Modelling and Optimisation of Device-Enhanced Drug Delivery to Tumours

The fraction of administered chemotherapeutic which successfully extravasates in tumour tissue has, historically, been very small. The fraction of the dose which does not reach the tumour gives rise to severe side effects such as nausea, fatigue and hair-loss. The encapsulation of chemotherapy drugs inside thermosensitive particles (liposomes), which release their drug upon heating were first theorised in the 1970s. In the latter half of the 2010s, a clinical trial used such a thermosensitive liposomal (TSL) drug delivery system in conjunction with extracorporeal focussed ultrasound to heat tumours deep within the body. This trial proved that not only was the technology safe, but that TSL drug delivery represents a modality whereby substantially larger fractions of administered drug reach the target tissue than in conventional chemotherapy. This offers hope for more efficacious treatment with fewer side effects.

Computational modelling of TSL drug delivery systems has shown that the modulation of liposome release properties (for constant hyperthermia protocols) can significantly affect the distribution of free drug in tumour tissue, while varying hyperthermia protocols for the same TSL system also has a significant effect on drug distribution. This suggests that for a given tumour, there will be an ideal treatment protocol, both in terms of liposome design, and ultrasound-mediated hyperthermia and dosing regimens.

The aim of this PhD project is to use a combination of computational simulations combined with in vitro experiments to establish guidance which can be used to further improve the effectiveness of TSL delivery in the clinic. The in vitro work involves obtaining a mathematical model for the effect of a chemotherapeutic drug on a given cell line; establishing whether a high dose for a short time is more efficacious than a lower dose for longer. The establishment of such models on cell lines of therapeutic relevance are not commonly found in the literature, since until the recent trial, the ability to control the doses and timescales of chemotherapeutics to solid tumours were non-existent.

Once this model has been obtained, a computational model of delivery of the therapeutic will be created across a physiologically-accurate tumour microvasculature. Modelling of the tumour is important, as for a treatment for cancer to be effective, almost all cells in the tumour must receive a therapeutic dose of drug. This model will therefore allow an assessment of the treatment for all cells; both those close to and far away from blood vessels. By changing input parameters such as dosing, hyperthermia protocols and cell density, it will be possible to see whether longer infusions with long hyperthermia should have a greater effect in the clinic than high doses, quickly infused with a short heating time.

This project fits in within the EPSRC Healthcare technologies research area.