Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Nanomaterial-based contrast agents

Nature Reviews Methods Primers volume 3, Article number: 30 (2023) Cite this article

Subjects

Abstract

Medical imaging, which empowers the detection of physiological and pathological processes within living subjects, has a vital role in both preclinical and clinical diagnostics. Contrast agents are often needed to accompany anatomical data with functional information or to provide phenotyping of the disease in question. Many newly emerging contrast agents are based on nanomaterials as their high payloads, unique physicochemical properties, improved sensitivity and multimodality capacity are highly desired for many advanced forms of bioimaging techniques and applications. Here, we review the developments in the field of nanomaterial-based contrast agents. We outline important nanomaterial design considerations and discuss the effect on their physicochemical attributes, contrast properties and biological behaviour. We also describe commonly used approaches for formulating, functionalizing and characterizing these nanomaterials. Key applications are highlighted by categorizing nanomaterials on the basis of their X-ray, magnetic, nuclear, optical and/or photoacoustic contrast properties. Finally, we offer our perspectives on current challenges and emerging research topics as well as expectations for future advancements in the field.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Design principles of nanomaterial-based contrast agents for various imaging modalities and biomedical applications.
Fig. 2: Overview of the approaches used for synthesizing, conjugating and purifying nanomaterial-based contrast agents.
Fig. 3: Examples of physical characterization, imaging assessments and biological interactions of nanomaterial-based contrast agents.
Fig. 4: Spectral computed tomographic imaging of atherosclerotic plaque composition with gold-loaded high-density lipoprotein.
Fig. 5: Superparamagnetic iron oxide nanoparticles labelled with 69Ge for lymph node mapping via positron emission tomography and MRI.
Fig. 6: Ag2S nanoparticles with theranostic functionality for tumour imaging and treatment.

Similar content being viewed by others

References

  1. Kim, J. et al. Use of nanoparticle contrast agents for cell tracking with computed tomography. Bioconjug. Chem. 28, 1581–1597 (2017).

    Article  Google Scholar 

  2. Dong, Y. C., Bouche, M., Uman, S., Burdick, J. A. & Cormode, D. P. Detecting and monitoring hydrogels with medical imaging. ACS Biomater. Sci. Eng. 7, 4027–4047 (2021).

    Article  Google Scholar 

  3. Cormode, D. P., Skajaa, T., Fayad, Z. A. & Mulder, W. J. Nanotechnology in medical imaging: probe design and applications. Arterioscler. Thromb. Vasc. Biol. 29, 992–1000 (2009).

    Article  Google Scholar 

  4. Choi, H. S. et al. Renal clearance of quantum dots. Nat. Biotechnol. 25, 1165–1170 (2007). To our knowledge, this is the first paper to systemically study the nanoparticle size and ligand coatings required for rapid and efficient renal excretion.

    Article  Google Scholar 

  5. Nieves, L. M. et al. Renally excretable silver telluride nanoparticles as contrast agents for X-ray imaging. ACS Appl. Mater. Interfaces 14, 34354–34364 (2022).

    Article  Google Scholar 

  6. Zhou, C., Long, M., Qin, Y., Sun, X. & Zheng, J. Luminescent gold nanoparticles with efficient renal clearance. Angew. Chem. Int. Ed. 50, 3168–3172 (2011).

    Article  Google Scholar 

  7. Cole, L. E., McGinnity, T. L., Irimata, L. E., Vargo-Gogola, T. & Roeder, R. K. Effects of bisphosphonate ligands and PEGylation on targeted delivery of gold nanoparticles for contrast-enhanced radiographic detection of breast microcalcifications. Acta Biomater. 82, 122–132 (2018).

    Article  Google Scholar 

  8. Sykes, E. A., Chen, J., Zheng, G. & Chan, W. C. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano 8, 5696–5706 (2014).

    Article  Google Scholar 

  9. Li, B. & Lane, L. A. Probing the biological obstacles of nanomedicine with gold nanoparticles. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1542 (2019).

    Article  Google Scholar 

  10. Nakamura, Y., Mochida, A., Choyke, P. L. & Kobayashi, H. Nanodrug delivery: is the enhanced permeability and retention effect sufficient for curing cancer? Bioconjug. Chem. 27, 2225–2238 (2016).

    Article  Google Scholar 

  11. Nieves, L. M., Mossburg, K., Hsu, J. C., Maidment, A. D. A. & Cormode, D. P. Silver chalcogenide nanoparticles: a review of their biomedical applications. Nanoscale 13, 19306–19323 (2021).

    Article  Google Scholar 

  12. Bouche, M. et al. Recent advances in molecular imaging with gold nanoparticles. Bioconjug. Chem. 31, 303–314 (2020).

    Article  Google Scholar 

  13. Cormode, D. P., Naha, P. C. & Fayad, Z. A. Nanoparticle contrast agents for computed tomography: a focus on micelles. Contrast Media Mol. Imaging 9, 37–52 (2014).

    Article  Google Scholar 

  14. Mulder, W. J. et al. Nanoparticulate assemblies of amphiphiles and diagnostically active materials for multimodality imaging. Acc. Chem. Res. 42, 904–914 (2009).

    Article  Google Scholar 

  15. Baig, R. B. N. & Varma, R. S. Alternative energy input: mechanochemical, microwave and ultrasound-assisted organic synthesis. Chem. Soc. Rev. 41, 1559–1584 (2012).

    Article  Google Scholar 

  16. Smith, B. R. & Gambhir, S. S. Nanomaterials for in vivo imaging. Chem. Rev. 117, 901–986 (2017).

    Article  Google Scholar 

  17. James, M. L. & Gambhir, S. S. A molecular imaging primer: modalities, imaging agents, and applications. Physiol. Rev. 92, 897–965 (2012).

    Article  Google Scholar 

  18. Padmanabhan, P., Kumar, A., Kumar, S., Chaudhary, R. K. & Gulyás, B. Nanoparticles in practice for molecular-imaging applications: an overview. Acta Biomater. 41, 1–16 (2016).

    Article  Google Scholar 

  19. Jendrasiak, G. L., Frey, G. D. & Heim, R. C. Jr Liposomes as carriers of iodolipid radiocontrast agents for CT scanning of the liver. Invest. Radiol. 20, 995–1002 (1985). This work introduces iodinated liposomes as one of the first nanoparticle-based CT contrast agents.

    Article  Google Scholar 

  20. Gazelle, G. S. et al. Hepatic imaging with iodinated nanoparticles: a comparison with iohexol in rabbits. Acad. Radiol. 2, 700–704 (1995).

    Article  Google Scholar 

  21. Seltzer, S. E., Gregoriadis, G. & Dick, R. Evaluation of the dehydration–rehydration method for production of contrast-carrying liposomes. Invest. Radiol. 23, 131–138 (1988).

    Article  Google Scholar 

  22. Hsu, J. C. et al. Nanoparticle contrast agents for X-ray imaging applications. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 12, e1642 (2020).

    Article  Google Scholar 

  23. Naha, P. C. et al. Dextran-coated cerium oxide nanoparticles: a computed tomography contrast agent for imaging the gastrointestinal tract and inflammatory bowel disease. ACS Nano 14, 10187–10197 (2020).

    Article  Google Scholar 

  24. Karunamuni, R., Tsourkas, A. & Maidment, A. D. Exploring silver as a contrast agent for contrast-enhanced dual-energy X-ray breast imaging. Br. J. Radiol. 87, 20140081 (2014).

    Article  Google Scholar 

  25. Karunamuni, R. & Maidment, A. D. Search for novel contrast materials in dual-energy X-ray breast imaging using theoretical modeling of contrast-to-noise ratio. Phys. Med. Biol. 59, 4311–4324 (2014).

    Article  Google Scholar 

  26. Lee, S. H., Kim, B. H., Na, H. B. & Hyeon, T. Paramagnetic inorganic nanoparticles as T1 MRI contrast agents. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 6, 196–209 (2014).

    Article  Google Scholar 

  27. Mulder, W. J., Strijkers, G. J., van Tilborg, G. A., Griffioen, A. W. & Nicolay, K. Lipid-based nanoparticles for contrast-enhanced MRI and molecular imaging. NMR Biomed. 19, 142–164 (2006).

