Abstract
In oncology, technologies for clinical molecular imaging are used to diagnose patients, establish the efficacy of treatments and monitor the recurrence of disease. Multiplexed methods increase the number of disease-specific biomarkers that can be detected simultaneously, such as the overexpression of oncogenic proteins, aberrant metabolite uptake and anomalous blood perfusion. The quantitative localization of each biomarker could considerably increase the specificity and the accuracy of technologies for clinical molecular imaging to facilitate granular diagnoses, patient stratification and earlier assessments of the responses to administered therapeutics. In this Review, we discuss established techniques for multiplexed imaging and the most promising emerging multiplexing technologies applied to the imaging of isolated tissues and cells and to non-invasive whole-body imaging. We also highlight advances in radiology that have been made possible by multiplexed imaging.
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References
Heinzmann, K., Carter, L. M., Lewis, J. S. & Aboagye, E. O. Multiplexed imaging for diagnosis and therapy. Nat. Biomed. Eng. 1, 697–713 (2017).
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
Janku, F. Tumor heterogeneity in the clinic: is it a real problem? Ther. Adv. Med. Oncol. 6, 43–51 (2014).
Giedt, R. J. et al. Single-cell barcode analysis provides a rapid readout of cellular signaling pathways in clinical specimens. Nat. Commun. 9, 4550 (2018).
Haun, J. B. et al. Micro-NMR for rapid molecular analysis of human tumor samples. Sci. Transl. Med. 3, 71ra16 (2011).
Nathan, E. Frenk et al. High-content biopsies facilitate molecular analyses and do not increase complication rates in patients with advanced solid tumors. JCO Precis. Oncol. 1, 1–9 (2017).
Kodack, D. P. et al. Primary patient-derived cancer cells and their potential for personalized cancer patient care. Cell Rep. 21, 3298–3309 (2017).
Whitley, M. J. et al. A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci. Transl. Med. 8, 320ra324 (2016).
Liao, L. J., Lo, W. C., Hsu, W. L., Cheng, P. W. & Wang, C. P. Assessment of pain score and specimen adequacy for ultrasound-guided fine-needle aspiration biopsy of thyroid nodules. J. Pain. Res 11, 61–66 (2018).
Umkehrer, C. et al. Isolating live cell clones from barcoded populations using CRISPRa-inducible reporters. Nat. Biotechnol. https://doi.org/10.1038/s41587-020-0614-0 (2020).
Ullal, A. V. et al. Cancer cell profiling by barcoding allows multiplexed protein analysis in fine-needle aspirates. Sci. Transl. Med. 6, 219ra219 (2014).
Chen, K. H., Boettiger, A. N., Moffitt, J. R., Wang, S. & Zhuang, X. RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells. Science 348, aaa6090 (2015).
Moffitt, J. R. et al. High-performance multiplexed fluorescence in situ hybridization in culture and tissue with matrix imprinting and clearing. Proc. Natl Acad. Sci. USA 113, 14456–14461 (2016).
Wang, G., Moffitt, J. R. & Zhuang, X. Multiplexed imaging of high-density libraries of RNAs with MERFISH and expansion microscopy. Sci. Rep. 8, 4847 (2018).
Wu, X., Mao, S., Ying, Y., Krueger, C. J. & Chen, A. K. Progress and challenges for live-cell imaging of genomic loci using CRISPR-based platforms. Genomics Proteom. Bioinform. https://doi.org/10.1016/j.gpb.2018.10.001 (2019).
Im, H. et al. Digital diffraction analysis enables low-cost molecular diagnostics on a smartphone. Proc. Natl Acad. Sci. USA 112, 5613–5618 (2015).
Pathania, D. et al. Holographic assessment of lymphoma tissue (HALT) for global oncology field applications. Theranostics 6, 1603–1610 (2016).
Im, H. et al. Design and clinical validation of a point-of-care device for the diagnosis of lymphoma via contrast-enhanced microholography and machine learning. Nat. Biomed. Eng. 2, 666–674 (2018).
Min, J. et al. Computational optics enables breast cancer profiling in point-of-care settings. ACS Nano 12, 9081–9090 (2018).
