Convection-enhanced delivery of macromolecules in the brain.

TLDR

Slow diffusion limits drug distribution in the brain after direct administration. The study examined whether convection could improve distribution of large and small molecules in brain parenchyma. Convection was achieved by maintaining a pressure gradient during interstitial infusion into white matter, creating bulk flow through the interstitium. Convection increased the volume of distribution linearly with infusion volume for both 111In‑Tf and sucrose, produced more homogeneous and gray‑matter penetration after 24 h, and achieved drug concentrations orders of magnitude above systemic levels.

Abstract

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 111In-labeled transferrin (111In-Tf; M(r), 80,000) and [14C]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 (Vd) containing > or = 1% concentration of infusion solution increased linearly with the infusion volume (Vi) for 111In-Tf(Vd/Vi, 6:1) and [14C]sucrose (Vd/Vi, 13:1). Twenty-four hours after infusion, the distribution of 111In-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.