    Article  Google Scholar 

  28. Dadfar, S. M. et al. Iron oxide nanoparticles: diagnostic, therapeutic and theranostic applications. Adv. Drug Deliv. Rev. 138, 302–325 (2019).

    Article  Google Scholar 

  29. Hu, Y., Mignani, S., Majoral, J. P., Shen, M. & Shi, X. Construction of iron oxide nanoparticle-based hybrid platforms for tumor imaging and therapy. Chem. Soc. Rev. 47, 1874–1900 (2018).

    Article  Google Scholar 

  30. Ali, M. M. et al. A nano-sized PARACEST-fluorescence imaging contrast agent facilitates and validates in vivo CEST MRI detection of glioma. Nanomedicine 7, 1827–1837 (2012). This study presents a dual-modality PARACEST and fluorescent contrast agent based on dendrimers conjugated with europium–DOTA–tetraglycinate and a fluorophore.

    Article  Google Scholar 

  31. Chan, K. W., Bulte, J. W. & McMahon, M. T. Diamagnetic chemical exchange saturation transfer (diaCEST) liposomes: physicochemical properties and imaging applications. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 6, 111–124 (2014).

    Article  Google Scholar 

  32. Wang, C., Adams, S. R. & Ahrens, E. T. Emergent fluorous molecules and their uses in molecular imaging. Acc. Chem. Res. 54, 3060–3070 (2021).

    Article  Google Scholar 

  33. Ashur, I., Allouche-Arnon, H. & Bar-Shir, A. Calcium fluoride nanocrystals: tracers for in vivo (19) F magnetic resonance imaging. Angew. Chem. Int. Ed. 57, 7478–7482 (2018).

    Article  Google Scholar 

  34. Duong, H. T. K. et al. A guide to the design of magnetic particle imaging tracers for biomedical applications. Nanoscale 14, 13890–13914 (2022).

    Article  Google Scholar 

  35. Irfan, M. & Dogan, N. Comprehensive evaluation of magnetic particle imaging (MPI) scanners for biomedical applications. IEEE Access 10, 86718–86732 (2022).

    Article  Google Scholar 

  36. Chakravarty, R., Hong, H. & Cai, W. Positron emission tomography image-guided drug delivery: current status and future perspectives. Mol. Pharm. 11, 3777–3797 (2014).

    Article  Google Scholar 

  37. Goel, S., England, C. G., Chen, F. & Cai, W. Positron emission tomography and nanotechnology: a dynamic duo for cancer theranostics. Adv. Drug Deliv. Rev. 113, 157–176 (2017).

    Article  Google Scholar 

  38. Sun, X., Cai, W. & Chen, X. Positron emission tomography imaging using radiolabeled inorganic nanomaterials. Acc. Chem. Res. 48, 286–294 (2015).

    Article  Google Scholar 

  39. Ametamey, S. M., Honer, M. & Schubiger, P. A. Molecular imaging with PET. Chem. Rev. 108, 1501–1516 (2008).

    Article  Google Scholar 

  40. Medintz, I. L., Uyeda, H. T., Goldman, E. R. & Mattoussi, H. Quantum dot bioconjugates for imaging, labelling and sensing. Nat. Mater. 4, 435–446 (2005).

    Article  ADS  Google Scholar 

  41. Jiang, P., Zhu, C. N., Zhang, Z. L., Tian, Z. Q. & Pang, D. W. Water-soluble Ag(2)S quantum dots for near-infrared fluorescence imaging in vivo. Biomaterials 33, 5130–5135 (2012).

    Article  Google Scholar 

  42. Li, W. & Chen, X. Gold nanoparticles for photoacoustic imaging. Nanomedicine 10, 299–320 (2015).

    Article  Google Scholar 

  43. Hajfathalian, M. et al. Wulff in a cage gold nanoparticles as contrast agents for computed tomography and photoacoustic imaging. Nanoscale 10, 18749–18757 (2018).

    Article  Google Scholar 

  44. Xie, C., Zhen, X., Lei, Q., Ni, R. & Pu, K. Self-assembly of semiconducting polymer amphiphiles for in vivo photoacoustic imaging. Adv. Funct. Mater. 27, 1605397 (2017). This work describes the first generation of amphiphilic optically active semiconducting polymer nanoparticles for PA and fluorescence imaging.

    Article  Google Scholar 

  45. Klibanov, A. L. Ultrasound contrast: gas microbubbles in the vasculature. Invest. Radiol. 56, 50–61 (2021).

    Article  Google Scholar 

  46. Exner, A. A. & Kolios, M. C. Bursting microbubbles: how nanobubble contrast agents can enable the future of medical ultrasound molecular imaging and image-guided therapy. Curr. Opin. Colloid. Interface. Sci. https://doi.org/10.1016/j.cocis.2021.101463 (2021). This review summarizes the recent developments of acoustically active nanobubbles as ultrasound contrast agents and as therapeutic vehicles.

    Article  Google Scholar 

  47. Duan, H., Wang, D. & Li, Y. Green chemistry for nanoparticle synthesis. Chem. Soc. Rev. 44, 5778–5792 (2015).

    Article  Google Scholar 

  48. Tao, H. et al. Nanoparticle synthesis assisted by machine learning. Nat. Rev. Mater. 6, 701–716 (2021).

    Article  ADS  Google Scholar 

  49. Gao, J., Wu, C., Deng, D., Wu, P. & Cai, C. Direct synthesis of water-soluble aptamer-Ag2 S quantum dots at ambient temperature for specific imaging and photothermal therapy of cancer. Adv. Healthc. Mater. 5, 2437–2449 (2016).

    Article  Google Scholar 

  50. Hsu, J. C. et al. Effect of nanoparticle synthetic conditions on ligand coating integrity and subsequent nano–biointeractions. ACS Appl. Mater. Interfaces 13, 58401–58410 (2021).

    Article  Google Scholar 

  51. Kim, D., Kim, J., Park, Y. I., Lee, N. & Hyeon, T. Recent development of inorganic nanoparticles for biomedical imaging. ACS Cent. Sci. 4, 324–336 (2018).

    Article  Google Scholar 

  52. Dong, Y. C. et al. Effect of gold nanoparticle size on their properties as contrast agents for computed tomography. Sci. Rep. 9, 14912 (2019).

    Article  ADS  Google Scholar 

  53. Luo, D., Wang, X., Burda, C. & Basilion, J. P. Recent development of gold nanoparticles as contrast agents for cancer diagnosis. Cancers https://doi.org/10.3390/cancers13081825 (2021).

    Article  Google Scholar 

  54. Jokerst, J. V., Cole, A. J., Van de Sompel, D. & Gambhir, S. S. Gold nanorods for ovarian cancer detection with photoacoustic imaging and resection guidance via Raman imaging in living mice. ACS Nano 6, 10366–10377 (2012).

    Article  Google Scholar 

  55. Xu, P. et al. A DM1-doped porous gold nanoshell system for NIR accelerated redox-responsive release and triple modal imaging guided photothermal synergistic chemotherapy. J. Nanobiotechnol. 19, 77 (2021).

    Article  Google Scholar 

  56. Kim, B. H. et al. Large-scale synthesis of uniform and extremely small-sized iron oxide nanoparticles for high-resolution T1 magnetic resonance imaging contrast agents. J. Am. Chem. Soc. 133, 12624–12631 (2011).

    Article  Google Scholar 

  57. Peng, Y.-K., Tsang, S. C. E. & Chou, P.-T. Chemical design of nanoprobes for T1-weighted magnetic resonance imaging. Mater. Today 19, 336–348 (2016).

    Article  Google Scholar 

  58. Kim, J. et al. High-quantum yield alloy-typed core/shell CdSeZnS/ZnS quantum dots for bio-applications. J. Nanobiotechnol. 20, 22 (2022).

    Article  Google Scholar 

  59. Shreyash, N. et al. Green synthesis of nanoparticles and their biomedical applications: a review. ACS Appl. Nano Mater. 4, 11428–11457 (2021).

    Article  Google Scholar 

  60. Xiao, L. et al. Enhanced in vitro and in vivo cellular imaging with green tea coated water-soluble iron oxide nanocrystals. ACS Appl. Mater. Interfaces 7, 6530–6540 (2015).

    Article  Google Scholar 

  61. Wu, L. et al. A green synthesis of carbon nanoparticle from honey for real-time photoacoustic imaging. Nano Res. 6, 312–325 (2013).

