(312d) Computational Study of Drug Transport in Realistic Models of Solid Tumour

Background:
The efficacy of anticancer therapy is often offset by serious side effects.
This is largely due to toxicity of the chemotherapy drug and its undesirable
uptake in vivo. Various attempts have been made to retain the anticancer
effect while reducing toxicities, including continuous infusion and liposomal
delivery of chemotherapy drugs. Since the outcome of an anticancer therapy depends
strongly on the pharmacokinetics of the drug as well as the properties of
tumour and its surrounding tissue, rational criteria for
choosing an optimal delivery mode and dose for different types of tumours are
not yet available.

Methods: In this study, a computational model is developed which
incorporates real tumour geometry reconstructed from magnetic resonance (MR)
images, and the key physical and biochemical processes involved. These include
time-dependent plasma clearance, drug transport through the blood and lymphatic
vessels, extracellular drug transport (convection and diffusion), binding with
proteins, lymphatic drainage, interactions with the surrounding normal tissue
and drug uptake by tumour cells. Anticancer efficacy is evaluated based on the faction
of survival tumour cells by directly solving the pharmacodynamics equation
using the predicted intracellular doxorubicin concentration. Comparisons are
made of the predicted efficacies of different modes of drug administration and
doses in a clinical relevant range. As a typical anti-tumour drug, doxorubicin
is employed in the computational model.

Results and Conclusion: Our results show that liposome-mediated drug
delivery performs best in reducing drug concentration in normal tissues, which
will help lower the risks of associated side effects. Bolus injection leads to
the highest extracellular concentration in both tumour and normal tissues, giving
the worst efficacy. Continuous infusion can effectively reduce the
extracellular concentration while increasing the intracellular concentration
(shown in Fig. 1), which mau help reduce the side effects caused by high
concentration in normal tissues. As shown in Fig. 2, rapid continuous infusions
lead to quick cell killing in the early phase of drug administration, but slow
infusion can kill more tumour cells over a longer time period. Moreover, continuous
infusion over 2-hour duration seems to offer the highest intracellular
concentration. In addition, the effects of tumour size and shape have been
investigated based on patient-specific MR images.

Fig.
1 Comparison of intracellular concentration among different modes of drug
administration (bolus injection, continuous infusion over durations of 3
minutes, 30 minutes, 1 hour, 2 hours, and 3 hours, respectively, and liposomal
release over 24 hours)

Fig.
2 Predicted anticancer efficacy for different modes of drug administration