The effect of tumour size on drug transport and uptake in 3-D tumour models reconstructed from magnetic resonance images.

Wenbo Zhan,Wladyslaw Gedroyc,Xiao Yun Xu,Han-Chung Wu

doi:10.1371/journal.pone.0172276

Abstract

Drug transport and its uptake by tumour cells are strongly dependent on tumour properties, which vary in different types of solid tumours. By simulating the key physical and biochemical processes, a numerical study has been carried out to investigate the transport of anti-cancer drugs in 3-D tumour models of different sizes. The therapeutic efficacy for each tumour is evaluated by using a pharmacodynamics model based on the predicted intracellular drug concentration. Simulation results demonstrate that interstitial fluid pressure and interstitial fluid loss vary non-linearly with tumour size. Transvascular drug exchange, driven by the concentration gradient of unbound drug between blood and interstitial fluid, is more efficient in small tumours, owing to the low spatial-mean interstitial fluid pressure and dense microvasculature. However, this has a detrimental effect on therapeutic efficacy over longer periods as a result of enhanced reverse diffusion of drug to the blood circulation after the cessation of drug infusion, causing more rapid loss of drug in small tumours.

Highlights

A variety of therapeutic agents are routinely delivered by intravenous administration in clinical cancer treatments
Numerical simulations have been carried out for 2-hour continuous infusion of 50 mg/m2 [16] doxorubicin, which corresponds to a standard treatment for a patient of 70 kg body weight [10]
This is followed by comparisons of doxorubicin concentration in the five tumour models to investigate the effect of tumour size on drug delivery

Summary

Introduction

A variety of therapeutic agents are routinely delivered by intravenous administration in clinical cancer treatments. The transport of therapeutic agents is determined by physicochemical properties of the drug and biologic properties of the tumour, including molecular structure of the drug, microvasculature density of the tumour and interstitial fluid pressure [1]. The biologic properties of a solid tumour, especially the density and distribution of tumour vasculature, could vary considerably depending on the particular tumour type, size and growth stage [2, 3]. Tortuous and dilated microvessels are often found in tumours, leading to a variety of vascular network structures which may evolve as tumours grow [4, 5]. It has been reported that large tumours have fewer microvessels than in small tumours [6]. Given the multiple processes involved in drug delivery and interactions between drugs and intratumoural environment, mathematical modelling has become an important tool to PLOS ONE | DOI:10.1371/journal.pone.0172276 February 17, 2017

Methods

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Discussion

Conclusion