Fereidouni, F. et al. Microscopy with ultraviolet surface excitation for rapid slide-free histology. Nat. Biomed. Eng. 1, 957–966 (2017).
Orringer, D. A. et al. Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated Raman scattering microscopy. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-016-0027 (2017).
Glaser, A. K. et al. Light-sheet microscopy for slide-free non-destructive pathology of large clinical specimens. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-017-0084 (2017).
Lin, J. R. et al. Highly multiplexed immunofluorescence imaging of human tissues and tumors using t-CyCIF and conventional optical microscopes. eLife https://doi.org/10.7554/eLife.31657 (2018).
Gerdes, M. J. et al. Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue. Proc. Natl Acad. Sci. USA 110, 11982–11987 (2013).
Yang, B. et al. Single-cell phenotyping within transparent intact tissue through whole-body clearing. Cell 158, 945–958 (2014).
Tanaka, N. et al. Three-dimensional single-cell imaging for the analysis of RNA and protein expression in intact tumour biopsies. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-020-0576-z (2020).
Richardson, D. S. & Lichtman, J. W. Clarifying tissue clearing. Cell 162, 246–257 (2015).
Liebmann, T. et al. Three-dimensional study of Alzheimer’s disease hallmarks using the iDISCO clearing method. Cell Rep. 16, 1138–1152 (2016).
Cuccarese, M. F. et al. Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging. Nat. Commun. 8, 14293 (2017).
Spraggins, J. M. et al. Next-generation technologies for spatial proteomics: integrating ultra-high speed MALDI-TOF and high mass resolution MALDI FTICR imaging mass spectrometry for protein analysis. Proteomics 16, 1678–1689 (2016).
Castellino, S., Groseclose, M. R. & Wagner, D. MALDI imaging mass spectrometry: bridging biology and chemistry in drug development. Bioanalysis 3, 2427–2441 (2011).
Giesen, C. et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat. Methods 11, 417–422 (2014).
Angelo, M. et al. Multiplexed ion beam imaging of human breast tumors. Nat. Med. 20, 436–442 (2014).
Shen, C. et al. 2D and 3D CT radiomics features prognostic performance comparison in non-small cell lung cancer. Transl. Oncol. 10, 886–894 (2017).
Echegaray, S. et al. A rapid segmentation-insensitive “digital biopsy” method for radiomic feature extraction: method and pilot study using CT images of non-small cell lung cancer. Tomography 2, 283–294 (2016).
Coursey, C. A. et al. Dual-energy multidetector CT: how does it work, what can it tell us, and when can we use it in abdominopelvic imaging? Radiographics 30, 1037–1055 (2010).
McCollough, C. H., Leng, S., Yu, L. & Fletcher, J. G. Dual- and multi-energy CT: principles, technical approaches, and clinical applications. Radiology 276, 637–653 (2015).
Yeh, B. M. et al. Opportunities for new CT contrast agents to maximize the diagnostic potential of emerging spectral CT technologies. Adv. Drug Deliv. Rev. 113, 201–222 (2017).
Beels, L. et al. Dose-length product of scanners correlates with DNA damage in patients undergoing contrast CT. Eur. J. Radiol. 81, 1495–1499 (2012).
Pathe, C. et al. The presence of iodinated contrast agents amplifies DNA radiation damage in computed tomography. Contrast Media Mol. Imaging 6, 507–513 (2011).
Piechowiak, E. I., Peter, J. F., Kleb, B., Klose, K. J. & Heverhagen, J. T. Intravenous iodinated contrast agents amplify DNA radiation damage at CT. Radiology 275, 692–697 (2015).
Rothkamm, K., Balroop, S., Shekhdar, J., Fernie, P. & Goh, V. Leukocyte DNA damage after multi-detector row CT: a quantitative biomarker of low-level radiation exposure. Radiology 242, 244–251 (2007).
Momose, A., Takeda, T., Itai, Y. & Hirano, K. Phase-contrast X-ray computed tomography for observing biological soft tissues. Nat. Med. 2, 473–475 (1996).
Baran, P. et al. Optimization of propagation-based X-ray phase-contrast tomography for breast cancer imaging. Phys. Med. Biol. 62, 2315–2332 (2017).
