CONVECTION-ENHANCED DELIVERY OF MACROMOLECULES IN THE BRAIN

For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules In-111-labeled transferrin (In-111-Tf; M(r), 80,000) and [C-14]sucrose (M(r), 359) over centimeter distances by maintaining a pressure gradient during interstitial infusion into white matter to generate bulk flow through the brain interstitium. The volume of distribution (V-d) containing greater than or equal to 1% concentration of infusion solution increased linearly with the infusion volume (V-i) for In-111-Tf(V-d/V-i, 6:1) and [C-14]sucrose (V-d/V-i, 13:1). Twenty-four hours after infusion, the distribution of In-111-Tf was increased and more homogeneous, and penetration into gray matter had occurred. By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.