Effective delivery of therapeutic agents to tumour cells is essential to the success of most cancer treatment therapies except for surgery. The transport of drug in solid tumour involves multiple biophysical and biochemical processes which are strongly dependent on the physicochemical properties of the drug and biological properties of the tumour. Owing to the complexities involved, mathematical models are playing an increasingly important role in identifying the factors leading to inadequate drug delivery to tumours. In this study, a computational model is developed which incorporates real tumour geometry reconstructed from magnetic resonance images, drug transport through the tumour vasculature and interstitial space, as well as drug uptake by tumour cells. The effectiveness of anticancer therapy is evaluated based on the percentage of survival tumour cells by directly solving the corresponding pharmacodynamics equation using predicted intracellular drug concentration. Computational simulations have been performed for the delivery of doxorubicin through various delivery modes, including bolus injection and continuous infusion of doxorubicin in free form, and thermo-sensitive liposome mediated doxorubicin delivery activated by high intensity focused ultrasound. Predicted results show that continuous infusion is far more effective than bolus injection in maintaining high levels of intracellular drug concentration, thereby increasing drug uptake by tumour cells. Moreover, multiple-administration is found to be more effective in improving the cytotoxic effect of drug compared to a single administration. The effect of heterogeneous distribution of microvasculature on drug transport in a realistic model of liver tumour is investigated, and the results indicate that although tumour interstitial fluid pressure is almost uniform, drug concentration is sensitive to the heterogeneous distribution of microvasculature within a tumour. Results from three prostate tumours of different sizes suggest a nonlinear relationship between transvascular transport of anticancer drugs and tumour size. Numerical simulations of thermo-sensitive liposome-mediated drug delivery coupled with high intensity focused ultrasound heating demonstrate the potential advantage of this novel drug delivery system for localised treatment while minimising drug concentration in normal tissue.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:679660 |
| Date | January 2014 |
| Creators | Zhan, Wenbo |
| Contributors | Xu, Xiao Yun |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/29111 |
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