Abstract
Objectives
Intravital imaging within heterogenic solid tumours is important for understanding blood perfusion profiles responsible for establishment of multiple parameters within the tumour mass, such as hypoxic and nutrition gradients, cell viability, proliferation and drug response potentials.
Methods
Herein, we developed a method based on a volumetric multispectral optoacoustic tomography (vMSOT) for cancer imaging in preclinical models and explored its capacity for three-dimensional imaging of anatomic, vascular and functional tumour profiles in real time.
Results
In contrast to methods based on cross-sectional (2D) image acquisition as a basis for 3D rendering, vMSOT has attained concurrent observations from the entire tumour volume at 10 volumetric frames per second. This truly four dimensional imaging performance has enabled here the simultaneous assessment of blood oxygenation gradients and vascularization in solid breast tumours and revealed different types of blood perfusion profiles in-vivo.
Conclusion
The newly introduced capacity for high-resolution three-dimensional tracking of fast tumour perfusion suggests vMSOT as a powerful method in preclinical cancer research and theranostics. As the imaging setup can be equally operated in both stationary and handheld mode, the solution is readily translatable for perfusion monitoring in a clinical setting.
Key Points
• vMSOT visualizes 3D anatomic, vascular and functional tumour profiles in real time.
• Three types of blood perfusion profiles are revealed in breast tumour model.
• The method is readily adaptable to operate in a handheld clinical mode.






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References
Dawson SJ, Rueda OM, Aparicio S, Caldas C (2013) A new genome-driven integrated classification of breast cancer and its implications. EMBO J 32:617–628
Bosetti C, Bertuccio P, Malvezzi M et al (2013) Cancer mortality in Europe, 2005-2009, and an overview of trends since 1980. Ann Oncol 24:2657–2671
Wojnar A, Bartosz Pula B, Podhorska-Okolow M, Dziegiel P (2013) Discrepancies between HER2 assessment from core needle biopsies and surgical specimens of invasive ductal breast carcinoma. Adv Clin Exp Med 22:27–31
Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454
Galmarini FC, Galmarini CM, Sarchi MI, Abulafia J, Galmarini D (2000) Heterogeneous distribution of tumor blood supply affects the response to chemotherapy in patients with head and neck cancer. Microcirculation 7:405–410
Alberti C (2012) From molecular imaging in preclinical/clinical oncology to theranostic applications in targeted tumor therapy. Eur Rev Med Pharmacol Sci 16:1925–1933
Ale A, Ermolayev V, Herzog E, Cohrs C, de Angelis MH, Ntziachristos V (2012) FMT-XCT: in vivo animal studies with hybrid fluorescence molecular tomography-X-ray computed tomography. Nat Methods 9:615–620
Alshetaiwi HS, Balivada S, Shrestha TB et al (2013) Luminol-based bioluminescence imaging of mouse mammary tumors. J Photochem Photobiol B 127:223–228
Han XJ, Sun LF, Nishiyama Y et al (2013) Theranostic protein targeting ErbB2 for bioluminescence imaging and therapy for cancer. PLoS One 8:e75288
Wang LV, Hu S (2012) Photoacoustic tomography: in vivo imaging from organelles to organs. Science 335:1458–1462
Condeelis J, Segall JE (2003) Intravital imaging of cell movement in tumours. Nat Rev Cancer 3:921–930
Ntziachristos V, Razansky D (2010) Molecular imaging by means of multispectral optoacoustic tomography (MSOT). Chem Rev 110:2783–2794
Buehler A, Herzog E, Razansky D, Ntziachristos V (2010) Video rate optoacoustic tomography of mouse kidney perfusion. Opt Lett 35:2475–2477
Herzog E, Taruttis A, Beziere N, Lutich AA, Razansky D, Ntziachristos V (2012) Optical imaging of cancer heterogeneity with multispectral optoacoustic tomography. Radiology 263:461–468
Kirscher L, Deán-Ben XL, Scadeng M, Zaremba A, Zhang Q, Kober C et al (2015) Doxycycline inducible melanogenic vaccinia virus as theranostic anti-cancer agent. Theranostics 5:1045–1057
Taruttis A, Wildgruber M, Kosanke K, Beziere N, Licha K, Haag R et al (2012) Multispectral optoacoustic tomography of myocardial infarction. Photoacoustics 1:3–8
Laufer J, Johnson P, Zhang E et al (2012) In vivo preclinical photoacoustic imaging of tumor vasculature development and therapy. J Biomed Opt 17:056016
Nasiriavanaki M, Xia J, Wan H, Bauer AQ, Culver JP, Wang LV (2014) High-resolution photoacoustic tomography of resting-state functional connectivity in the mouse brain. Proc Natl Acad Sci U S A 111:21–26
Razansky D, Harlaar NJ, Hillebrands JL et al (2012) Multispectral optoacoustic tomography of matrix metalloproteinase activity in vulnerable human carotid plaques. Mol Imaging Biol 14:277–285
Mallidi S, Kim S, Karpiouk A, Joshi PP, Sokolov K, Emelianov S (2015) Visualization of molecular composition and functionality of cancer cells using nanoparticle-augmented ultrasound-guided photoacoustics. Photoacoustics 3:26–34