Symons, R. et al. Photon-counting CT for simultaneous imaging of multiple contrast agents in the abdomen: an in vivo study. Med. Phys. 44, 5120–5127 (2017).
Trueb, P., Zambon, P. & Broennimann, C. Assessment of the spectral performance of hybrid photon counting X-ray detectors. Med. Phys. 44, e207–e214 (2017).
Taguchi, K. & Iwanczyk, J. S. Vision 20/20: single photon counting x-ray detectors in medical imaging. Med. Phys. 40, 100901 (2013).
Carter, L. M., Poty, S., Sharma, S. K. & Lewis, J. S. Preclinical optimization of antibody-based radiopharmaceuticals for cancer imaging and radionuclide therapy—model, vector, and radionuclide selection. J. Labelled Comp. Radiopharm. https://doi.org/10.1002/jlcr.3612 (2018).
Cornelis, F. H. et al. Long-half-life (89)Zr-labeled radiotracers can guide percutaneous biopsy within the PET/CT suite without reinjection of radiotracer. J. Nucl. Med. 59, 399–402 (2018).
Phillips, E. et al. Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe. Sci. Transl. Med. 6, 260ra149 (2014).
Black, N. F., McJames, S. & Kadrmas, D. J. Rapid multi-tracer PET tumor imaging with F-FDG and secondary shorter-lived tracers. IEEE Trans. Nucl. Sci. 56, 2750–2758 (2009).
Kadrmas, D. J., Rust, T. C. & Hoffman, J. M. Single-scan dual-tracer FLT+FDG PET tumor characterization. Phys. Med. Biol. 58, 429–449 (2013).
Weissleder, R., Schwaiger, M. C., Gambhir, S. S. & Hricak, H. Imaging approaches to optimize molecular therapies. Sci. Transl. Med. 8, 355ps316 (2016).
Black, K. C. et al. Dual-radiolabeled nanoparticle SPECT probes for bioimaging. Nanoscale 7, 440–444 (2015).
Sharir, T. & Slomka, P. Dual-isotope myocardial perfusion SPECT imaging: past, present, and future. J. Nucl. Cardiol. https://doi.org/10.1007/s12350-017-0966-0 (2017).
Berg, E., Roncali, E., Kapusta, M., Du, J. & Cherry, S. R. A combined time-of-flight and depth-of-interaction detector for total-body positron emission tomography. Med. Phys. 43, 939–950 (2016).
Zhang, X., Zhou, J., Cherry, S. R., Badawi, R. D. & Qi, J. Quantitative image reconstruction for total-body PET imaging using the 2-meter long EXPLORER scanner. Phys. Med. Biol. 62, 2465–2485 (2017).
Cherry, S. R. et al. Total-body PET: maximizing sensitivity to create new opportunities for clinical research and patient care. J. Nucl. Med. 59, 3–12 (2018).
Wibmer, A. G., Hricak, H., Ulaner, G. A. & Weber, W. Trends in oncologic hybrid imaging. Eur. J. Hybrid. Imaging 2, 1 (2018).
Sanguedolce, F. et al. Baseline multiparametric MRI for selection of prostate cancer patients suitable for active surveillance: which features matter? Clin. Genitourin. Cancer https://doi.org/10.1016/j.clgc.2017.10.020 (2017).
Kesch, C. et al. Multiparametric MRI fusion-guided biopsy for the diagnosis of prostate cancer. Curr. Opin. Urol. https://doi.org/10.1097/mou.0000000000000461 (2017).
Brembilla, G. et al. Preoperative multiparametric MRI of the prostate for the prediction of lymph node metastases in prostate cancer patients treated with extended pelvic lymph node dissection. Eur. Radiol. https://doi.org/10.1007/s00330-017-5229-6 (2017).
Ma, D. et al. Magnetic resonance fingerprinting. Nature 495, 187–192 (2013).
European Society of, R. Magnetic resonance fingerprinting - a promising new approach to obtain standardized imaging biomarkers from MRI. Insights Imaging 6, 163–165 (2015).
Harisinghani, M. G. et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N. Engl. J. Med. 348, 2491–2499 (2003).
