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

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✓ 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.

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Address reprint requests to: Edward H. Oldfield, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Building 10, Room 5D37, National Institutes of Health, Bethesda, Maryland 20892.

© AANS, except where prohibited by US copyright law.

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References
  • 1.

    Blasberg RGNakagawa HBourdon MAet al: Regional localization of a glioma-associated antigen defined by monoclonal antibody 81C6 in vivo: kinetics and implications for diagnosis and therapy. Cancer Res 47:443244431987Blasberg RG Nakagawa H Bourdon MA et al: Regional localization of a glioma-associated antigen defined by monoclonal antibody 81C6 in vivo: kinetics and implications for diagnosis and therapy. Cancer Res 47:4432–4443 1987

    • Search Google Scholar
    • Export Citation
  • 2.

    Bobo RHLaske DWAkbasak Aet al: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91:207620801994Bobo RH Laske DW Akbasak A et al: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91:2076–2080 1994

    • Search Google Scholar
    • Export Citation
  • 3.

    Bradbury MWB: The Concept of a Blood-Brain Barrier. New York: J Wiley1979Bradbury MWB: The Concept of a Blood-Brain Barrier. New York: J Wiley 1979

    • Search Google Scholar
    • Export Citation
  • 4.

    Curran REMosher MBOwens ESet al: Cerebrospinal fluid production rates determined by simultaneous albumin and inulin perfusion. Exp Neurol 29:5465531970Curran RE Mosher MB Owens ES et al: Cerebrospinal fluid production rates determined by simultaneous albumin and inulin perfusion. Exp Neurol 29:546–553 1970

    • Search Google Scholar
    • Export Citation
  • 5.

    Hill JMRuff MRWeber RJet al: Transferrin receptors in rat brain: neuropeptide-like pattern and relationship to iron distribution. Proc Natl Acad Sci USA 82:455345571985Hill JM Ruff MR Weber RJ et al: Transferrin receptors in rat brain: neuropeptide-like pattern and relationship to iron distribution. Proc Natl Acad Sci USA 82:4553–4557 1985

    • Search Google Scholar
    • Export Citation
  • 6.

    Hnatowich DJLayne WWChilds RLet al: Radioactive labeling of antibody: a simple and efficient method. Science 220:6136151983Hnatowich DJ Layne WW Childs RL et al: Radioactive labeling of antibody: a simple and efficient method. Science 220:613–615 1983

    • Search Google Scholar
    • Export Citation
  • 7.

    Iosilevsky GIsrael OFrenkel Aet al: A practical SPECT technique for quantitation of drug delivery to human tumors and organ absorbed radiation dose. Semin Nucl Med 19:33461989Iosilevsky G Israel O Frenkel A et al: A practical SPECT technique for quantitation of drug delivery to human tumors and organ absorbed radiation dose. Semin Nucl Med 19:33–46 1989

    • Search Google Scholar
    • Export Citation
  • 8.

    Jaszczak RJ: SPECT: state-of-the-art scanners and reconstruction strategies in Diksic M Reba RC (eds): Radiopharmaceuticals and Brain Pathology Studied with PET and SPECT. Boca Raton, FL: CRC Press1991 pp 93115Jaszczak RJ: SPECT: state-of-the-art scanners and reconstruction strategies in Diksic M Reba RC (eds): Radiopharmaceuticals and Brain Pathology Studied with PET and SPECT. Boca Raton FL: CRC Press 1991 pp 93–115

    • Search Google Scholar
    • Export Citation
  • 9.

    Jefferies WABrandon MRBHunt SVet al: Transferrin receptor on endothelium of brain capillaries. Nature 312:1621631984Jefferies WA Brandon MRB Hunt SV et al: Transferrin receptor on endothelium of brain capillaries. Nature 312:162–163 1984

    • Search Google Scholar
    • Export Citation
  • 10.

    Johnson VGWrobel CWilson Det al: Improved tumor-specific immunotoxins in the treatment of CNS and leptomeningeal neoplasia. J Neurosurg 70:2402481989Johnson VG Wrobel C Wilson D et al: Improved tumor-specific immunotoxins in the treatment of CNS and leptomeningeal neoplasia. J Neurosurg 70:240–248 1989

    • Search Google Scholar
    • Export Citation
  • 11.

    Lieberman DMLaske DWMorrison PFet al: Convectionenhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:102110291995Lieberman DM Laske DW Morrison PF et al: Convectionenhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:1021–1029 1995

    • Search Google Scholar
    • Export Citation
  • 12.

    Lux WE JrFenstermacher JD: Cerebrospinal fluid formation in ventricles and spinal subarachnoid space of the rhesus monkey. J Neurosurg 42:6746781975Lux WE Jr Fenstermacher JD: Cerebrospinal fluid formation in ventricles and spinal subarachnoid space of the rhesus monkey. J Neurosurg 42:674–678 1975

    • Search Google Scholar
    • Export Citation
  • 13.

    Milhorat THHammock MKFenstermacher JDet al: Cerebrospinal fluid production by the choroid plexus and brain. Science 173:3303321971Milhorat TH Hammock MK Fenstermacher JD et al: Cerebrospinal fluid production by the choroid plexus and brain. Science 173:330–332 1971

    • Search Google Scholar
    • Export Citation
  • 14.

    Morrison PFLaske DWBobo Het al: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266:R292R3051994Morrison PF Laske DW Bobo H et al: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266:R292–R305 1994

    • Search Google Scholar
    • Export Citation
  • 15.

    Neirinckx RDBurke JFHarrison RCet al: The retention mechanism of technetium-99m-HM-PAO: intracellular reaction with glutathione. J Cereb Blood Flow Metab 8 (Suppl):S4S121988Neirinckx RD Burke JF Harrison RC et al: The retention mechanism of technetium-99m-HM-PAO: intracellular reaction with glutathione. J Cereb Blood Flow Metab 8 (Suppl):S4–S12 1988

    • Search Google Scholar
    • Export Citation
  • 16.

    Paik CHEbbert MAMurphy PRet al: Factors influencing DTPA conjugation of antibodies by cyclic DTPA anhydride. J Nucl Med 24:115811631983Paik CH Ebbert MA Murphy PR et al: Factors influencing DTPA conjugation of antibodies by cyclic DTPA anhydride. J Nucl Med 24:1158–1163 1983

    • Search Google Scholar
    • Export Citation
  • 17.

    Pretorius PHVan Aswegen AHerbst CPet al: The effects of different correction techniques on absolute volume determination with SPECT using a threshold edge detection method. Med Phys 18:3903931991Pretorius PH Van Aswegen A Herbst CP et al: The effects of different correction techniques on absolute volume determination with SPECT using a threshold edge detection method. Med Phys 18:390–393 1991

    • Search Google Scholar
    • Export Citation
  • 18.

    Rapoport SI: A model for brain edema in Inaba YKlatzo ISpatz M (eds): Brain Edema. Berlin: Springer-Verlag1985 pp 5971Rapoport SI: A model for brain edema in Inaba Y Klatzo I Spatz M (eds): Brain Edema. Berlin: Springer-Verlag 1985 pp 59–71

    • Search Google Scholar
    • Export Citation
  • 19.

    Rosenberg GAKyner WTEstrada E: Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238:F42F491980Rosenberg GA Kyner WT Estrada E: Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238:F42–F49 1980

    • Search Google Scholar
    • Export Citation
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