C.H. Wang and J. Li, “Three Dimensional Simulation of IgG Delivery to Tumors”, Chem. Eng. Sci., 53(20), 3579-3600 (1998).
A simulation method is developed to study the extravascular and transvascular transport of interstitial fluids and MAbs in PNET (Primitive Neuroectodermal Tumors). Two cases of drug delivery are investigated: systemic administration & polymer based controlled release. The effects of necrotic core, lymphatic vessels and binding kinetics on the drug distribution are examined. A few indices (mean concentration, ISN and SR) are used to characterize the distribution of MAbs. It is found that the controlled drug release from polymer is basically a localized release in which drug concentration in the vicinity of polymer is high. Compared with systemic administration, polymeric controlled release gives higher drug concentration with reduced systemic toxicity. Penetration depth of the drug is more dependent on the transvascular permeability than the diffusivity. In searching for the optimal location of the polymer, the implantation in the viable zone of tumor seems to be a better choice since it can give higher drug concentrations in both the viable zone and the necrotic core. Functional lymphatic vessels drastically reduce the interstitial pressure and the MAb concentration. The binding of drug with tissues reduces the free drug concentrations in the viable zone and normal tissues.
MRI pictures of a PNET and the reconstructed finite-element mesh plot of the calculated geometry, (a) two MRI pictures. The white dotted curve encircles the tumor. (b) mesh plot of the calculated geometry for the polymer in the core case. (A) necrotic core, (B) viable zone, (C) surrounding normal tissues and (D) polymer cylinder. (c) mesh plot for the surgical model, while (a*), (b*), (c*) and (d*) represent different cut sections. The locations are selected roughly at the top, 30%, 70%, and the bottom of the tumor, respectively.
Temporal evolution of drug concentration (a*) t=1 hour. (b*) t=60 hours. (c*) t=100 hours. (d*) t=200 hours. (e*) t=300 hours. (f*) t=400 hours.
K.H. Tan, F.J. Wang, T. Lee and C.H. Wang, “Delivery of Etanidazole to Brain Tumor from PLGA Wafers: A Double Burst Release System”, Biotechnology and Bioengineering 82(3), 278-288 (2003).
This work examines the computer simulation results on the delivery of Etanidazole (radiosensitiser) to the brain tumor and examines several factors affecting the delivery. The simulation consists of a cut section of tumor with poly (lactide-co -glycolide) (PLGA) wafers of 1% Etanidzole loading implanted in the resected cavi ty. The coupled mass and momentum equations are solved to obtain the transient so lution of the drug distribution in the tumor. The polymeric delivery shows high therapeutic index, indicating the wafers’ success in delivering more drugs to the tumor rather than to the tissue. The penetration distance of Etanidazole was fou nd to decrease from about 14 mm (at 5th/40th day after implantation) to about 6.5 mm (at 30th/75th day), suggesting an initial high burst of drug release which ca use nearby tissue toxicity and a low effective drug delivery towards the later st ages. The short penetration depth is due to Etanidazole having low transvascular Peclet number and high elimination/diffusion modulus. Vasogenic edema modeling is included and the simulation shows that it reduces the therapeutic index by 20% i n the initial 6-12 hours. Simulations on the open tumor geometry show significant ly lower efficacy of the drug delivery due to the uneven distribution of drug in the tumor zone. A simulation on a zero-order release from wafers suggested that i t does not guaranteed best release as there is increasing toxicity complications with increasing release span.
Contour plot of Etanidazole distribution in a planar cut section parallel to the z axis and perpendicular to the x and y axis. The concentration scale has units of kg/m3. The contour plot shows that Etanidazole has limited penetration depth into the nearby tissue spaces. The tissue zone and wafer zones are depicted by red and blue meshes respectively. Some of the wafers are partially/totally hidden from view by the contour plot. (Time = 20th hour)
Contour plot of Etanidazole distribution in the eight wafers. This is of the same view as the previous figure but showing the exact locations of the wafers. The red and green meshes depict tissue and wafer zones respectively. (Time = 20th hour)
3D Patient-specific Chemotherapeutic Drug Delivery to Brain Tumors
Davis Yohanes Arifin, Chi-Hwa Wang, and Kenneth A. Smith
This study aims to develop a computer-assisted model of a commercial drug delivery implant system, i.e. Gliadel® wafers, in patient-specific brain tumors with the exact geometry from magnetic resonance imaging (MRI) reconstructed by Mimics. When appropriate boundary conditions are applied to the reconstructed geometry, a baseline case of human brain simulation is developed. The baseline case predicts the interstitial fluid flows in normal and tumor-bearing brain. In the latter case, elevated interstitial fluid pressure is observed. The therapeutic efficacy of the current dosage form of “Gliadel” wafers has been investigated in a post-surgery patient-specific model. The subsequent simulation cases show the influence of different dosage forms and drug delivery strategy on the drug distribution in the brain tumor.
Fig. 1. The 3D reconstruction flow chart MR images 3D volume grid for computational fluid dynamics (CFD) analysis. The reconstruction involves the generation of three surfaces of interest by FEA module of Mimics, which are parenchyma (in gray), ventricle (in blue), and tumor (in red). It allows the original positions of each surface so that the accuracy of model is highly preserved.
Fig. 2. The 3D pressure contours of (a) normal and (b) tumor brain. The result of tumor predicts well with literature that pressure can be as high as 1,300 Pa at the tumor site.