Kircher, M. F. et al. In vivo high resolution three-dimensional imaging of antigen-specific cytotoxic T-lymphocyte trafficking to tumors. Cancer Res. 63, 6838–6846 (2003).
Miller, M. A., Arlauckas, S. & Weissleder, R. Prediction of anti-cancer nanotherapy efficacy by imaging. Nanotheranostics 1, 296–312 (2017).
Weissleder, R., Saini, S., Stark, D. D., Wittenberg, J. & Ferrucci, J. T. Dual-contrast MR imaging of liver cancer in rats. AJR Am. J. Roentgenol. 150, 561–566 (1988).
Anderson, C. E. et al. Dual contrast - magnetic resonance fingerprinting (DC-MRF): a platform for simultaneous quantification of multiple MRI contrast agents. Sci. Rep. 7, 8431 (2017).
Hurd, R. E., Yen, Y. F., Chen, A. & Ardenkjaer-Larsen, J. H. Hyperpolarized 13C metabolic imaging using dissolution dynamic nuclear polarization. J. Magn. Reson. Imaging 36, 1314–1328 (2012).
Nelson, S. J. et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1-(1)(3)C]pyruvate. Sci. Transl. Med. 5, 198ra108 (2013).
Miloushev, V. Z. et al. Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients. Cancer Res. https://doi.org/10.1158/0008-5472.can-18-0221 (2018).
Wilson, D. M. et al. Multi-compound polarization by DNP allows simultaneous assessment of multiple enzymatic activities in vivo. J. Magn. Reson. 205, 141–147 (2010).
Klippel, S., Freund, C. & Schroder, L. Multichannel MRI labeling of mammalian cells by switchable nanocarriers for hyperpolarized xenon. Nano Lett. 14, 5721–5726 (2014).
Koch, M. & Ntziachristos, V. Advancing surgical vision with fluorescence imaging. Annu. Rev. Med. 67, 153–164 (2016).
Yun, S. H. & Kwok, S. J. J. Light in diagnosis, therapy and surgery. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-016-0008 (2017).
Kobayashi, H. et al. Simultaneous multicolor imaging of five different lymphatic basins using quantum dots. Nano Lett. 7, 1711–1716 (2007).
Erogbogbo, F. et al. In vivo targeted cancer imaging, sentinel lymph node mapping and multi-channel imaging with biocompatible silicon nanocrystals. ACS Nano 5, 413–423 (2011).
Behrooz, A. et al. Multispectral open-air intraoperative fluorescence imaging. Opt. Lett. 42, 2964–2967 (2017).
Keating, J. et al. Identification of breast cancer margins using intraoperative near-infrared imaging. J. Surg. Oncol. 113, 508–514 (2016).
Keating, J. J. et al. Intraoperative molecular imaging of lung adenocarcinoma can identify residual tumor cells at the surgical margins. Mol. Imaging Biol. 18, 209–218 (2016).
Zeng, C. et al. Intraoperative identification of liver cancer microfoci using a targeted near-infrared fluorescent probe for imaging-guided surgery. Sci. Rep. 6, 21959 (2016).
van den Berg, N. S., Buckle, T., KleinJan, G. H., van der Poel, H. G. & van Leeuwen, F. W. B. Multispectral fluorescence imaging during robot-assisted laparoscopic sentinel node biopsy: a first step towards a fluorescence-based anatomic roadmap. Eur. Urol. 72, 110–117 (2017).
Miampamba, M. et al. Sensitive in vivo visualization of breast cancer using ratiometric protease-activatable fluorescent imaging agent, AVB-620. Theranostics 7, 3369–3386 (2017).
Lamberts, L. E. et al. Tumor-specific uptake of fluorescent Bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study. Clin. Cancer Res. 23, 2730–2741 (2017).
Carney, B., Kossatz, S. & Reiner, T. Molecular imaging of PARP. J. Nucl. Med. 58, 1025–1030 (2017).
van Dam, G. M. et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-alpha targeting: first in-human results. Nat. Med. 17, 1315–1319 (2011).
Stummer, W. et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 7, 392–401 (2006).