    Article  Google Scholar 

  62. Tassa, C., Shaw, S. Y. & Weissleder, R. Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy. Acc. Chem. Res. 44, 842–852 (2011).

    Article  Google Scholar 

  63. Naha, P. C. et al. Dextran coated bismuth–iron oxide nanohybrid contrast agents for computed tomography and magnetic resonance imaging. J. Mater. Chem. B 2, 8239–8248 (2014).

    Article  Google Scholar 

  64. Kim, J. et al. Ultrasmall antioxidant cerium oxide nanoparticles for regulation of acute inflammation. ACS Appl. Mater. Interfaces 13, 60852–60864 (2021).

    Article  Google Scholar 

  65. Cormode, D. P., Jarzyna, P. A., Mulder, W. J. & Fayad, Z. A. Modified natural nanoparticles as contrast agents for medical imaging. Adv. Drug Deliv. Rev. 62, 329–338 (2010).

    Article  Google Scholar 

  66. Lobatto, M. E. et al. Multimodal positron emission tomography imaging to quantify uptake of 89Zr-labeled liposomes in the atherosclerotic vessel wall. Bioconjug. Chem. 31, 360–368 (2020).

    Article  Google Scholar 

  67. Lin, W. et al. Doxorubicin-loaded unimolecular micelle-stabilized gold nanoparticles as a theranostic nanoplatform for tumor-targeted chemotherapy and computed tomography Imaging. Biomacromolecules 18, 3869–3880 (2017).

    Article  Google Scholar 

  68. Guo, M. et al. Dual imaging-guided photothermal/photodynamic therapy using micelles. Biomaterials 35, 4656–4666 (2014).

    Article  Google Scholar 

  69. Cormode, D. P. et al. Nanocrystal core high-density lipoproteins: a multimodality contrast agent platform. Nano Lett. 8, 3715–3723 (2008). This work uses HDL to create various nanoparticle–inorganic material composites for multimodality imaging of atherosclerosis.

    Article  ADS  Google Scholar 

  70. Rakhshan, S., Alberti, D., Stefania, R., Bitonto, V. & Geninatti Crich, S. LDL mediated delivery of paclitaxel and MRI imaging probes for personalized medicine applications. J. Nanobiotechnol. 19, 208 (2021).

    Article  Google Scholar 

  71. Perez-Medina, C. et al. PET imaging of tumor-associated macrophages with 89Zr-labeled high-density lipoprotein nanoparticles. J. Nucl. Med. 56, 1272–1277 (2015).

    Article  Google Scholar 

  72. Sanchez-Gaytan, B. L. et al. HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages. Bioconjug. Chem. 26, 443–451 (2015).

    Article  Google Scholar 

  73. Pérez-Medina, C. et al. In vivo PET imaging of HDL in multiple atherosclerosis models. JACC Cardiovasc. Imaging 9, 950–961 (2016).

    Article  Google Scholar 

  74. Yuan, Y. et al. Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy. Nat. Mater. 18, 1376–1383 (2019). This study describes the self-assembly of a peptide–drug conjugate into large intracellular NPs via the activity of furin, a tumour-associated enzyme, for enhanced cancer theranostics.

    Article  ADS  Google Scholar 

  75. Yuan, Y. et al. Furin-mediated self-assembly of olsalazine nanoparticles for targeted Raman imaging of tumors. Angew. Chem. Int. Ed. 60, 3923–3927 (2021).

    Article  Google Scholar 

  76. Srikar, R., Upendran, A. & Kannan, R. Polymeric nanoparticles for molecular imaging. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 6, 245–267 (2014).

    Article  Google Scholar 

  77. Pu, K. et al. Semiconducting polymer nanoparticles as photoacoustic molecular imaging probes in living mice. Nat. Nanotechnol. 9, 233–239 (2014).

    Article  ADS  Google Scholar 

  78. Pu, K. et al. Diketopyrrolopyrrole-based semiconducting polymer nanoparticles for in vivo photoacoustic imaging. Adv. Mater. 27, 5184–5190 (2015).

    Article  Google Scholar 

  79. Cheheltani, R. et al. Tunable, biodegradable gold nanoparticles as contrast agents for computed tomography and photoacoustic imaging. Biomaterials 102, 87–97 (2016).

    Article  Google Scholar 

  80. Peng, C. et al. PEGylated dendrimer-entrapped gold nanoparticles for in vivo blood pool and tumor imaging by computed tomography. Biomaterials 33, 1107–1119 (2012).

    Article  Google Scholar 

  81. Zhao, J. et al. CREKA peptide-conjugated dendrimer nanoparticles for glioblastoma multiforme delivery. J. Colloid Interface Sci. 450, 396–403 (2015).

    Article  ADS  Google Scholar 

  82. Chen, M. et al. Multifunctional dendrimer-entrapped gold nanoparticles for labeling and tracking T cells via dual-modal computed tomography and fluorescence imaging. Biomacromolecules 21, 1587–1595 (2020).

    Article  Google Scholar 

  83. Cai, Q. Y. et al. Colloidal gold nanoparticles as a blood-pool contrast agent for X-ray computed tomography in mice. Invest. Radiol. 42, 797–806 (2007).

    Article  Google Scholar 

  84. Xie, J., Gao, J., Michalski, M. & Chen, X. in Nanoplatform‐based Molecular Imaging (ed. Chen, X.) 47–73 (Wiley, 2011).

  85. Voskuil, F. J. et al. Exploiting metabolic acidosis in solid cancers using a tumor-agnostic pH-activatable nanoprobe for fluorescence-guided surgery. Nat. Commun. 11, 3257 (2020).

    Article  ADS  Google Scholar 

  86. Yu, M. K., Park, J. & Jon, S. Targeting strategies for multifunctional nanoparticles in cancer imaging and therapy. Theranostics 2, 3–44 (2012). This review provides a comprehensive summary of targeting strategies, targeting moieties and conjugation methods used for functionalizing NP agents.

    Article  Google Scholar 

  87. Mao, W., Kim, H. S., Son, Y. J., Kim, S. R. & Yoo, H. S. Doxorubicin encapsulated clicked gold nanoparticle clusters exhibiting tumor-specific disassembly for enhanced tumor localization and computerized tomographic imaging. J. Control. Release 269, 52–62 (2018).

    Article  Google Scholar 

  88. Cai, W. et al. Peptide-labeled near-infrared quantum dots for imaging tumor vasculature in living subjects. Nano Lett. 6, 669–676 (2006).

    Article  ADS  Google Scholar 

  89. Allijn, I. E. et al. Gold nanocrystal labeling allows low-density lipoprotein imaging from the subcellular to macroscopic level. ACS Nano 7, 9761–9770 (2013).

    Article  Google Scholar 

  90. Cho, E. J. et al. Nanoparticle characterization: state of the art, challenges, and emerging technologies. Mol. Pharm. 10, 2093–2110 (2013). This review offers a critical review of current and emerging in vitro and in vivo techniques used for characterizing NP agents.

    Article  Google Scholar 

  91. Lim, J., Yeap, S. P., Che, H. X. & Low, S. C. Characterization of magnetic nanoparticle by dynamic light scattering. Nanoscale Res. Lett. 8, 381 (2013).

    Article  ADS  Google Scholar 

  92. Eaton, P. et al. A direct comparison of experimental methods to measure dimensions of synthetic nanoparticles. Ultramicroscopy 182, 179–190 (2017).

    Article  Google Scholar 

  93. Bhattacharjee, S. DLS and zeta potential — what they are and what they are not? J. Control. Relase 235, 337–351 (2016).

    Article  Google Scholar 

  94. Filipe, V., Hawe, A. & Jiskoot, W. Critical evaluation of nanoparticle tracking analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. Pharm. Res. 27, 796–810 (2010).

    Article  Google Scholar 

  95. Jazani, S. et al. An alternative framework for fluorescence correlation spectroscopy. Nat. Commun. 10, 3662 (2019).

    Article  ADS  Google Scholar 

  96. Kim, A., Ng, W. B., Bernt, W. & Cho, N. J. Validation of size estimation of nanoparticle tracking analysis on polydisperse macromolecule assembly. Sci. Rep. 9, 2639 (2019).

