]
    Busche, S.; Gallinat, S.; Bohle, R. M.; Reinecke, A.; Seebeck, J.; Franke, F.; Fink, L.; Zhu, M. Y.; Sumners, C.; Unger, T. Expression of angiotensin AT1 and AT2 receptors in adult rat cardiomyocytes after myocardial infarction: A single-cell reverse transcriptase-polymerase chain reaction study. Am. J. Pathol. 2000, 157, 605–611.CrossRefGoogle Scholar
  48. [48]
    Bell, R. M.; Mocanu, M. M.; Yellon, D. M. Retrograde heart perfusion: The Langendorff technique of isolated heart perfusion. J. Mol. Cell. Cardiol. 2011, 50, 940–950.CrossRefGoogle Scholar
  49. [49]
    Ostadal, B.; Netuka, I.; Maly, J.; Besik, J.; Ostadalova, I. Gender differences in cardiac ischemic injury and protection—experimental aspects. Exp. Biol. Med. 2009, 234, 1011–1019.CrossRefGoogle Scholar
  50. [50]
    Jeong, S.; Jung, Y.; Bok, S.; Ryu, Y. M.; Lee, S.; Kim, Y. E.; Song, J.; Kim, M.; Kim, S. Y.; Ahn, G. O. et al. Multiplexed in vivo imaging using size-controlled quantum dots in the second near-infrared window. Adv. Health. Mater. 2018, 7, 1800695.CrossRefGoogle Scholar
  51. [51]
    Benayas, A.; Ren, F. Q.; Carrasco, E.; Marzal, V.; del Rosal, B.; Gonfa, B. A.; Juarranz, Á Sanz-Rodríguez, F.; Jaque, D.; García-Solé, J. et al. PbS/CdS/ZnS quantum dots: A multifunctional platform for in vivo nearinfrared low-dose fluorescence imaging. Adv. Funct. Mater. 2015, 25, 6650–6659.CrossRefGoogle Scholar
  52. [52]
    Robinson, J. T.; Hong, G. S.; Liang, Y. Y.; Zhang, B.; Yaghi, O. K.; Dai, H. J. In vivo fluorescence imaging in the second near-infrared window with long circulating carbon nanotubes capable of ultrahigh tumor uptake. J. Am. Chem. Soc. 2012, 134, 10664–10669.CrossRefGoogle Scholar
  53. [53]
    Bhavane, R.; Starosolski, Z.; Stupin, I.; Ghaghada, K. B.; Annapragada, A. NIR-II fluorescence imaging using indocyanine green nanoparticles. Sci. Rep. 2018, 8, 14455.CrossRefGoogle Scholar
  54. [54]
    Carr, J. A.; Franke, D.; Caram, J. R.; Perkinson, C. F.; Saif, M.; Askoxylakis, V.; Datta, M.; Fukumura, D.; Jain, R. K.; Bawendi, M. G. et al. Shortwave infrared fluorescence imaging with the clinically approved near-infrared dye indocyanine green. Proc. Natl. Acad. Sci. USA 2018, 115, 4465–4470.CrossRefGoogle Scholar
  55. [55]
    Ortgies, D. H.; Tan, M. L.; Ximendes, E. C.; del Rosal, B.; Hu, J.; Xu, L.; Wang, X. D.; Martín Rodríguez, E.; Jacinto, C.; Fernandez, N. et al. Lifetime-encoded infrared-emitting nanoparticles for in vivo multiplexed imaging. ACS Nano 2018, 12, 4362–4368.CrossRefGoogle Scholar
  56. [56]
    Yang, B. C.; Li, D. Y.; Phillips, M. I.; Mehta, P.; Mehta, J. L. Myocardial angiotensin II receptor expression and ischemia-reperfusion injury. Vasc. Med. 1998, 3, 121–130.CrossRefGoogle Scholar
  57. [57]
    Anversa, P.; Leri, A.; Li, B. S.; Liu, Y.; Di Somma, S.; Kajstura, J. Ischemic cardiomyopathy and the cellular renin-angiotensin system. J. Heart Lung Transplant. 2000, 19, S1–S11.CrossRefGoogle Scholar
  58. [58]
    Sato, M.; Engelman, R. M.; Otani, H.; Maulik, N.; Rousou, J. A.; Flack III, J. E.; Deaton, D. W.; Das, D. K. Myocardial protection by preconditioning of heart with losartan, an angiotensin II type 1-receptor blocker: Implication of bradykinin-dependent and bradykinin-independent mechanisms. Circulation 2000, 102, III346–III351.Google Scholar
  59. [59]
    Greish, K. Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting. In Cancer Nanotechnology: Methods and Protocols. Grobmyer, S. R.; Moudgil, B. M., Eds.; Humana Press: Totowa, N.J., 2010.Google Scholar
  60. [60]
    Wang, L. V.; Hu, S. Photoacoustic tomography: In vivo imaging from organelles to organs. Science 2012, 335, 1458–1462.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Dirk H. Ortgies
    • 1
    • 2
  • Ángel Luis García-Villalón
    • 3
  • Miriam Granado
    • 3
  • Sara Amor
    • 3
  • Emma Martín Rodríguez
    • 1
    • 4
  • Harrisson D. A. Santos
    • 2
    • 5
  • Jingke Yao
    • 2
  • Jorge Rubio-Retama
    • 6
  • Daniel Jaque
    • 1
    • 2
    Email author
  1. 1.Nanobiology Group, Instituto Ramón y Cajal de Investigación SanitariaIRYCISMadridSpain
  2. 2.Fluorescence Imaging Group, Departamento de Física de Materiales – Facultad de CienciasUniversidad Autónoma de MadridMadridSpain
  3. 3.Fluorescence Imaging Group, Departamento de Fisiología – Facultad de Medicina, Avda. Arzobispo Morcillo 2Universidad Autónoma de MadridMadridSpain
  4. 4.Fluorescence Imaging Group, Departamento de Física Aplicada – Facultad de CienciasUniversidad Autonoma de MadridMadridSpain
  5. 5.Grupo de Nano-Fotônica e Imagens, Instituto de FísicaUniversidade Federal de AlagoasMaceióBrazil
  6. 6.Departamento de Química Física en Ciencias Farmacéuticas, Facultad de Farmacia, Plaza de Ramón y Cajal, s/nUniversidad Complutense de MadridMadridSpain

Personalised recommendations