Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with singlephoton emission computerized tomography imaging

Abstract

✓ High-flow interstitial infusion into the brain, which uses bulk fluid flow to achieve a relatively homogeneous drug distribution in the extracellular space of the brain, has the potential to perfuse large volumes of brain. The authors report reproducible long-term delivery of 111In—diethylenetriamine pentaacetic acid—apotransferrin (111In-DTPA-Tf) (molecular mass 81 kD) to Macaca mulatta brain and monitoring with single-photon emission computerized tomography (SPECT). The 111In-DTPA-Tf was infused at 1.9 µl/minute over 87 hours into the frontal portion of the centrum semiovale using a telemetry-controlled, fully implanted pump. On Days 1, 3, 4, 8, 11, and 15 after beginning the infusion, planar and SPECT scans of 111In-DTPA-Tf were obtained. Spread of protein in the brain ranged from 2 to 3 cm and infusion volumes ranged from 3.9 to 6.7 cm3. Perfusion of over one-third of the white matter of the infused hemisphere was achieved. From brain SPECT images of 99mTc—hexamethylpropyleneamine oxime, which was administered intravenously before each 111In scan, the authors also found that blood perfusion in the infused region was reduced by less than 5% relative to corresponding noninfused regions. Histological examination at 30 days revealed only mild gliosis limited to the area immediately surrounding the needle tract. These findings indicate that long-term interstitial brain infusion is effective for the delivery of drugs on a multicentimeter scale in the primate brain. The results also indicate that it should be possible to perfuse targeted regions of the brain for extended intervals to investigate the potential utility of neurotrophic factors, antitumor agents, and other materials for the treatment of central nervous system disorders.