Georges, J. F. et al. Delta-aminolevulinic acid-mediated photodiagnoses in surgical oncology: a historical review of clinical trials. Front. Surg. 6, 45 (2019).
Haider, S. A., Lim, S., Kalkanis, S. N. & Lee, I. Y. The impact of 5-aminolevulinic acid on extent of resection in newly diagnosed high grade gliomas: a systematic review and single institutional experience. J. Neurooncol. 141, 507–515 (2019).
Lanahan, C. R. et al. Real-time, intraoperative detection of residual breast cancer in lumpectomy cavity margins using the LUM imaging system: results of a feasibility study. Cancer Res. 78 (4 Suppl.), abstr. P2-12-05 (2018).
Mohan, J. F. et al. Imaging the emergence and natural progression of spontaneous autoimmune diabetes. Proc. Natl Acad. Sci. USA 114, E7776–E7785 (2017).
Wang, Y. W., Reder, N. P., Kang, S., Glaser, A. K. & Liu, J. T. C. Multiplexed optical imaging of tumor-directed nanoparticles: a review of imaging systems and approaches. Nanotheranostics 1, 369–388 (2017).
Ntziachristos, V. & Razansky, D. Molecular imaging by means of multispectral optoacoustic tomography (MSOT). Chem. Rev. 110, 2783–2794 (2010).
Ntziachristos, V. Going deeper than microscopy: the optical imaging frontier in biology. Nat. Methods 7, 603–614 (2010).
Stoffels, I. et al. Metastatic status of sentinel lymph nodes in melanoma determined noninvasively with multispectral optoacoustic imaging. Sci. Transl. Med. 7, 317ra199 (2015).
Neuschmelting, V., Lockau, H., Ntziachristos, V., Grimm, J. & Kircher, M. F. Lymph node micrometastases and in-transit metastases from melanoma: in vivo detection with multispectral optoacoustic imaging in a mouse model. Radiology 280, 137–150 (2016).
Schwarz, M., Buehler, A., Aguirre, J. & Ntziachristos, V. Three-dimensional multispectral optoacoustic mesoscopy reveals melanin and blood oxygenation in human skin in vivo. J. Biophoton. 9, 55–60 (2016).
Neuschmelting, V. et al. WST11 vascular targeted photodynamic therapy effect monitoring by multispectral optoacoustic tomography (MSOT) in mice. Theranostics 8, 723–734 (2018).
Johnson, S. P., Ogunlade, O., Lythgoe, M. F., Beard, P. & Pedley, R. B. Longitudinal photoacoustic imaging of the pharmacodynamic effect of vascular targeted therapy on tumors. Clin. Cancer Res. 25, 7436–7447 (2019).
Reshetnyak, Y. K. Imaging tumor acidity: pH-low insertion peptide probe for optoacoustic tomography. Clin. Cancer Res. 21, 4502–4504 (2015).
Xie, B. et al. Optoacoustic detection of early therapy-induced tumor cell death using a targeted imaging agent. Clin. Cancer Res. 23, 6893–6903 (2017).
Yin, W. et al. Tumor specific liposomes improve detection of pancreatic adenocarcinoma in vivo using optoacoustic tomography. J. Nanobiotechnol. 13, 90 (2015).
Banala, S. et al. Quinone-fused porphyrins as contrast agents for photoacoustic imaging. Chem. Sci. 8, 6176–6181 (2017).
Roberts, S. A. et al. Sonophore-enhanced nanoemulsions for optoacoustic imaging of cancer. Chem. Sci. https://doi.org/10.1039/C8SC01706A (2018).
Aguirre, J. et al. Precision assessment of label-free psoriasis biomarkers with ultra-broadband optoacoustic mesoscopy. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-017-0068 (2017).
Cheng, J. X. & Xie, X. S. Vibrational spectroscopic imaging of living systems: an emerging platform for biology and medicine. Science 350, aaa8870 (2015).
Fu, D., Yang, W. & Xie, X. S. Label-free imaging of neurotransmitter acetylcholine at neuromuscular junctions with stimulated raman scattering. J. Am. Chem. Soc. 139, 583–586 (2017).
