| Summary: | Oxygen-enhanced cancer therapy is a promising emergent strategy for treating aggressive malignancies such as pancreatic ductal adenocarcinoma. Reversal of the hypoxic tumour microenvironment (TME) through the application of biocompatible oxygen carriers may improve treatment outcomes using conventional therapies and/or enhance the efficacy of immunotherapies. There is currently limited understanding of the mechanisms by which these carriers, particularly oxygen micro and nanobubbles, deliver oxygen to hypoxic tumours. One hypothesis is that the oxygen carriers are reoxygenated on each pass of the circulation, when traversing the highly oxygenated alveolar capillaries, enabling ongoing deposition of oxygen. Another is that carriers enhance the rate of oxygen diffusion from red blood cells. Two computational models were developed to test these hypotheses in silico. The first model was used to simulate the molar oxygen flux from a monodisperse nanobubble population traversing the circulation. Reoxygenation of the injected nanobubbles was found to be a significant (> 90%) contributor to total oxygen deposition in the TME. Quantitatively, the predicted oxygen deposition was within the range of in vivo experimental data reported in Owen et al. (2016). To investigate the spatial and temporal variation in oxygen deposition within tumour tissue, a second model was developed which simulated the irregular tumour microvasculature in greater detail. Within this perfused TME model, varying oxygen diffusivity was observed to have minimal effect on the level of oxygen deposition, suggesting that reoxygenation of the nanobubbles is a more important mechanism for oxygen delivery.
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