| Polymeric controlled release has emerged as a promising new technique to bypass the blood-brain barrier and deliver sustained, locally high amounts of drugs to the brain for various neurological applications. In conjunction with the development of novel drug carriers has emerged the challenge of determining the fate of drug molecules delivered in this manner to the brain. The objective of this thesis is to develop a rigorous theoretical framework of transport in the brain to meet this challenge and to provide a rational basis for the design of drug carriers.; The mathematical model of transport was developed from basic physical principles, without the use of any adjustable parameters and employed to study drug transport in 2-D transverse sections of the rabbit and rat brains. Since the geometry of the brain is complicated with anisotropic tissue properties, and both diffusion and convection are important in the spread of drugs, we solved the governing equations of transport numerically using the method of finite elements (FEM). In conjunction, using magnetic resonance imaging (MRI), we tracked the transport of paramagnetic contrast markers in the brain of the same animal non-invasively. To study the effect of drugs with different molecular weights, we linked Gd-DTPA, a paramagnetic contrast agent, to dextran sugars of different sizes. Using spin echo imaging and acquiring T{dollar}sb1{dollar}-weighted and proton density images, we were able to study transport in a quantitative manner. The insights gained from these experiments enabled us to confer spatial heterogeneity and boundary transport characteristics to the model. Defined and improved by the experimental input, the model was used to study the major determinants of transport in the brain.; The model predicts that at early times post-delivery, edema caused by the surgical procedure creates conditions of high convection around the delivery site, which is the major determinant of transport. In all cases, the properties of the drug, its interaction with tissue, the conditions in the tissue (normal or edematous) all interact in a complex manner to determine the ultimate fate of the drug molecule. Such information can be useful in the rational design of a drug carrier, with its release kinetics tailored specifically for a particular application. |