Lu, F. K. et al. Label-free DNA imaging in vivo with stimulated Raman scattering microscopy. Proc. Natl Acad. Sci. USA 112, 11624–11629 (2015).
Zhang, R. R. & Kuo, J. S. Detection of human brain tumor infiltration with quantitative stimulated Raman scattering microscopy. Neurosurgery 78, N9–N11 (2016).
Freudiger, C. W. et al. Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science 322, 1857–1861 (2008).
Evans, C. L. et al. Chemically-selective imaging of brain structures with CARS microscopy. Opt. Express 15, 12076–12087 (2007).
Andreou, C., Kishore, S. A. & Kircher, M. F. Surface-enhanced Raman spectroscopy: a new modality for cancer imaging. J. Nucl. Med. 56, 1295–1299 (2015).
Xia, Q., Chen, Z., Zhou, Y. & Liu, R. Near-infrared organic fluorescent nanoparticles for long-term monitoring and photodynamic therapy of cancer. Nanotheranostics 3, 156–165 (2019).
Reichel, D., Tripathi, M., Butte, P., Saouaf, R. & Perez, J. M. Tumor-activatable clinical nanoprobe for cancer imaging. Nanotheranostics 3, 196–211 (2019).
Wei, L. et al. Fabrication of positively charged fluorescent polymer nanoparticles for cell imaging and gene delivery. Nanotheranostics 2, 157–167 (2018).
Li, J. et al. Two-color-based nanoflares for multiplexed micrornas imaging in live cells. Nanotheranostics 2, 96–105 (2018).
Choi, D. et al. Iodinated echogenic glycol chitosan nanoparticles for X-ray CT/US dual imaging of tumor. Nanotheranostics 2, 117–127 (2018).
Pallaoro, A., Braun, G. B. & Moskovits, M. Biotags based on surface-enhanced Raman can be as bright as fluorescence tags. Nano Lett. 15, 6745–6750 (2015).
Andreou, C. et al. Imaging of liver tumors using surface-enhanced raman scattering nanoparticles. ACS Nano 10, 5015–5026 (2016).
Harmsen, S. et al. Rational design of a chalcogenopyrylium-based surface-enhanced resonance Raman scattering nanoprobe with attomolar sensitivity. Nat. Commun. 6, 6570 (2015).
Harmsen, S. et al. Surface-enhanced resonance Raman scattering nanostars for high-precision cancer imaging. Sci. Transl. Med. 7, 271ra277 (2015).
Nayak, T. R. et al. Tissue factor-specific ultra-bright SERRS nanostars for Raman detection of pulmonary micrometastases. Nanoscale 9, 1110–1119 (2017).
Ye, L. et al. Comparing semiconductor nanocrystal toxicity in pregnant mice and non-human primates. Nanotheranostics 3, 54–65 (2019).
Karabeber, H. et al. Guiding brain tumor resection using surface-enhanced Raman scattering nanoparticles and a hand-held Raman scanner. ACS Nano 8, 9755–9766 (2014).
Kircher, M. F. et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat. Med. 18, 829–834 (2012).
Zavaleta, C. L. et al. Multiplexed imaging of surface enhanced Raman scattering nanotags in living mice using noninvasive Raman spectroscopy. Proc. Natl Acad. Sci. USA 106, 13511–13516 (2009).
Oseledchyk, A., Andreou, C., Wall, M. A. & Kircher, M. F. Folate-targeted surface-enhanced resonance raman scattering nanoprobe ratiometry for detection of microscopic ovarian cancer. ACS Nano 11, 1488–1497 (2017).
Wang, Y. W. et al. Raman-encoded molecular imaging with topically applied SERS nanoparticles for intraoperative guidance of lumpectomy. Cancer Res. 77, 4506–4516 (2017).
Wang, Y. W. et al. Multiplexed molecular imaging of fresh tissue surfaces enabled by convection-enhanced topical staining with SERS-coded nanoparticles. Small 12, 5612–5621 (2016).
Nicolson, F. et al. Non-invasive in vivo imaging of cancer using Surface-Enhanced Spatially Offset Raman Spectroscopy (SESORS). Theranostics 9, 5899–5913 (2019).