    Article  ADS  Google Scholar 

  97. Glasscott, M. W., Pendergast, A. D., Choudhury, M. H. & Dick, J. E. Advanced characterization techniques for evaluating porosity, nanopore tortuosity, and electrical connectivity at the single-nanoparticle level. ACS Appl. Nano Mater. 2, 819–830 (2019).

    Article  Google Scholar 

  98. Mourdikoudis, S., Pallares, R. M. & Thanh, N. T. K. Characterization techniques for nanoparticles: comparison and complementarity upon studying nanoparticle properties. Nanoscale 10, 12871–12934 (2018).

    Article  Google Scholar 

  99. Barenholz, Y. & Amselem, S. J. L. T. Quality control assays in the development and clinical use of liposome-based formulations. Pharmaceutics 1, 527–616 (1993).

    Google Scholar 

  100. Moore, T. L. et al. Nanoparticle colloidal stability in cell culture media and impact on cellular interactions. Chem. Soc. Rev. 44, 6287–6305 (2015).

    Article  Google Scholar 

  101. Baimanov, D., Cai, R. & Chen, C. Understanding the chemical nature of nanoparticle–protein interactions. Bioconjug. Chem. 30, 1923–1937 (2019).

    Article  Google Scholar 

  102. Bouche, M. et al. Novel treatment for glioblastoma delivered by a radiation responsive and radiopaque hydrogel. ACS Biomater. Sci. Eng. 7, 3209–3220 (2021).

    Article  Google Scholar 

  103. Zhang, G., Naha, P. C., Gautam, P., Cormode, D. P. & Chan, J. M. W. Water-dispersible bismuth-organic materials with computed tomography contrast properties. ACS Appl. Bio Mater. 1, 1918–1926 (2018).

    Article  Google Scholar 

  104. Si-Mohamed, S. et al. Evaluation of spectral photon counting computed tomography K-edge imaging for determination of gold nanoparticle biodistribution in vivo. Nanoscale 9, 18246–18257 (2017).

    Article  Google Scholar 

  105. Kim, J. et al. Radioprotective garment-inspired biodegradable polymetal nanoparticles for enhanced CT contrast production. Chem. Mater. 32, 381–391 (2020).

    Article  Google Scholar 

  106. Zhang, Z. & Seeram, E. The use of artificial intelligence in computed tomography image reconstruction — a literature review. J. Med. Imaging Radiat. Sci. 51, 671–677 (2020).

    Article  Google Scholar 

  107. Lauritzen, A. D. et al. An artificial intelligence-based mammography screening protocol for breast cancer: outcome and radiologist workload. Radiology 304, 41–49 (2022).

    Article  Google Scholar 

  108. Galper, M. W. et al. Effect of computed tomography scanning parameters on gold nanoparticle and iodine contrast. Invest. Radiol. 47, 475–481 (2012).

    Article  Google Scholar 

  109. Hsu, J. C. et al. Renally excretable and size-tunable silver sulfide nanoparticles for dual-energy mammography or computed tomography. Chem. Mater. 31, 7845–7854 (2019).

    Article  Google Scholar 

  110. Kim, J. et al. Assessment of candidate elements for development of spectral photon-counting CT specific contrast agents. Sci. Rep. 8, 12119 (2018).

    Article  ADS  Google Scholar 

  111. Christoffersson, J. O., Olsson, L. E. & Sjoberg, S. Nickel-doped agarose gel phantoms in MR imaging. Acta Radiol. 32, 426–431 (1991).

    Article  Google Scholar 

  112. Jeon, M., Halbert, M. V., Stephen, Z. R. & Zhang, M. Iron oxide nanoparticles as T1 contrast agents for magnetic resonance imaging: fundamentals, challenges, applications, and prospectives. Adv. Mater. 33, 1906539 (2021).

    Article  Google Scholar 

  113. Jahromi, A. H. et al. Fluorous-soluble metal chelate for sensitive fluorine-19 magnetic resonance imaging nanoemulsion probes. ACS Nano 13, 143–151 (2019). This work presents a nanoemulsion probe based on a fluorophilic chelating agent for hot-spot detection of inflammation-associated macrophages via 19F MRI.

    Article  Google Scholar 

  114. Kenny, G. D. et al. A bisphosphonate for (19)F-magnetic resonance imaging. J. Fluor. Chem. 184, 58–64 (2016).

    Article  Google Scholar 

  115. Lesniak, W. G. et al. Salicylic acid conjugated dendrimers are a tunable, high performance CEST MRI nanoplatform. Nano Lett. 16, 2248–2253 (2016).

    Article  ADS  Google Scholar 

  116. Chen, F. et al. In vivo integrity and biological fate of chelator-free zirconium-89-labeled mesoporous silica nanoparticles. ACS Nano 9, 7950–7959 (2015).

    Article  Google Scholar 

  117. Ni, D. et al. Ceria nanoparticles meet hepatic ischemia–reperfusion injury: the perfect imperfection. Adv. Mater. 31, e1902956 (2019).

    Article  Google Scholar 

  118. Xu, C. et al. Bacteria-like mesoporous silica-coated gold nanorods for positron emission tomography and photoacoustic imaging-guided chemo-photothermal combined therapy. Biomaterials 165, 56–65 (2018). This study demonstrates the utility of drug-loaded mesoporous silica-coated gold nanorods for PET/PAI-guided combination therapy and triggered drug release for enhanced cancer theranostics.

    Article  Google Scholar 

  119. Higbee-Dempsey, E. et al. Indocyanine green-coated gold nanoclusters for photoacoustic imaging and photothermal therapy. Adv. Ther. https://doi.org/10.1002/adtp.201900088 (2019).

    Article  Google Scholar 

  120. Bohndiek, S. E., Bodapati, S., Van De Sompel, D., Kothapalli, S. R. & Gambhir, S. S. Development and application of stable phantoms for the evaluation of photoacoustic imaging instruments. PLoS ONE 8, e75533 (2013).

    Article  ADS  Google Scholar 

  121. Teraphongphom, N. et al. Nanoparticle loaded polymeric microbubbles as contrast agents for multimodal imaging. Langmuir 31, 11858–11867 (2015).

    Article  Google Scholar 

  122. Henriksen-Lacey, M., Carregal-Romero, S. & Liz-Marzán, L. M. Current challenges toward in vitro cellular validation of inorganic nanoparticles. Bioconjug. Chem. 28, 212–221 (2017).

    Article  Google Scholar 

  123. De Lorenzi, F. et al. Profiling target engagement and cellular uptake of cRGD-decorated clinical-stage core-crosslinked polymeric micelles. Drug Deliv. Transl. Res. https://doi.org/10.1007/s13346-022-01204-8 (2022).

    Article  Google Scholar 

  124. Ruenraroengsak, P. & Tetley, T. D. Differential bioreactivity of neutral, cationic and anionic polystyrene nanoparticles with cells from the human alveolar compartment: robust response of alveolar type 1 epithelial cells. Part. Fibre Toxicol. 12, 19 (2015).

    Article  Google Scholar 

  125. Rosenkrans, Z. T. et al. Selenium-doped carbon quantum dots act as broad-spectrum antioxidants for acute kidney injury management. Adv. Sci. 7, 2000420 (2020).

    Article  Google Scholar 

  126. Shilo, M., Reuveni, T., Motiei, M. & Popovtzer, R. Nanoparticles as computed tomography contrast agents: current status and future perspectives. Nanomedicine 7, 257–269 (2012).

    Article  Google Scholar 

  127. Cormode, D. P. et al. Multicolor spectral photon-counting computed tomography: in vivo dual contrast imaging with a high count rate scanner. Sci. Rep. 7, 4784 (2017).

    Article  ADS  Google Scholar 

  128. Hallouard, F. et al. Radiopaque iodinated nano-emulsions for preclinical X-ray imaging. RSC Adv. 1, 792–801 (2011).

    Article  ADS  Google Scholar 

  129. Ghaghada, K. B., Sato, A. F., Starosolski, Z. A., Berg, J. & Vail, D. M. Computed tomography imaging of solid tumors using a liposomal-iodine contrast agent in companion dogs with naturally occurring cancer. PLoS ONE 11, e0152718 (2016).

    Article  Google Scholar 

  130. Yin, Q. et al. Poly(iohexol) nanoparticles as contrast agents for in vivo X-ray computed tomography imaging. J. Am. Chem. Soc. 135, 13620–13623 (2013).

