The final mesh consists of 3922 triangular elements. This is obtained based on mesh independence tests which show that the difference in predicted drug concentration between the adopted mesh and a 10-time finer mesh is less than 3%. Figure 1 Model

geometry. 2.6. Model Parameters Since the growth of tumour and normal GDC-0068 nmr tissues is ignored, all the geometric and transport parameters used in this study are assumed to be constant. These are summarized in Tables ​Tables1,1, ​,2,2, and ​and33 for parameters related to the tissue, liposome, and doxorubicin, respectively. Table 1 Parameters for tumour and normal tissues (symbols are defined near the equations in which they first appear). Table 2 Parameters Inhibitors,research,lifescience,medical for liposome (symbols are defined near the equations in which they first appear). Table 3 Parameters for doxorubicin (symbols are defined near the equations in which they first appear). 2.6.1. Vascular Permeability Vascular permeability coefficient measures the capacity of a blood vessel (often capillary Inhibitors,research,lifescience,medical in tumour) wall to allow for the flow of substances, typically nutrients or pharmaceutical agents in and out of the vasculature. The permeability Inhibitors,research,lifescience,medical of polyethylene glycol coated liposomes of 100nm through tumour capillaries was measured at 37°C by Yuan et al. [23] and Wu et al. [24] as 2.0 × 10−10 and 3.42 ± 0.78 × 10−9m/s, respectively. In normal granulation

tissues permeability of the same liposomes was 0.8 − 0.9 × 10−9m/s at the same temperature. Wu et al. [26] also measured the permeability of albumin (corresponding to albumin-bound doxorubicin) in tumour and granulation Inhibitors,research,lifescience,medical tissues at 37°C and obtained the values of 7.8 ± 1.2 × 10−9m/s and 2.5 ± 0.8 × 10−9m/s, respectively. The mean values of the above measurements are adopted in this Inhibitors,research,lifescience,medical study. Gaber et al. [5] noticed a 76-fold increase in the liposome extracellular concentration on 45°C heating. The permeability to liposome at 42°C can be estimated by interpolation, which gives a 71-folder increase. Dalmark and Storm [40] measured the permeability of free doxorubicin at various temperatures, and their results showed that the permeability to doxorubicin at 42°C was 2.56-time higher at 37°C.

Hence, temperature-dependent vascular permeability for both liposome and doxorubicin is adopted to allow for enhanced permeability at hyperthermia. 2.6.2. Reflection Coefficient The reflection coefficient determines the old efficiency of the oncotic pressure gradient in driving transport across the vascular wall. It is related to the sizes of drug and pores on the vasculature wall [41]. For the same drug, this parameter may vary in different types of tissues [42, 43]. Wolf et al. [32] measured the reflection coefficient for albumin and found this to be 0.82 ± 0.08. The sizes of albumin and liposome are 3.5nm and 100nm, respectively. The reflection coefficient for liposome is estimated to be greater than 0.90; hence it is assumed to be 0.95 in this study.