Interstitial Fluid Flow and Drug Delivery in Vascularized Tumors: A Computational Model

Abstract

Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider–with the help of a theoretical model–the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various strategies to increase drug exposure time of tumor cells.

The intra-tumoral relationship between microcirculation, interstitial fluid pressure and liposome accumulation

“…These results suggest that a complex interplay between TBF and IFP drives the heterogeneous intratumoral distribution of liposomes [25][26][27].…”

Osmotic stress affects functional properties of human melanoma cell lines

“…The role of IFP for drug delivery was also analyzed computationally in Ref. [11]. In general, understanding the influence of mechanical stress on cancer growth could shed new light on tumour development and progression.…”

<b>Characteristics of interstitial fluid flow along with blood flow inside a cylindrical tumor: a numerical simulation

“…Most of the cancers are made of solid tumors. Cancerous cells of solid tumors have under gone mutations all of which combined lead to cancer (Welter & Rieger, 2013). Chemo (drug/chemical) therapy, radiation, surgical ablation and hyperthermia methods are options generally available in cancer treatment (Attaluri, Ma, Qiu, Li, & Zhu, 2011).…”