title: Distribution of nerve growth factor following direct delivery to brain interstitium.
abstract: Several studies suggest the potential of nerve growth factor (NGF) in the treatment of patients with Alzheimer's disease. To characterize NGF transport within the brain interstitium, we implanted controlled release polymers containing NGF and [125I]NGF into the brains of adult male rats and measured spatial distributions of NGF for up to one week. NGF concentration in the brain was quantified using ELISA, radiation counting, and autoradiography. At 2 days post-implantation, quantities of NGF in excess of 50 pg per section were detected within thick (1 mm) coronal slices of the hemisphere ipsilateral to the site of implantation up to 3 mm rostral and caudal to the edge of the polymer. Lower levels of radioactivity (> 5 pg but < 50 pg NGF per section) could be detected throughout the rest of the brain. Levels were highest in the tissue sections containing the polymer, reaching 9.5 ng per section. Autoradiography of thin (20 microns) coronal sections indicated that local NGF concentrations immediately adjacent to the polymer approached 40 micrograms/ml. Analysis of sequential sections on the autoradiograph confirmed that NGF was transported only 2-3 mm from the polymer in any direction. At one week post-implantation, the pattern of NGF distribution was similar to that seen at 2 days, and concentrations remained high near the site of the implant. Comparison of local NGF concentration profiles to simple models of diffusion with first-order elimination suggests that the NGF moved through the tissue by diffusion through the interstitial space with a half-life on the order of 0.5 h. The limited range of NGF transport in brain tissue indicates that: (i) protein drug agents such as NGF will probably need to be delivered almost directly to the site of action for efficacy; and (ii) toxicities associated with delivery of NGF and other protein agents to non-target cells, as often occurs with systemic delivery of drugs, may be reduced by local, interstitial delivery since therapy can be restricted to a small volume of the brain.
authors.affiliation: Department of Chemical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Krewson
authors.forename: M L
authors.initials: ML
authors.lastname: Klarman
authors.forename: W M
authors.initials: WM
authors.lastname: Saltzman
mesh_terms: D000818:Animals; D001345:Autoradiography; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D004058:Diffusion; D004343:Drug Implants; D004797:Enzyme-Linked Immunosorbent Assay; D007457:Iodine Radioisotopes; D008297:Male; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011108:Polymers; D019736:Prostheses and Implants; D011859:Radiography; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D004343:Drug Implants; D007457:Iodine Radioisotopes; D009414:Nerve Growth Factors; D011108:Polymers