    Article  Google Scholar 

  131. Hsu, J. C. et al. An all-in-one nanoparticle (AION) contrast agent for breast cancer screening with DEM-CT-MRI-NIRF imaging. Nanoscale 10, 17236–17248 (2018). This is the first study to develop silver telluride NPs as a novel contrast agent for breast imaging with DEM.

    Article  Google Scholar 

  132. Naha, P. C. et al. Gold silver alloy nanoparticles (GSAN): an imaging probe for breast cancer screening with dual-energy mammography or computed tomography. Nanoscale 8, 13740–13754 (2016).

    Article  ADS  Google Scholar 

  133. Nieves, L. M., Hsu, J. C., Lau, K. C., Maidment, A. D. A. & Cormode, D. P. Silver telluride nanoparticles as biocompatible and enhanced contrast agents for X-ray imaging: an in vivo breast cancer screening study. Nanoscale 13, 163–174 (2021).

    Article  Google Scholar 

  134. Yin, L., Zhang, K., Sun, Y. & Liu, Z. Nanoparticle-assisted diagnosis and treatment for abdominal aortic aneurysm. Front. Med. 8, 665846 (2021).

    Article  Google Scholar 

  135. Si-Mohamed, S. A. et al. In vivo molecular k-edge imaging of atherosclerotic plaque using photon-counting CT. Radiology 300, 98–107 (2021). This report illustrates the use of spectral photon-counting CT in combination with gold NPs to detect and quantify atherosclerotic macrophages.

    Article  Google Scholar 

  136. Cormode, D. P. et al. Atherosclerotic plaque composition: analysis with multicolor CT and targeted gold nanoparticles. Radiology 256, 774–782 (2010).

    Article  Google Scholar 

  137. Meir, R. & Popovtzer, R. Cell tracking using gold nanoparticles and computed tomography imaging. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. https://doi.org/10.1002/wnan.1480 (2018).

    Article  Google Scholar 

  138. Astolfo, A. et al. In vivo visualization of gold-loaded cells in mice using X-ray computed tomography. Nanomedicine 9, 284–292 (2013).

    Article  Google Scholar 

  139. Betzer, O. et al. In-vitro optimization of nanoparticle-cell labeling protocols for in-vivo cell tracking applications. Sci. Rep. 5, 15400 (2015).

    Article  ADS  Google Scholar 

  140. Meir, R. et al. Nanomedicine for cancer immunotherapy: tracking cancer-specific T-cells in vivo with gold nanoparticles and CT imaging. ACS Nano 9, 6363–6372 (2015). This report evaluates the migration and distribution of gold NP-labelled T cells via CT imaging, which exemplifies the application of CT to cell tracking.

    Article  Google Scholar 

  141. Kim, T. et al. In vivo micro-CT imaging of human mesenchymal stem cells labeled with gold-poly-l-lysine nanocomplexes. Adv. Funct. Mater. https://doi.org/10.1002/adfm.201604213 (2017).

    Article  Google Scholar 

  142. Chhour, P. et al. Effect of gold nanoparticle size and coating on labeling monocytes for CT tracking. Bioconjug. Chem. 28, 260–269 (2017).

    Article  Google Scholar 

  143. Ashton, J. R. et al. Dual-energy CT imaging of tumor liposome delivery after gold nanoparticle-augmented radiation therapy. Theranostics 8, 1782–1797 (2018).

    Article  Google Scholar 

  144. Yu, N. et al. Thiol-capped Bi nanoparticles as stable and all-in-one type theranostic nanoagents for tumor imaging and thermoradiotherapy. Biomaterials 161, 279–291 (2018).

    Article  Google Scholar 

  145. FitzGerald, P. F. et al. A proposed computed tomography contrast agent using carboxybetaine zwitterionic tantalum oxide nanoparticles: imaging, biological, and physicochemical performance. Invest. Radiol. 51, 786–796 (2016). This work presents a tantalum oxide NP CT contrast agent with one of the highest renal clearance efficiencies reported to date.

    Article  Google Scholar 

  146. Dong, Y. C. et al. Ytterbium nanoparticle contrast agents for conventional and spectral photon-counting CT and their applications for hydrogel imaging. ACS Appl. Mater. Interfaces 14, 39274–39284 (2022).

    Article  Google Scholar 

  147. Li, Y. et al. Spectral computed tomography with inorganic nanomaterials: state-of-the-art. Adv. Drug Deliv. Rev. 189, 114524 (2022).

    Article  Google Scholar 

  148. Shin, T. H., Choi, Y., Kim, S. & Cheon, J. Recent advances in magnetic nanoparticle-based multi-modal imaging. Chem. Soc. Rev. 44, 4501–4516 (2015).

    Article  Google Scholar 

  149. Huang, Y., Hsu, J. C., Koo, H. & Cormode, D. P. Repurposing ferumoxytol: diagnostic and therapeutic applications of an FDA-approved nanoparticle. Theranostics 12, 796–816 (2022).

    Article  Google Scholar 

  150. Zhao, Z. et al. Recent advances in engineering iron oxide nanoparticles for effective magnetic resonance imaging. Bioact. Mater. 12, 214–245 (2022).

    Article  Google Scholar 

  151. Chen, W. et al. Collagen-specific peptide conjugated HDL nanoparticles as MRI contrast agent to evaluate compositional changes in atherosclerotic plaque regression. JACC Cardiovasc. Imaging 6, 373–384 (2013).

    Article  Google Scholar 

  152. Ni, D. et al. Integrating anatomic and functional dual-mode magnetic resonance imaging: design and applicability of a bifunctional contrast agent. ACS Nano 10, 3783–3790 (2016).

    Article  Google Scholar 

  153. Xiao, J. et al. Ultrahigh relaxivity and safe probes of manganese oxide nanoparticles for in vivo imaging. Sci. Rep. 3, 3424 (2013).

    Article  Google Scholar 

  154. Zhen, Z. & Xie, J. Development of manganese-based nanoparticles as contrast probes for magnetic resonance imaging. Theranostics 2, 45–54 (2012).

    Article  Google Scholar 

  155. Kim, T. et al. Mesoporous silica-coated hollow manganese oxide nanoparticles as positive T1 contrast agents for labeling and MRI tracking of adipose-derived mesenchymal stem cells. J. Am. Chem. Soc. 133, 2955–2961 (2011).

    Article  Google Scholar 

  156. Shin, J. et al. Hollow manganese oxide nanoparticles as multifunctional agents for magnetic resonance imaging and drug delivery. Angew. Chem. Int. Ed. 48, 321–324 (2009).

    Article  Google Scholar 

  157. Huang, G. et al. Tunable T1 and T2 contrast abilities of manganese-engineered iron oxide nanoparticles through size control. Nanoscale 6, 10404–10412 (2014). This report examines the effect of nanoparticle size on the mode of detection as well as contrast generation in MRI.

    Article  ADS  Google Scholar 

  158. Toth, G. B. et al. Current and potential imaging applications of ferumoxytol for magnetic resonance imaging. Kidney Int. 92, 47–66 (2017). This review provides details on the properties and applications of ferumoxytol in contrast-enhanced MRI.

    Article  Google Scholar 

  159. Cormode, D. P., Sanchez-Gaytan, B. L., Mieszawska, A. J., Fayad, Z. A. & Mulder, W. J. Inorganic nanocrystals as contrast agents in MRI: synthesis, coating and introduction of multifunctionality. NMR Biomed. 26, 766–780 (2013).

    Article  Google Scholar 

  160. Daldrup-Link, H. E. et al. MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clin. Cancer Res. 17, 5695–5704 (2011).

    Article  Google Scholar 

  161. Daldrup-Link, H. E. et al. Detection of stem cell transplant rejection with ferumoxytol MR imaging: correlation of MR imaging findings with those at intravital microscopy. Radiology 284, 495–507 (2017).

    Article  Google Scholar 

  162. Ahrens, E. T. & Bulte, J. W. Tracking immune cells in vivo using magnetic resonance imaging. Nat. Rev. Immunol. 13, 755–763 (2013).

    Article  Google Scholar 

  163. Chen, W., Cormode, D. P., Fayad, Z. A. & Mulder, W. J. M. Nanoparticles as magnetic resonance imaging contrast agents for vascular and cardiac diseases. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 3, 146–161 (2011).

