Convection-Enhanced Delivery of Macromolecules in the Brain

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 6; pp. 2076 - 2080
• Main Authors: Bobo, R. Hunt, Laske, Douglas W., Akbasak, Aytac, Morrison, Paul F., Dedrick, Robert L., Oldfield, Edward H.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.03.1994; National Acad Sciences; National Academy of Sciences
• Subjects: Animals; Antineoplastics; Biological and medical sciences; Biological Transport; Biology; Brain; Brain - metabolism; Brain edema; Cats; Central nervous system; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cerebral hemispheres; Convection; Diffusion; Fundamental and applied biological sciences. Psychology; Image Processing, Computer-Assisted; Injections, Intraventricular; Macromolecular Substances; Molecular Weight; Molecules; Pressure gradients; Scientific imaging; Space life sciences; Sucrose - administration & dosage; Sucrose - metabolism; Transferrin - administration & dosage; Transferrin - metabolism; Tumors; Vertebrates: nervous system and sense organs; Autoradiography; Macromolecule; Convection; Central nervous system; Distribution; Brain (vertebrata)
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.6.2076

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 molecules111In-labeled transferrin (111In-Tf; Mr, 80,000) and [14C]sucrose (Mr, 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 ≥1% concentration of infusion solution increased linearly with the infusion volume (Vi) for111In-Tf(Vd/Vi, 6:1) and [14C]sucrose (Vd/Vi, 13:1). Twenty-four hours after infusion, the distribution of111In-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.