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 bra in parenchyma. We investigated convection as a means to enhance the di stribution 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 centimet er distances by maintaining a pressure gradient during interstitial in fusion into white matter to generate bulk flow through the brain inter stitium. The volume of distribution (V-d) containing greater than or e qual 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]sucros e (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 dif fusion, enhanced distribution of large and small molecules can be obta ined in the brain while achieving drug concentrations orders of magnit ude greater than systemic levels.