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 la...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1994-03, Vol.91 (6), p.2076-2080
Main Authors: Bobo, R. Hunt, Laske, Douglas W., Akbasak, Aytac, Morrison, Paul F., Dedrick, Robert L., Oldfield, Edward H.
Format: Article
Language:English
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
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.91.6.2076