Mathematical Modelling of Convection Enhanced Delivery of Carmustine and Paclitaxel for Brain Tumour Therapy.

PURPOSE: Convection enhanced delivery (CED) is a promising method of anticancer treatment to bypass the blood-brain barrier. This paper is aimed to study drug transport under different CED operating conditions. METHODS: The convection enhanced delivery of chemotherapeutics to an intact and a remnant brain tumour after resection is investigated by means of mathematical modelling of the key physical and physiological processes of drug transport. Realistic models of brain tumour and its holding tissue are reconstructed from magnetic resonance images. Mathematical modelling is performed for the delivery of carmustine and paclitaxel with different infusion rates, solution concentrations and locations of infusion site. RESULTS: Modelling predications show that drug penetration can be improved by raising the infusion rate and the infusion solution concentration. The delivery of carmustine with CED is highly localised. High drug concentration only can be achieved around the infusion site. The transport of paclitaxel is more sensitive to CED-enhanced interstitial fluid as compared to carmustine, with deeper penetration into tumour interior. Infusing paclitaxel in the upstream of interstitial fluid flow leads to high spatial averaged concentration and relatively uniform distribution. CONCLUSION: Results obtained in this study can be used to guide the design and optimisation of CED treatment regimens.

Core/shell microspheres via coaxial electrohydrodynamic atomization for sequential and parallel release of drugs.

Herein, it is demonstrated that coaxial electrohydrodynamic atomization can be used for the fabrication of microspheres with distinct core/shell structure. This allows the encapsulation of two different types of drugs in different compartments in one single step. In Group A, we prepared microspheres in which the core and the shell contain hydrophobic and hydrophilic drugs, respectively. In contrast, in Group B, the opposite is prepared. While the former can be achieved by using amphiphilic polymers in aqueous environment, the latter is difficult to be prepared. The release patterns of the two groups are significantly different. The release of drugs from Group A microspheres is rather sequential, whereas group B microspheres release drugs in a parallel (co-release) manner. Nevertheless, in both groups, we found that the release of drugs can be easily tailored by altering outer/inner flow ratios. These findings present the advantages and possible application of this multi-drug release system in chemotherapy. Moreover, cell culture experiments have been performed to testify the performances of different microspheres in cytotoxicity and cellular apoptosis in vitro.

Role of convective flow in carmustine delivery to a brain tumor.

PURPOSE: This paper presents a three-dimensional patient-specific simulation of carmustine delivery to brain tumor. The simulation investigates several crucial factors, particularly the role of convective flow, affecting drug delivery efficacy. METHODS: The simulation utilizes a complete three-dimensional tissue geometry constructed from magnetic resonance images (MRI) of a brain tumor patient in whom commercially available Gliadel wafers were implanted for sustained delivery of carmustine following excision of the tumor. This method permits an estimation of the convective flow field (in the irregularly shaped anatomical region) which can be used for prediction of drug penetration into the domain of interest, i.e. remnant tumor. A finite volume method is utilized to perform all simulations. RESULTS: Drug exposure exceeds its threshold therapeutic concentration (approximately 15 microM) but for only a limited time (i.e. less than a week) and only in the immediately adjacent tissue (i.e. less than 2 mm). A quasi-steady transport process is established within 1 day following treatment, in which the drug is eliminated rapidly by transcapillary exchange, while its penetration into the tumor is mainly by diffusion. Convection appears to be crucial in influencing the drug distribution in the tumor: the remnant tumor near the ventricle is, by one to two orders of magnitude, less exposed to the drug than is the distal remnant tumor. CONCLUSIONS: Carmustine penetration from Gliadel wafers implanted in brain is limited by rapid elimination via transcapillary exchange. Therefore, it could be useful to consider other therapeutic agents such as paclitaxel. In addition, local convective flow within the cavity appears to be a crucial factor in distributing the drug so that the tumor domain near the ventricle is prone to minimal drug exposure. Thus, complete removal of the tumor from this region is of particular concern.

Chemotherapeutic drug transport to brain tumor.

Implantation of polymeric wafers to deliver a chemotherapeutic drug is the most popular strategy against a brain tumor, but the understanding on local drug transport to influence the treatment efficacy is often overlooked. In this work, we employ a computational fluid dynamics simulation to study the suitability of four chemotherapeutic agents from a transport perspective, which specifically are carmustine, paclitaxel, 5-fluorouracil (5-FU), and methotrexate (MTX). The study is based on the diffusion/reaction/convection model, in which Darcy's law is used to account the convective contribution of the interstitial fluid. A realistic three-dimensional (3D) tissue geometry is extracted from magnetic resonance images (MRI) of a brain tumor. Our analysis explains how the distribution of the drug in the brain tumor is sensitively coupled to its physico-chemical properties. For the postulated conditions, only paclitaxel exhibits minimal degradation within the cavity: its effective cavity concentration is at least two times higher than those of others. It also exhibits the best penetration of the remnant tumor, so that the tumor is exposed to higher effective concentration up to two orders of magnitude as compared to others. It is also found that tumor receives uneven distribution of drug concentration, in which, even paclitaxel fails to provide adequate penetration on that part of the cavity surface nearest to the ventricles. In addition, we consider antiangiogenic treatment, which has been postulated to be a way to avoid drug loss from the treatment region by convection. It is shown that convection is of only marginal importance and that renormalization has little effect.

Mathematical modeling and simulation of drug release from microspheres: Implications to drug delivery systems.

This article aims to provide a comprehensive review of existing mathematical models and simulations of drug release from polymeric microspheres and of drug transport in adjacent tissues. In drug delivery systems, mathematical modeling plays an important role in elucidating the important drug release mechanisms, thus facilitating the development of new pharmaceutical products by a systematic, rather than trial-and-error, approach. The mathematical models correspond to the known release mechanisms, which are classified as diffusion-, swelling-, and erosion-controlled systems. Various practical applications of these models which explain experimental data are illustrated. The effect of gamma-irradiation sterilization on drug release mechanism from erosion-controlled systems will be discussed. The application of existing models to nanoscale drug delivery systems specifically for hydrophobic and hydrophilic molecules is evaluated. The current development of drug transport modeling in tissues utilizing computational fluid dynamics (CFD) will also be described.