(102g) Targeted Drug Delivery into the Human Brain

Drug delivery to specific locations in the brain is a challenging task in the treatment of diseases related to Central Nervous System (CNS) such as brain tumors, epilepsy, Parkinson's, Alzheimer's and Huntington's diseases owing to the blood-brain barrier (BBB). There is an interest from medical community in delivering Glial-Derived Neurotrophic Factor (GDNF) and Brain-Derived Neurotrophic Factor (BDNF) drugs at specific locations to CNS [1]. It is also known that these drugs consisting of big molecules cannot overcome the BBB. A promising solution to this problem is to deliver the required drug into the targeted location by invasive techniques as the convection enhanced delivery (CED).

In this work, computational fluid dynamics (CFD) techniques are utilized to study invasive drug delivery in multi-dimensional brain geometries with the consideration of the chemical interactions that the drug undergoes while it diffuses into the brain tissue. A challenge is to accurately reconstruct the three-dimensional structure of the human brain. We are able to resolve very accurately the brain geometry and render physiologically consistent the distribution of the complex brain inner organization. We distinguish between gray and white matter and assign transport properties of relevance according to the data obtained by MR images or histological data. We will quantify with numerical simulations the diffusive and convective transport phenomena in the porous brain tissues and the effectiveness of the drug release to a desired region. This approach will help to evaluate precisely the penetration depth of the drug and the concentration profiles need to surpass set thresholds in order to ensure proper efficacy of the drug. We rigorously examine the variables that influence CED and pose constraints to the treatment. These include effect of infusate (bulk) flow rate, concentration of the infusate, drug diffusivity, effect of molecular weight of the drug, and effect of white matter anisotropy, infusate leak-back by considering metabolic uptake by the parenchyma cells and re-absorption of the bulk fluid [2].

Understanding the parameters that could possibly influence the convective delivery of drugs in the CNS is very important because, it will improve the current medical approaches. The proposed methodology will provide a systematic approach to optimally choose catheter dimensions, infusion rates, drug concentrations etc. The information obtained from these accurate simulations could be used to model inverse kinetic problems capable of predicting the mass diffusivity of the drug and the kind of metabolism that actually takes place.

[1] Hamilton J.F., Morrison P.F., Chen M.Y., Harvey-White J., Pernaute R.S., Phillips H., Oldfield E., Bankiewicz K.S., Heparin Coinfusion during Convection-Enchanced Delivery (CED) Increases the Distribution of the Glial-Derived Neurotrophic Factor (GDNF) Ligand Family in Rat Striatum and Enhances the Pharmocological Activity of Neurturin, Experimental Neurology, 168, 155-161, 2001.

[2] Chen, M. Y, Lonser, R. R, Morrison, P. F, Governale, L. S, Oldfield, E. H, ?Variables affecting convection-enchanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time?, Journal of Neurosurgery, 90, 315-320, 1999.