Hence at a sufficiently resolution model predictions could be the heterogeneous tumor microvasculature in an attempt

By doing so, the underlying tissue hydraulic conductivity may also change and it might be important to study how this affects the drug distribution. Mathematically, this was implemented by varying the empirical parameter m in the expression for tissue hydraulic conductivity. The parameter m could be thought of as a variable to either amplify or reduce the fluid flows in the heterogeneous pathways in the whole leg determined by the 2-compartmental model. Increasing m caused more interstitial fluid to leak away from the tumor periphery and reduced the tumor IFP as shown in Figure 9. Increasing the hydraulic conductivity has been previously shown to reduce IFP and thus increase extravasation of macromolecules. The results of this sensitivity analysis indicated reduction in peak tumor IFP compared to baseline simulation, however the resulting CED tracer distribution volumes were also reduced. This was because of increase in convective velocity heterogeneity resulting from very high reduction in the tumor IFP, which directed the interstitial fluid and albumin tracer away from the tumor into adjacent normal tissue. The amplified hydraulic conductivity in the whole tissue volume opened up various low resistant fluid pathways through which the tracer got transported away from the tumor. High interstitial velocity at the anterior cut end compared to the posterior side is due to the high Ktrans described in the earlier paragraph. These results demonstrate the importance of transport heterogeneity and measuring extracellular transport, especially changes in extracellular space for a given tumor, in order to achieve improved understanding of spatial drug distribution within the tumor. In this study, an image-based tumor model was developed which incorporates realisitic tumor vascular BEZ235 leakiness with anatomical geometries, and used to predict heterogeneous/ asymmetric drug distribution following direct infusions. Although the results discussed in this study are restricted to the mouse hind limb tumor under study, it should be noted that the applicability of such a voxelized model to a wide range of tumors is possible. With further experimental validation and measure of tissue properties, this model could be potentially applied towards patient-specific treatments and to more accurately investigate effects of flow patterns on heterogeneous tumor drug delivery. The model however has some limitations at present: 1) model parameter values such as average hydraulic conductivity, diffusivity, scaling factor for the leakiness term obtained from literature varies across tumors and needs to be determined experimentally for a given tumor; 2) modeling heterogeneous tumor microvasculature based on fluid exchange between blood plasma and tissue compartments is only approximate since one assumption is that each MR voxel consists of tissue and blood vessels.

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