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High-resolution optoacoustic imaging of tissue responses to vascular-targeted therapies

Nature Biomedical Engineering volume 4, pages 286–297 (2020)Cite this article

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Abstract

The monitoring of vascular-targeted therapies using magnetic resonance imaging, computed tomography or ultrasound is limited by their insufficient spatial resolution. Here, by taking advantage of the intrinsic optical properties of haemoglobin, we show that raster-scanning optoacoustic mesoscopy (RSOM) provides high-resolution images of the tumour vasculature and of the surrounding tissue, and that the detection of a wide range of ultrasound bandwidths enables the distinction of vessels of differing size, providing detailed insights into the vascular responses to vascular-targeted therapy. Using RSOM to examine the responses to vascular-targeted photodynamic therapy in mice with subcutaneous xenografts, we observed a substantial and immediate occlusion of the tumour vessels followed by haemorrhage within the tissue and the eventual collapse of the entire vasculature. Using dual-wavelength RSOM, which distinguishes oxyhaemoglobin from deoxyhaemoglobin, we observed an increase in oxygenation of the entire tumour volume immediately after the application of the therapy, and a second wave of oxygen reperfusion approximately 24 h thereafter. We also show that RSOM enables the quantification of differences in neoangiogenesis that predict treatment efficacy.

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Fig. 1: RSOM imaging of CT26 colon carcinoma tumours and mouse brain.
Fig. 2: RSOM imaging of pharmacological vasoconstriction in CT26 tumours after injection of adrenaline or endothelin-1.
Fig. 3: RSOM imaging of padeliporfin VTP in CT26 tumours and skin vessels over time.
Fig. 4: Short- and long-term longitudinal RSOM imaging of the effects of padeliporfin VTP in CT26 tumours.
Fig. 5: Dual-wavelength RSOM imaging before and 1 h after padeliporfin VTP to visualize tumour oxygenation.
Fig. 6: Dual-wavelength RSOM imaging of tumour oxygenation and vascularization in CT26 tumours over time after padeliporfin VTP.
Fig. 7: Comparison of vascularization between bladder tumours in which VTP is differentially effective.

Data availability

The authors declare that all data from this study are available within the Article and its Supplementary Information. Raw data for the individual measurements are available on reasonable request.

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Acknowledgements

We thank N. Fan of the MSKCC Molecular Cytology Core Facility for assistance with histology; Y. Romin for support and feedback on image analysis; and D. Yarilin of the MSKCC Molecular Cytology Core Facility for immunohistochemistry. This study was funded by the Thompson Family Foundation (Wade F. B. Thompson grant to J.C., A.S. and J.G.) and the National Cancer Institute (grant no. R01 CA212379 to J.G.). The study was also supported in part by the European grant INNODERM (no. 687866) Horizon 2020. We acknowledge P. Zanzonico and V. Ann Longo of the Small Animal Imaging Core Facility of MSKCC for their support (the Core is funded by the NIH Cancer Centre Support grant no. P30 CA008748).

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Authors and Affiliations

  1. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Katja Haedicke, Magdalena Skubal & Jan Grimm

  2. Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot, Israel

    Lilach Agemy & Avigdor Scherz

  3. Chair for Biological Imaging, Technical University Munich, Munich, Germany

    Murad Omar, Andrei Berezhnoi & Vasilis Ntziachristos

  4. Institute for Biological and Medical Imaging, Helmholtz Center Munich, Neuherberg, Germany

    Murad Omar, Andrei Berezhnoi & Vasilis Ntziachristos

  5. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sheryl Roberts, Camila Longo-Machado, Hsiao-Ting Hsu, Thomas Reiner & Jan Grimm

  6. Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Karan Nagar, Kwanghee Kim & Jonathan Coleman

  7. Department of Radiology, Weill Cornell Medical College, New York, NY, USA

    Thomas Reiner & Jan Grimm

  8. Department of Urology, Weill Cornell Medical College, New York, NY, USA

    Jonathan Coleman

  9. Pharmacology Program, Weill Cornell Medical College, New York, NY, USA

    Jan Grimm

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Contributions

K.H. designed and performed all of the experiments, processed and analysed the RSOM data, evaluated histological sections and wrote the manuscript. L.A. performed the VTP experiments in CT26 tumours and provided practical input for study planning and performance. M.O. developed the RSOM system, supplied technical input and performed the dual-wavelength RSOM measurements and analysis. A.B. conducted the dual-wavelength RSOM experiments and analysis. S.R. and M.S. conducted the craniotomy and performed the imaging of the mouse brain. K.N. performed the VTP experiments in bladder tumour models and supported RSOM imaging. H.-T.H. performed the VTP experiments in bladder tumour models and supported histological analysis with C.L.-M. K.K. provided conceptual input and designed the experiments in bladder tumour models. T.R. provided input for the design of the brain experiments. J.C. provided input and designed the VTP experiments. V.N. provided technical input for RSOM imaging and supervised the dual-wavelength measurements. A.S. supervised the VTP experiments, provided conceptual input and designed the experiments. J.G. supervised the study, provided input for all of the experiments and the study concept, and edited the paper.

Corresponding author

Correspondence to Jan Grimm.

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Competing interests

V.N. is a shareholder in iThera Medical GmbH in Munich, Germany, which produces a commercial version of the monospectral RSOM (not used in this study). A.S. is an inventor of padeliporfin and has a financial interest from licensing fees.

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Supplementary information

Supplementary Information

Supplementary figures and tables, and the caption for Supplementary Video 1.

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Supplementary Video 1

Rotating 3D volume of a CT26 tumour.

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Haedicke, K., Agemy, L., Omar, M. et al. High-resolution optoacoustic imaging of tissue responses to vascular-targeted therapies. Nat Biomed Eng 4, 286–297 (2020). https://doi.org/10.1038/s41551-020-0527-8

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