Biology subjects

Pedley, R. B.

Publications and source records attributed to Pedley, R. B..

3 recordsLinked to original sources

bioRxiv2017

Combining optical imaging of cleared tissue with mathematical modelling to predict drug delivery and therapeutic response

Understanding how drugs are delivered to diseased tissue, and their subsequent spatial and temporal distribution, is a key factor 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 significantly between individuals. In cancer, suboptimal dosing resulting from poor delivery can cause reduced treatment efficacy, upregulation of resistance mechanisms and can even stimulate growth. Preclinical tools to better understand drug delivery are therefore urgently required, which incorporate the inherent variability and heterogeneity of human disease. To meet this need, we have combined multiscale mathematical modelling, high-resolution optical imaging of intact, optically-cleared tumour tissue from animal models, and in vivo magnetic resonance imaging (MRI). Our framework, named REANIMATE (REAlistic Numerical Image-based Modelling of biologicAl Tissue substratEs) allows large tissue samples to be investigated as if it were a living sample, in detailed, highly controlled, computational experiments. Specifically, we show that REANIMATE can be used to predict the heterogeneous delivery of specific therapeutic agents, in disparate two murine xenograft models of human colorectal carcinoma. Given the wide adoption of optical clearing equipment in biomedical research laboratories, REANIMATE enables a new paradigm in cancer drug development, which could also be applied to other disease areas.

biophysics↗

bioRxiv2017

Investigating low-velocity fluid flow in tumours using convection-MRI

Several distinct fluid flow phenemena occur in solid tumours, including intravascular blood flow and interstitial convection. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we have developed a novel magnetic resonance imaging (MRI) technique named convection-MRI. It uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extra-vascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations and tumor xenograft models to investigate the technical feasibility of convection-MRI. We report a good correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma and show that convection-MRI can provide insights into the growth and response to vascular-targeting therapy in colorectal cancers.

biophysics↗

bioRxiv2017

Development of noninvasive biomarkers of response to proteasome inhibitor therapy (ixazomib) by imaging disrupted protein homeostasis in mouse models of solid tumors

With clinically-approved proteasome inhibitors now a standard of care for multiple myeloma, and increasing interest in their use in solid tumors, methods for monitoring therapeutic response in vivo are critically required. Here, we show that tumor protein homeostasis can be noninvasively monitored, using chemical exchange (CEST) magnetic resonance imaging (MRI) as a surrogate marker for proteasome inhibition, alongside diffusion MRI and relaxometry. We show that the in vivo CEST signal associated with amides and amines increases in proportion to proteasome inhibitor dose (ixazomib) and the magnitude of therapeutic effect in colorectal cancer xenografts. Moreover, we show that SW1222 and LS174T human colorectal cancer cell lines demonstrate differing sensitivities to ixazomib, which was reflected in our MRI measurements. We also found evidence of a mild stimulation in tumor growth at low ixazomib doses. Our results therefore identify CEST MRI as a promising method for safely and noninvasively monitoring changes in tumor protein homeostasis.

biophysics↗