This project is concerned with characterizing and improving the delivery of pharmacologic and diagnostic agents to the central nervous system. (1) Final refinements and publication of a methodology that employs iopamidol (MW 777 Da) to track the in vivo distribution of compounds delivered to the brain by convection-enhanced delivery (CED) were completed. (2) The characteristics of AAV viral transport by CED and associated transfection of a GFP marker gene were further explored. Volumes of distribution were measured by magnetic resonance imaging (MRI) using Combidex particles. The associated transfection volume was measured by quantitative imaging fluorescence (Fuji FLA5000). Transfection volume has proven highly variable and causes are under investigation. (3) A finite element model of the distribution of muscimol in hippocampus was developed for high flow delivery (1.4 microliter/min) from a 1.3 mm OD catheter. The model's prediction was compared to autoradiographic data: relative to results from a simpler more-diffusion-based analysis, a slightly greater backflow length and larger total clearance rate were determined to be optimal. (4) Finite element models were developed for representative agents from three classes of antiepileptic drugs, namely quinolinic acid (QA), ibotenic acid (IBO), and botulinum toxin A (BTX), as well as the macromolecular marker albumin. The models were then used to identify the most promising candidate. Drugs were ranked by order of the maximum tissue penetration (at a fixed percentage of infusate concentration) achieved with an Adtech electrode-bearing catheter operating at its maximum backflow-limited inflow rate in the hippocampus. All compounds were described by convective and diffusive flows through the interstitial space, including dilution effects secondary to the extrachoroidal production of cerebrospinal fluid (CSF). QA distributions in both interstitial and intracellular spaces and clearance by organic anion transporters were parameterized from values derived from microdialysis. Drawing on experimental models and kinetics, IBO distributions across the blood-brain barrier (BBB) and cell plasma membranes were described as arising from either neutral or acid amino acid transport in which endogenous amino acids act as competitors to IBO; intracellular sources and sinks, including interactions with the tricarboxylic acid cycle, were also taken into account. BTX distributions were derived from a model that accounted for interstitial transport together with btx-A-receptor binding. QA and IBO distributions were found to easily reach steady state before reaching the hippocampal/amygdala boundaries but penetration was limited in all cases to under 3 mm. BTX delivery was transient within the anatomical boundaries, but easily filled the tissue target with relatively uniform concentration. BTX was identified as the best potential agent for drug delivery of the three drugs examined. (5) Finite element models of gemcitabine, GdDTPA, and sucrose were developed and used to determine the relative abilities of GdDTPA, sucrose, and (from earlier work) iopamidol to act as real-time tracers of gemcitabine delivery in vivo. Based solely on Vd reproduction at steady state, the best tracer is iopamidol followed next by sucrose. GdDTPA is limited by slow microvascular clearance. (6) Autoradiography of 125-I-IL13-PE protein toxin delivery to the primate brainstem was performed and used to confirm the expectation that Gd-albumin could serve as an excellent in vivo marker for the large MW toxin. (7) A finite element model of the transport of GDNF in the human putamen/pallidi nuclei was developed and used to determine if the differing patient responses to GDNF reported in three recent Parkinson's disease clinical trials were caused by differences in drug delivery. GDNF distribution was modeled as arising from fluxes through the interstitial space combined with binding to heparan sulfate moieties, passive microvascular clearance, and extrachoroidal fluid dilution. Trial-specific end-hole and multiport catheters were described together with estimates of associated backflow effects. Steady state and transient results were computed. Superposition of predicted distributions on Talaraich Atlas MRI-derived images ultimately showed that 2 trials of reportedly differing clinical outcome were not expected to have significantly different drug distribution. Factors other than drug distribution are thus indicated as responsible for the varying outcomes.