Bohndiek, S. E. et al. A small animal Raman instrument for rapid, wide-area, spectroscopic imaging. Proc. Natl Acad. Sci. USA 110, 12408–12413 (2013).
Thomas, G. et al. Evaluating feasibility of an automated 3-dimensional scanner using Raman spectroscopy for intraoperative breast margin assessment. Sci. Rep. 7, 13548 (2017).
Garai, E. et al. A real-time clinical endoscopic system for intraluminal, multiplexed imaging of surface-enhanced Raman scattering nanoparticles. PLoS ONE 10, e0123185 (2015).
Thakor, A. S. et al. The fate and toxicity of Raman-active silica-gold nanoparticles in mice. Sci. Transl. Med. 3, 79ra33 (2011).
Dubey, R. D. et al. Novel hyaluronic acid conjugates for dual nuclear imaging and therapy in CD44-expressing tumors in mice in vivo. Nanotheranostics 1, 59–79 (2017).
Zhang, S., Gupta, S., Fitzgerald, T. J. & Bogdanov, A. A.Jr. Dual radiosensitization and anti-STAT3 anti-proliferative strategy based on delivery of gold nanoparticle—oligonucleotide nanoconstructs to head and neck cancer cells. Nanotheranostics 2, 1–11 (2018).
Zhang, Q. et al. Construction of multifunctional Fe3O4-MTX@HBc nanoparticles for MR imaging and photothermal therapy/chemotherapy. Nanotheranostics 2, 87–95 (2018).
Liu, R., Tang, J., Xu, Y., Zhou, Y. & Dai, Z. Nano-sized indocyanine green J-aggregate as a one-component theranostic agent. Nanotheranostics 1, 430–439 (2017).
Liu, L., Ruan, Z., Yuan, P., Li, T. & Yan, L. Oxygen self-sufficient amphiphilic polypeptide nanoparticles encapsulating BODIPY for potential near infrared imaging-guided photodynamic therapy at low energy. Nanotheranostics 2, 59–69 (2018).
Lin, S. Y., Huang, R. Y., Liao, W. C., Chuang, C. C. & Chang, C. W. Multifunctional PEGylated albumin/IR780/iron oxide nanocomplexes for cancer photothermal therapy and MR imaging. Nanotheranostics 2, 106–116 (2018).
Gupta, M. K. et al. Recent strategies to design vascular theranostic nanoparticles. Nanotheranostics 1, 166–177 (2017).
Thurber, G. M., Figueiredo, J. L. & Weissleder, R. Multicolor fluorescent intravital live microscopy (FILM) for surgical tumor resection in a mouse xenograft model. PLoS ONE 4, e8053 (2009).
Herzog, E. et al. Optical imaging of cancer heterogeneity with multispectral optoacoustic tomography. Radiology 263, 461–468 (2012).
Acknowledgements
The work of R.W. was supported by the National Institute of Health grants R33CA202064, UH2CA202637, RO1CA204019, RO1CA206890 and UO1CA206997. The work of M.F.K. was supported by the National Institute of Health grants R01EB017748 and R01CA222836, a Pershing Square Sohn Prize, and the Parker Institute for Cancer Immunotherapy. This work is dedicated to the memory of Moritz F. Kircher, our colleague, student, mentor and friend.
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R.W. has received consultancy payments from ModeRNA, Tarveda Pharmaceuticals, Alivio Therapeutics and Accure Health, and is a shareholder of T2Biosystems, Lumicell and Accure Health. All patents associated with R.W. have been assigned to and are handled by the Massachusetts General Hospital. M.F.K is a co-founder of RIO Imaging, which did not contribute to this manuscript. All patents associated with M.F.K. have been assigned to and are handled by Stanford University or Memorial Sloan Kettering Cancer Center, respectively. C.A. declares no competing interests.
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Andreou, C., Weissleder, R. & Kircher, M.F. Multiplexed imaging in oncology. Nat. Biomed. Eng 6, 527–540 (2022). https://doi.org/10.1038/s41551-022-00891-5
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DOI: https://doi.org/10.1038/s41551-022-00891-5
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Nature Biomedical Engineering (2023)