A multi-physics model for thermosensitive liposome drug delivery to solid tumour
Creators: name: Huang, Yu
Publisher: name: Imperial College London
Year: 2019

description: Thermosensitive liposome (TSL)-mediated drug delivery in combination with focused ultrasound (FUS) induced hyperthermia has been considered as a promising alternative to conventional chemotherapy. Tumour cells residing in tumour interstitial space can only be killed when they are exposed to therapeutic levels of drug concentration. Interstitial transport, as an essential step to carry drug molecules to tumour cells, must be examined in detail to gain mechanistic understandings of TSL delivery in combination with hyperthermia exposure. The process starting from the infusion of drug-loaded TSL to the uptake of chemotherapy drug by tumour cells involves multiple physical and biochemical steps; these include acoustic wave propagation in tissue upon the application of FUS, heat transfer in response to FUS heating, diffusive and convective transport of TSL and released drug from the blood stream and across the vessel wall into the interstitial space, as well as the transfer of bioavailable drug across the cell membrane and its eventual uptake by tumour cells. To understand the transport mechanism and the interactions among the different steps, mathematical models have been developed to simulate the TSL drug delivery system. First, a multi-compartmental model is developed and applied to idealised tumour cord geometry with an aim to identify the key transport parameters that affect the predicted therapeutic outcome. Results suggest that hyperthermia duration and drug release rates are the most influential parameters. Based on this finding, multivariable optimisation is carried out in searching for the optimal conditions that would maximise tumour cell killing while minimising the risk of side effect. This is followed by the development of a multiphysics continuum-based model for detailed examination of spatial and temporal distributions of key variables (e.g. temperature and drug concentration) in realistic tumour geometry reconstructed from magnetic resonance images. The results provide more insights into the spatial profiles of temperature upon the application of FUS and hyperthermia-induced drug release. Comparisons are made between two TSL delivery systems, a conventional TSL loaded with doxorubicin (DOX) and a novel imageable TSL (iTSL) loaded with topotecan (TOP). Results show that the iTSL-TOP system achieves much higher cancer cell killing fraction than the conventional TSL-DOX system. Since non-uniform temperature profile and heterogeneous drug distribution at the tumour site are identified as limiting factors, initial attempts are made to determine the influences of the number and location of ultrasound focal points on temperature distribution. Although the computational models employed in the present study have a number of limitations, they are capable of providing detailed spatiotemporal information that cannot be obtained in vivo. The modelling framework can serve as a useful tool for evaluation and optimisation of therapeutic efficacy of FUS-TSL drug delivery systems.