Razansky D, Buehler A, Ntziachristos V (2011) Volumetric real-time multispectral optoacoustic tomography of biomarkers. Nat Protoc 6:1121–1129
Xia J, Chatni MR, Maslov K et al (2012) Whole-body ring-shaped confocal photoacoustic computed tomography of small animals in vivo. J Biomed Opt 17:050506
Buehler A, Deán-Ben XL, Razansky D, Ntziachristos V (2013) Volumetric optoacoustic imaging with multi-bandwidth deconvolution. IEEE Trans Med Imaging 33:814–821
Queiros D, Deán-Ben XL, Buehler A, Razansky D, Rosenthal A, Ntziachristos V (2013) Modeling the shape of cylindrically focused transducers in three-dimensional optoacoustic tomography. J Biomed Opt 18:76014
Brecht HP, Su R, Fronheiser M, Ermilov SA, Conjusteau A, Oraevsky AA (2009) Whole-body three-dimensional optoacoustic tomography system for small animals. J Biomed Opt 14:064007
Van de Sompel D, Sasportas LS, Dragulescu-Andrasi A, Bohndiek S, Gambhir SS (2012) Improving image quality by accounting for changes in water temperature during a photoacoustic tomography scan. PLoS One 7:e45337
Deán-Ben XL, Razansky D (2013) Portable spherical array probe for volumetric real-time optoacoustic imaging at centimeter scale depths. Opt Express 21:28062–28071
Deán Ben XL, Oezbek A, Razansky D (2013) Volumetric real-time tracking of peripheral human vasculature with GPU-accelerated three-dimensional optoacoustic tomography. IEEE Trans Med Imaging 32:2050–2055
Deán-Ben XL, Ntziachristos V, Razansky D (2012) Acceleration of optoacoustic model-based reconstruction using angular image discretization. IEEE Trans Med Imaging 31:1154–1162
Razansky D, Distel M, Vinegoni C et al (2009) Multispectral opto-acoustic tomography of deep-seated fluorescent proteins in vivo. Nat Photonics 3:412–417
Beziere N, Lozano N, Nunes A, Salichs J, Queiros D, Kostarelos K et al (2015) Dynamic imaging of PEGylated indocyanine green (ICG) liposomes within the tumor microenvironment using multi-spectral optoacoustic tomography (MSOT). Biomaterials 37:415–424
Sarantopoulos A, Themelis G, Ntziachristos V (2011) Imaging the bio-distribution of fluorescent probes using multispectral epi-illumination cryoslicing imaging. Mol Imaging Biol 13:874–885
Lillie RD, Pizzolato P, Donaldson PT (1976) Nuclear stains with soluble metachrome metal mordant dye lakes. The effect of chemical endgroup blocking reactions and the artificial introduction of acid groups into tissues. Histochemistry 49:23–35
Jacques SL (2013) Optical properties of biological tissues: a review. Phys Med Biol 58:R37–R61
Bertout JA, Patel SA, Simon MC (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8:967–975
Yitta S, Joe BN, Wisner DJ, Price ER, Hylton NM (2013) Recognizing artifacts and optimizing breast MRI at 1.5 and 3 T. AJR Am J Roentgenol 200:W673–W682
Bauerle T, Komljenovic D, Berger MR, Semmler W (2012) Multi-modal imaging of angiogenesis in a nude rat model of breast cancer bone metastasis using magnetic resonance imaging, volumetric computed tomography and ultrasound. J Vis Exp. doi:10.3791/4178:e4178
Buehler A, Herzog E, Ale A, Smith BA, Ntziachristos V, Razansky D (2012) High resolution targeting of tumor apoptosis in living mice by means of multispectral optoacoustic tomography. Eur J Nucl Med Mol Imaging Res 2:14
Lutzweiler C, Razansky D (2013) Optoacoustic imaging and tomography: reconstruction approaches and outstanding challenges in image performance and quantification. Sensors 13:7345–7384
Deán Ben XL, Fehm TF, Gostic M, Razansky D (2015) Volumetric hand-held optoacoustic angiography as a tool for real-time screening of dense breast. J Biophotonics. doi:10.1002/jbio.201500008
Acknowledgments
The authors thank Sarah Glasl and Uwe Klemm for excellent technical assistance.
The scientific guarantor of this publication is Daniel Razansky, Helmholtz Zentrum Muenchen, email: dr@tum.de. The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. This study has received funding by European Research Council under grant agreement ERC-2010-StG-260991. VN acknowledges funding from the German Federal Ministry of Education and Science (BMBF) research grant MOBIMED (Molecular Imaging in Medicine) and sub-grant MOBITUM (Watching Tumour Biology by Molecular Imaging). No complex statistical methods were necessary for this paper. Institutional Review Board approval was obtained. Written informed consent was not required for this study because no patients were involved. Approval from the institutional animal care committee was obtained. Methodology: prospective, experimental, performed at one institution.
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Vladimir Ermolayev and Xose Luis Deán-Ben contributed equally to this work.
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Ermolayev, V., Dean-Ben, X.L., Mandal, S. et al. Simultaneous visualization of tumour oxygenation, neovascularization and contrast agent perfusion by real-time three-dimensional optoacoustic tomography. Eur Radiol 26, 1843–1851 (2016). https://doi.org/10.1007/s00330-015-3980-0
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DOI: https://doi.org/10.1007/s00330-015-3980-0