Multiscale Tumor Spatiokinetic Model for Intraperitoneal Therapy

Abstract

Abstract. This study established a multiscale computational model for intraperitoneal (IP) chemotherapy, to depict the time-dependent and spatial-dependent drug concentrations in peritoneal tumors as functions of drug properties (size, binding, diffusivity, permeability), transport mechanisms (diffusion, convection), spatial-dependent tumor heterogeneities (vessel density, cell density, pressure gradient), and physiological properties (peritoneal pressure, peritoneal fluid volume). Equations linked drug transport and clearance on three scales (tumor, IP cavity, whole organism). Paclitaxel was the test compound. The required model parameters (tumor diffusivity, tumor hydraulic conductivity, vessel permeability and surface area, microvascular hydrostatic pressure, drug association with cells) were obtained from literature reports, calculation, and/or experimental measurements. Drug concentration-time profiles in peritoneal fluid and plasma were the boundary conditions for tumor domain and blood vessels, respectively. The finite element method was used to numerically solve the nonlinear partial differential equations for fluid and solute transport. The resulting multiscale model accounted for intratumoral spatial heterogeneity, depicted diffusive and convective drug transport in tumor interstitium and across blood vessels, and provided drug flux and concentration as a function of time and spatial position in the tumor. Comparison of model-predicted tumor spatiokinetics with experimental results (autoradiographic data of 3H-paclitaxel in IP ovarian tumors in mice, 6 h posttreatment) showed good agreement (1% deviation for area under curve and 23% deviations for individual data points, which were several-fold lower compared to the experimental intertumor variations). The computational multiscale model provides a tool to quantify the effects of drug-, tumor-, and host-dependent variables on the concentrations and residence time of IP therapeutics in tumors.

Modelling drug transport during intraperitoneal chemotherapy

“…Parameters that were assumed to be spatially varying were the volume fractions of the different components (interstitium, vasculature and cellular), the drug diffusivity, the surface to volume ratio of the vascular component, and the tissue permeability. The model was validated using the data of a mouse model with IP tumours (n = 4) and the experimental results were in good agreement with the simulated results with a 1 % deviation for the total drug AUC and 23 % deviations for individual data points [47].…”

“…The incorporation of accurate IFP profiles might offer a significant advantage over using an idealized pressure profile. Au et al [47] created three different tumour zones in their model to account for the spatial variations of certain parameters within the tumour tissue.…”

“…In 2014, a spatiokinetic model for intraperitoneal administration of paclitaxel was described by Au et al [47]. In a single spherical tumour nodule model (r = 2 mm) which consists of three separate layers, the cellular level of the tumour tissue was averaged and modelled as a homogeneous, isotropic porous medium.…”

Versatility of Particulate Carriers: Development of Pharmacodynamically Optimized Drug-Loaded Microparticles for Treatment of Peritoneal Cancer

“…The current report summarizes our findings in IP therapy; detailed information can be found in our earlier research publications and reviews (3)(4)(5)(6)(7)(8)(9).…”

“…To our knowledge, there have been no or few studies to address these critical issues. For example, there have been multiple studies, including several from our group, on the pharmacokinetics of IP therapy (e.g., 3,7,8,15,25,87). But these studies primarily deal with the time scale and not the spatial scale.…”