    Article  Google Scholar 

  164. Ghosh, D. et al. M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer. Nat. Nanotechnol. 7, 677–682 (2012).

    Article  ADS  Google Scholar 

  165. Gallo, J. et al. CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging. Angew. Chem. Int. Ed. 53, 9550–9554 (2014).

    Article  Google Scholar 

  166. Lee, J. H. et al. High-contrast in vivo visualization of microvessels using novel FeCo/GC magnetic nanocrystals. Magn. Reson. Med. 62, 1497–1509 (2009).

    Article  Google Scholar 

  167. Wang, Q. et al. Artificially engineered cubic iron oxide nanoparticle as a high-performance magnetic particle imaging tracer for stem cell tracking. ACS Nano 14, 2053–2062 (2020).

    Article  Google Scholar 

  168. Song, G. et al. Carbon-coated FeCo nanoparticles as sensitive magnetic-particle-imaging tracers with photothermal and magnetothermal properties. Nat. Biomed. Eng. 4, 325–334 (2020).

    Article  Google Scholar 

  169. Cutler, C. S., Hennkens, H. M., Sisay, N., Huclier-Markai, S. & Jurisson, S. S. Radiometals for combined imaging and therapy. Chem. Rev. 113, 858–883 (2013).

    Article  Google Scholar 

  170. Chen, F. et al. Ultrasmall targeted nanoparticles with engineered antibody fragments for imaging detection of HER2-overexpressing breast cancer. Nat. Commun. 9, 4141 (2018).

    Article  ADS  Google Scholar 

  171. Yu, B. et al. Reassembly of (89) Zr-labeled cancer cell membranes into multicompartment membrane-derived liposomes for PET-trackable tumor-targeted theranostics. Adv. Mater. 30, e1704934 (2018).

    Article  Google Scholar 

  172. Bhatnagar, P. et al. Imaging of genetically engineered T cells by PET using gold nanoparticles complexed to copper-64. Integr. Biol. 5, 231–238 (2013).

    Article  Google Scholar 

  173. Orbay, H., Hong, H., Zhang, Y. & Cai, W. Positron emission tomography imaging of atherosclerosis. Theranostics 3, 894–902 (2013).

    Article  Google Scholar 

  174. Majmudar, M. D. et al. Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques. Circ. Res. 112, 755–761 (2013).

    Article  Google Scholar 

  175. Cheng, L. et al. Chelator-free labeling of metal oxide nanostructures with zirconium-89 for positron emission tomography imaging. ACS Nano 11, 12193–12201 (2017). This work presents a general and simple method for chelator-free radiolabelling of various metal oxide nanostructures for PET imaging.

    Article  Google Scholar 

  176. Chrastina, A. & Schnitzer, J. E. Iodine-125 radiolabeling of silver nanoparticles for in vivo SPECT imaging. Int. J. Nanomed. 5, 653–659 (2010).

    Google Scholar 

  177. Esposito, E. et al. Biodistribution of nanostructured lipid carriers: a tomographic study. Eur. J. Pharm. Biopharm. 89, 145–156 (2015).

    Article  Google Scholar 

  178. Zhang, Y. et al. Positron emission tomography imaging of CD105 expression with a 64Cu-labeled monoclonal antibody: NOTA is superior to DOTA. PLoS ONE 6, e28005 (2011).

    Article  ADS  Google Scholar 

  179. Yang, X. et al. cRGD-functionalized, DOX-conjugated, and (6)(4)Cu-labeled superparamagnetic iron oxide nanoparticles for targeted anticancer drug delivery and PET/MR imaging. Biomaterials 32, 4151–4160 (2011).

    Article  Google Scholar 

  180. Chen, F. et al. In vivo tumor targeting and image-guided drug delivery with antibody-conjugated, radiolabeled mesoporous silica nanoparticles. ACS Nano 7, 9027–9039 (2013).

    Article  Google Scholar 

  181. Chen, F. et al. In vivo tumor vasculature targeted PET/NIRF imaging with TRC105(Fab)-conjugated, dual-labeled mesoporous silica nanoparticles. Mol. Pharm. 11, 4007–4014 (2014).

    Article  Google Scholar 

  182. Guo, J. et al. Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles. Biomaterials 34, 8323–8332 (2013).

    Article  Google Scholar 

  183. Goel, S., Chen, F., Ehlerding, E. B. & Cai, W. Intrinsically radiolabeled nanoparticles: an emerging paradigm. Small 10, 3825–3830 (2014).

    Article  Google Scholar 

  184. Zhou, M. et al. A chelator-free multifunctional [64Cu]CuS nanoparticle platform for simultaneous micro-PET/CT imaging and photothermal ablation therapy. J. Am. Chem. Soc. 132, 15351–15358 (2010).

    Article  Google Scholar 

  185. Zhao, Y. et al. Copper-64-alloyed gold nanoparticles for cancer imaging: improved radiolabel stability and diagnostic accuracy. Angew. Chem. Int. Ed. 53, 156–159 (2014).

    Article  Google Scholar 

  186. Zhan, Y. et al. Intrinsically zirconium-89 labeled Gd2O2S:Eu nanoprobes for in vivo positron emission tomography and gamma-ray-induced radioluminescence imaging. Small 12, 2872–2876 (2016).

    Article  Google Scholar 

  187. Zhan, Y. et al. Intrinsically zirconium-89-labeled manganese oxide nanoparticles for in vivo dual-modality positron emission tomography and magnetic resonance imaging. J. Biomed. Nanotechnol. 14, 900–909 (2018).

    Article  ADS  Google Scholar 

  188. Chakravarty, R. et al. Intrinsically germanium-69-labeled iron oxide nanoparticles: synthesis and in-vivo dual-modality PET/MR imaging. Adv. Mater. 26, 5119–5123 (2014).

    Article  Google Scholar 

  189. Liu, T. et al. Iron oxide decorated MoS2 nanosheets with double PEGylation for chelator-free radiolabeling and multimodal imaging guided photothermal therapy. ACS Nano 9, 950–960 (2015).

    Article  Google Scholar 

  190. Campbell, J. L. et al. Multimodal assessment of SERS nanoparticle biodistribution post ingestion reveals new potential for clinical translation of Raman imaging. Biomaterials 135, 42–52 (2017).

    Article  Google Scholar 

  191. Choi, H. S. et al. Design considerations for tumour-targeted nanoparticles. Nat. Nanotechnol. 5, 42–47 (2010).

    Article  ADS  Google Scholar 

  192. Hong, G. et al. In vivo fluorescence imaging with Ag2S quantum dots in the second near-infrared region. Angew. Chem. Int. Ed. 51, 9818–9821 (2012).

    Article  Google Scholar 

  193. Tang, R. et al. Tunable ultrasmall visible-to-extended near-infrared emitting silver sulfide quantum dots for integrin-targeted cancer imaging. ACS Nano 9, 220–230 (2015).

    Article  Google Scholar 

  194. Liu, X., Braun, G. B., Qin, M., Ruoslahti, E. & Sugahara, K. N. In vivo cation exchange in quantum dots for tumor-specific imaging. Nat. Commun. 8, 343 (2017). This study describes the quenching of excess untargeted quantum dots through cation exchange with an etchant to facilitate renal clearance of metal ions and to further enhance tumour-specific detection.

    Article  ADS  Google Scholar 

  195. Cao, L. et al. Competitive performance of carbon ‘quantum’ dots in optical bioimaging. Theranostics 2, 295–301 (2012).

    Article  Google Scholar 

  196. Hong, G. et al. Through-skull fluorescence imaging of the brain in a new near-infrared window. Nat. Photonics 8, 723–730 (2014).

    Article  ADS  Google Scholar 

  197. Wu, T. J. et al. Tracking the engraftment and regenerative capabilities of transplanted lung stem cells using fluorescent nanodiamonds. Nat. Nanotechnol. 8, 682–689 (2013).

    Article  ADS  Google Scholar 

  198. Yoo, J. M., Kang, J. H. & Hong, B. H. Graphene-based nanomaterials for versatile imaging studies. Chem. Soc. Rev. 44, 4835–4852 (2015).

    Article  Google Scholar 

  199. Zhong, Y. et al. Boosting the down-shifting luminescence of rare-earth nanocrystals for biological imaging beyond 1500 nm. Nat. Commun. 8, 737 (2017).

