This project is concerned with characterizing and improving the delivery of pharmacologic and diagnostic agents to the central nervous system. (1) The ability to deliver growth factors by convection-enhanced delivery (CED) was characterized. These trophic factors normally have small volumes of distribution (Vd) with CED because of their binding to heparin binding sites in the extracellular matrix. Co-infusion of heparin with GDNF, neurturin, and artemin was found to be effective in overcoming this binding and increasing the baseline Vds of these agents by 5-, 7-, and 10-fold, respectively. (2) A finite element model of the rat, swine, and human spinal cord has been constructed for the purpose of predicting drug delivery associated with both intrathecal and CED. Gray and white matter regions are volume rendered from MRI scans and the gray matter is subdivided into the laminae of Rexed. Diffusive and convective flows are allowed in both the gray and white matter regions, and flow through the white matter is anisotropic with the principal axis of flow aligned parallel to the fiber tracts. Tensor components of white matter hydraulic conductivity and average-white to gray matter conductivity values have been determined from observed distributions of 14C-albumin in the cord following its delivery by CED to the dorsal columns. Application to the distribution of selected nocitoxins to the dorsal horns has been undertaken, including the accounting of target receptor binding and recycling, desensitization, and dose-response. (3) Estimated delivery characteristics by CED of selected GABA-agonists to the hippocampus and amygdala were determined. Taking metabolism and cannula backflow into account, optimal agents were chosen based upon their expected confinement to the target structures.
