Understanding the uptake of a drug by diseased tissue, and the drug’s subsequent spatiotemporal distribution, are central factors in the development of effective targeted therapies. However, the interaction between the pathophysiology of diseased tissue and individual therapeutic agents can be complex, and can vary across tissue types and across subjects. Here, we show that the combination of mathematical modelling, high-resolution optical imaging of intact and optically cleared tumour tissue from animal models, and in vivo imaging of vascular perfusion predicts the heterogeneous uptake, by large tissue samples, of specific therapeutic agents, as well as their spatiotemporal distribution. In particular, by using murine models of colorectal cancer and glioma, we report and validate predictions of steady-state blood flow and intravascular and interstitial fluid pressure in tumours, of the spatially heterogeneous uptake of chelated gadolinium by tumours, and of the effect of a vascular disrupting agent on tumour vasculature.
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The authors acknowledge support received for the Kings College London & UCL CR-UK and EPSRC Comprehensive Cancer Imaging Centre, in association with the MRC and Department of Health (England) (C1519/A10331), Wellcome Trust (WT100247MA) and Rosetrees Trust/Stoneygate Trust (M135-F1 and M601). The authors thank OXiGENE for supplying OXi4503.
The authors declare no competing interests.
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Electronic supplementary material
Supplementary Figures 1–8, Supplementary Tables 1–3, Supplementary Results, Supplementary References 1–4 and Supplementary Video Captions 1–4.
Three-dimensional rendering of REANIMATE simulation results, describing the passage of a bolus of the commonly used MRI contrast agent Gd‐DTPA through tumour vasculature.
REANIMATE simulation of the delivery of the MRI contrast agent Gd‐DTPA using the vascular network from the LS174T colorectal tumour-xenograft model.
Dual-fluorescence labelling of the vasculature in an LS174T colorectal xenograft model, following treatment with the vascular targeting agent OXi4503.
REANIMATE simulation of the delivery of the vascular targeting agent OXi4503 to an LS174T colorectal xenograft model.
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d’Esposito, A., Sweeney, P.W., Ali, M. et al. Computational fluid dynamics with imaging of cleared tissue and of in vivo perfusion predicts drug uptake and treatment responses in tumours. Nat Biomed Eng 2, 773–787 (2018). https://doi.org/10.1038/s41551-018-0306-y
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