    Article  ADS  Google Scholar 

  200. Hong, G. et al. Ultrafast fluorescence imaging in vivo with conjugated polymer fluorophores in the second near-infrared window. Nat. Commun. 5, 4206 (2014).

    Article  ADS  Google Scholar 

  201. Li, Z. et al. Plant protein-directed synthesis of luminescent gold nanocluster hybrids for tumor imaging. ACS Appl. Mater. Interfaces 10, 83–90 (2018).

    Article  Google Scholar 

  202. Sun, C. et al. Fine-tuned H-ferritin nanocage with multiple gold clusters as near-infrared kidney specific targeting nanoprobe. Bioconjug. Chem. 26, 193–196 (2015).

    Article  Google Scholar 

  203. Zhang, Y., Hong, H. & Cai, W. Imaging with Raman spectroscopy. Curr. Pharm. Biotechnol. 11, 654–661 (2010).

    Article  Google Scholar 

  204. Jokerst, J. V., Miao, Z., Zavaleta, C., Cheng, Z. & Gambhir, S. S. Affibody-functionalized gold-silica nanoparticles for Raman molecular imaging of the epidermal growth factor receptor. Small 7, 625–633 (2011).

    Article  Google Scholar 

  205. Zavaleta, C. L. et al. A Raman-based endoscopic strategy for multiplexed molecular imaging. Proc. Natl Acad. Sci. USA 110, E2288–E2297 (2013).

    Article  Google Scholar 

  206. Harmsen, S. et al. Surface-enhanced resonance Raman scattering nanostars for high-precision cancer imaging. Sci. Transl. Med. 7, 271ra277 (2015). This work introduces a new generation of SERS imaging agents based on gold nanostars for accurate detection of macroscopic malignant lesions and microscopic foci.

    Article  Google Scholar 

  207. Harmsen, S. et al. Rational design of a chalcogenopyrylium-based surface-enhanced resonance Raman scattering nanoprobe with attomolar sensitivity. Nat. Commun. 6, 6570 (2015).

    Article  ADS  Google Scholar 

  208. Eremina, O. E. et al. Expanding the multiplexing capabilities of Raman imaging to reveal highly specific molecular expression and enable spatial profiling. ACS Nano https://doi.org/10.1021/acsnano.2c00353 (2022).

    Article  Google Scholar 

  209. Jiang, X., Du, B., Tang, S., Hsieh, J. T. & Zheng, J. Photoacoustic imaging of nanoparticle transport in the kidneys at high temporal resolution. Angew. Chem. Int. Ed. 58, 5994–6000 (2019).

    Article  Google Scholar 

  210. García-Álvarez, R. et al. Optimizing the geometry of photoacoustically active gold nanoparticles for biomedical imaging. ACS Photonics 7, 646–652 (2020).

    Article  Google Scholar 

  211. Bouche, M. et al. Activatable hybrid polyphosphazene-AuNP nanoprobe for ROS detection by bimodal PA/CT imaging. ACS Appl. Mater. Interfaces 11, 28648–28656 (2019).

    Article  Google Scholar 

  212. Moore, C. & Jokerst, J. V. Strategies for image-guided therapy, surgery, and drug delivery using photoacoustic imaging. Theranostics 9, 1550–1571 (2019).

    Article  Google Scholar 

  213. Dinish, U. S. et al. Single molecule with dual function on nanogold: biofunctionalized construct for in vivo photoacoustic imaging and SERS biosensing. Adv. Funct. Mater. 25, 2316–2325 (2015).

    Article  Google Scholar 

  214. Zhen, X., Pu, K. & Jiang, X. Photoacoustic imaging and photothermal therapy of semiconducting polymer nanoparticles: signal amplification and second near-infrared construction. Small 17, e2004723 (2021).

    Article  Google Scholar 

  215. Cui, D. et al. Thermoresponsive semiconducting polymer nanoparticles for contrast-enhanced photoacoustic imaging. Adv. Funct. Mater. 29, 1903461 (2019).

    Article  Google Scholar 

  216. Yang, K. et al. Visualization of protease activity in vivo using an activatable photo-acoustic imaging probe based on CuS nanoparticles. Theranostics 4, 134–141 (2014).

    Article  MathSciNet  Google Scholar 

  217. Chen, Y. S., Zhao, Y., Yoon, S. J., Gambhir, S. S. & Emelianov, S. Miniature gold nanorods for photoacoustic molecular imaging in the second near-infrared optical window. Nat. Nanotechnol. 14, 465–472 (2019).

    Article  ADS  Google Scholar 

  218. Jokerst, J. V., Thangaraj, M., Kempen, P. J., Sinclair, R. & Gambhir, S. S. Photoacoustic imaging of mesenchymal stem cells in living mice via silica-coated gold nanorods. ACS Nano 6, 5920–5930 (2012).

    Article  Google Scholar 

  219. Qian, X., Shen, S., Liu, T., Cheng, L. & Liu, Z. Two-dimensional TiS(2) nanosheets for in vivo photoacoustic imaging and photothermal cancer therapy. Nanoscale 7, 6380–6387 (2015).

    Article  ADS  Google Scholar 

  220. Yang, T. et al. Size-dependent Ag2S nanodots for second near-infrared fluorescence/photoacoustics imaging and simultaneous photothermal therapy. ACS Nano 11, 1848–1857 (2017).

    Article  Google Scholar 

  221. Maji, S. K. et al. Upconversion nanoparticles as a contrast agent for photoacoustic imaging in live mice. Adv. Mater. 26, 5633–5638 (2014).

    Article  Google Scholar 

  222. Faria, M. et al. Minimum information reporting in bio–nano experimental literature. Nat. Nanotechnol. 13, 777–785 (2018). This perspective piece proposes a list of standards with respect to nanomaterial characterization and data reporting in an effort to improve reproducibility and to facilitate further discussion in the field of nano–bio science research.

    Article  ADS  Google Scholar 

  223. Lammers, T. & Storm, G. Setting standards to promote progress in bio–nano science. Nat. Nanotechnol. 14, 626 (2019).

    Article  ADS  Google Scholar 

  224. Florindo, H. F., Madi, A. & Satchi-Fainaro, R. Challenges in the implementation of MIRIBEL criteria on nanobiomed manuscripts. Nat. Nanotechnol. 14, 627–628 (2019).

    Article  ADS  Google Scholar 

  225. Hühn, J. et al. Selected standard protocols for the synthesis, phase transfer, and characterization of inorganic colloidal nanoparticles. Chem. Mater. 29, 399–461 (2017).

    Article  Google Scholar 

  226. Leong, H. S. et al. On the issue of transparency and reproducibility in nanomedicine. Nat. Nanotechnol. 14, 629–635 (2019).

    Article  ADS  Google Scholar 

  227. Mendes, B. B. et al. Nanodelivery of nucleic acids. Nat. Rev. Methods Primers https://doi.org/10.1038/s43586-022-00104-y (2022).

    Article  Google Scholar 

  228. Li, C. A targeted approach to cancer imaging and therapy. Nat. Mater. 13, 110–115 (2014).

    Article  ADS  Google Scholar 

  229. Kothapalli, S. R. et al. Deep tissue photoacoustic imaging using a miniaturized 2-D capacitive micromachined ultrasonic transducer array. IEEE Trans. Biomed. Eng. 59, 1199–1204 (2012).

    Article  Google Scholar 

  230. Ra, H. et al. Three-dimensional in vivo imaging by a handheld dual-axes confocal microscope. Opt. Express 16, 7224–7232 (2008).

    Article  ADS  Google Scholar 

  231. Park, J. H. et al. Cooperative nanoparticles for tumor detection and photothermally triggered drug delivery. Adv. Mater. 22, 880–885 (2010).

    Article  Google Scholar 

  232. Xie, J. et al. PET/NIRF/MRI triple functional iron oxide nanoparticles. Biomaterials 31, 3016–3022 (2010).

    Article  Google Scholar 

  233. Chien, C. Y., Chuang, H. C., Huang, S. H., Lin, W. C. & Huang, H. Y. A pilot study of segmental mandibulectomy with surgical navigation using fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography. Laryngoscope 122, 2205–2209 (2012).

    Article  Google Scholar 

  234. Christensen, A. et al. Feasibility of real-time near-infrared fluorescence tracer imaging in sentinel node biopsy for oral cavity cancer patients. Ann. Surg. Oncol. 23, 565–572 (2016).

    Article  Google Scholar 

  235. Higgins, L. M. & Pierce, M. C. Design and characterization of a handheld multimodal imaging device for the assessment of oral epithelial lesions. J. Biomed. Opt. 19, 086004 (2014).

    Article  ADS  Google Scholar 

  236. Lee, D. et al. In vivo near infrared virtual intraoperative surgical photoacoustic optical coherence tomography. Sci. Rep. 6, 35176 (2016).

    Article  ADS  Google Scholar 

  237. Lovell, J. F. et al. Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nat. Mater. 10, 324–332 (2011).

    Article  ADS  Google Scholar 

  238. Meershoek, P. et al. Three-dimensional tumor margin demarcation using the hybrid tracer indocyanine Green-(99m)Tc-nanocolloid: a proof-of-concept study in tongue cancer patients scheduled for sentinel node biopsy. J. Nucl. Med. 60, 764–769 (2019).

    Article  Google Scholar 

  239. Sun, I. C. et al. Heparin-coated gold nanoparticles for liver-specific CT imaging. Chemistry 15, 13341–13347 (2009).

    Article  Google Scholar 

  240. Nicolson, F. et al. Non-invasive in vivo imaging of cancer using surface-enhanced spatially offset Raman spectroscopy (SESORS). Theranostics 9, 5899–5913 (2019).

    Article  Google Scholar 

  241. Croissant, J. G. & Brinker, C. J. Biodegradable silica-based nanoparticles: dissolution kinetics and selective bond cleavage. Enzymes 43, 181–214 (2018).

    Article  Google Scholar 

  242. Yang, Y. et al. Biodegradable nanostructures: degradation process and biocompatibility of iron oxide nanostructured arrays. Mater. Sci. Eng. C Mater Biol. Appl. 85, 203–213 (2018).

    Article  Google Scholar 

  243. Tsoi, K. M., Dai, Q., Alman, B. A. & Chan, W. C. Are quantum dots toxic? Exploring the discrepancy between cell culture and animal studies. Acc. Chem. Res. 46, 662–671 (2013).

    Article  Google Scholar 

  244. Derfus, A. M., Chan, W. C. W. & Bhatia, S. N. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett. 4, 11–18 (2004).

    Article  ADS  Google Scholar 

  245. Zhu, S. et al. A general route to make non-conjugated linear polymers luminescent. Chem. Commun. 48, 10889–10891 (2012).

    Article  Google Scholar 

  246. Zavaleta, C. L. et al. Preclinical evaluation of Raman nanoparticle biodistribution for their potential use in clinical endoscopy imaging. Small 7, 2232–2240 (2011).

    Article  Google Scholar 

  247. van de Looij, S. M. et al. Gold nanoclusters: imaging, therapy, and theranostic roles in biomedical applications. Bioconjug. Chem. 33, 4–23 (2022).

    Article  Google Scholar 

  248. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  ADS  Google Scholar 

  249. Li, X., Anton, N., Zuber, G. & Vandamme, T. Contrast agents for preclinical targeted X-ray imaging. Adv. Drug Deliv. Rev. 76, 116–133 (2014).

    Article  Google Scholar 

  250. Hansen, A. E. et al. Positron emission tomography based elucidation of the enhanced permeability and retention effect in dogs with cancer using copper-64 liposomes. ACS Nano 9, 6985–6995 (2015). This report investigates the EPR effect-induced accumulation of NPs in solid tumours of large animals using nanocarrier-radiotracers via PET/CT imaging.

    Article  Google Scholar 

  251. Miller, M. A. et al. Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug. Nat. Commun. 6, 8692 (2015).

    Article  ADS  Google Scholar 

  252. Hui, J. Z. & Tsourkas, A. Optimization of photoactive protein Z for fast and efficient site-specific conjugation of native IgG. Bioconjug. Chem. 25, 1709–1719 (2014).

    Article  Google Scholar 

  253. Anselmo, A. C. & Mitragotri, S. Nanoparticles in the clinic: an update post COVID-19 vaccines. Bioeng. Transl. Med. 6, e10246 (2021).

    Article  Google Scholar 

  254. Miyasato, D. L., Mohamed, A. W. & Zavaleta, C. A path toward the clinical translation of nano-based imaging contrast agents. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 13, e1721 (2021).

    Article  Google Scholar 

  255. Shen, Z., Wu, A. & Chen, X. Iron oxide nanoparticle based contrast agents for magnetic resonance imaging. Mol. Pharm. 14, 1352–1364 (2017).

    Article  Google Scholar 

  256. Jain, S., Hirst, D. G. & O’Sullivan, J. M. Gold nanoparticles as novel agents for cancer therapy. Br. J. Radiol. 85, 101–113 (2012).

    Article  Google Scholar 

  257. Llop, J. & Lammers, T. Nanoparticles for cancer diagnosis, radionuclide therapy and theranostics. ACS Nano https://doi.org/10.1021/acsnano.1c09139 (2021).

    Article  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge funding from the NIH (R01-CA227142 and R21-EB029158 both to D.P.C.). In addition, J.C.H. acknowledges support from the NIH (T32-CA009206) and the Brody Family Medical Trust Fund. C.Z. acknowledges support from USC’s Zumberge Diversity and Inclusion Research Award and USC’s Ming Hsieh Institute. O.E.E. gratefully acknowledges the support of Agilent Technologies through an Agilent Fellowship.

Author information

Authors and Affiliations

  1. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

    Jessica C. Hsu & David P. Cormode

  2. Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, WI, USA

    Jessica C. Hsu, Zhongmin Tang & Weibo Cai

  3. Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA

    Olga E. Eremina & Cristina Zavaleta

  4. Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    Alexandros Marios Sofias & Twan Lammers

  5. Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA

    Jonathan F. Lovell

Authors
  1. Jessica C. Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhongmin Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olga E. Eremina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandros Marios Sofias
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Twan Lammers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jonathan F. Lovell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cristina Zavaleta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weibo Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David P. Cormode
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (J.C.H. and D.P.C.); Experimentation (J.C.H., J.F.L. and D.P.C.); Results (J.C.H., A.M.S., T.L. and D.P.C.); Applications (J.C.H., Z.T., W.C. and D.P.C.); Reproducibility and data deposition (J.C.H. and D.P.C.); Limitations and optimizations (J.C.H., O.E.E., C.Z. and D.P.C.); Outlook (J.C.H., O.E.E., C.Z. and D.P.C.).

Corresponding author

Correspondence to David P. Cormode.

Ethics declarations

Competing interests

W.C. is a scientific advisor, stockholder and grantee of Focus-X Therapeutics, Inc.; a consultant and grantee of Actithera, Inc.; and a scientific advisor of Portrai, Inc. D.P.C. is named as an inventor on patents pertaining to nanoparticle contrast agents and holds stock in Daimroc Imaging. All other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Methods Primers thanks Jeff Bulte, Bryan Smith, Yapei Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Brust method

A commonly used method to synthesize gold nanoparticles in non-aqueous solutions.

Contrast agents

Substances administered in medical imaging procedures to facilitate disease diagnosis via altering image contrast.

Enhanced permeation and retention (EPR) effect

The phenomenon of elevated retention of nanomaterials in certain diseased tissues (for example, tumours and sites of inflammation) owing to leaky vessels and poor lymphatic drainage.

Hot-spot imaging

Imaging of certain tracers, such as fluorinated nanoparticles with 19F-magnetic resonance imaging, allows for specific detection in vivo without endogenous background signal.

Nano-based contrast agents

Contrast agents that are within the nano-size range, typically 1–400 nm.

Phantom

A device composed of tissue-equivalent materials that is used to evaluate imaging performance of contrast agents.

Quantum confinement effect

When a critical threshold size (2–10 nm) is reached, nanomaterials present tunable fluorescence properties reflecting small differences in particle size.

T 1 agents

Contrast agents for magnetic resonance imaging that are used to shorten T1 relaxation. They typically involve gadolinium or manganese.

T 2-shortening agents

Contrast agents for magnetic resonance imaging that are used to shorten T2 relaxation. They are most frequently iron oxide nanoparticles.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hsu, J.C., Tang, Z., Eremina, O.E. et al. Nanomaterial-based contrast agents. Nat Rev Methods Primers 3, 30 (2023). https://doi.org/10.1038/s43586-023-00211-4

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s43586-023-00211-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing