Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging.
OBJECTIVE
Convection-enhanced delivery (CED), the delivery and distribution of drugs by the slow bulk movement of fluid in the extracellular space, allows delivery of therapeutic agents to large volumes of the brain at relatively uniform concentrations. This mode of drug delivery offers great potential for the treatment of many neurological disorders, including brain tumors, neurodegenerative diseases, and seizure disorders. An analysis of the treatment efficacy and toxicity of this approach requires confirmation that the infusion is distributed to the targeted region and that the drug concentrations are in the therapeutic range.


METHODS
To confirm accurate delivery of therapeutic agents during CED and to monitor the extent of infusion in real time, albumin-linked surrogate tracers that are visible on images obtained using noninvasive techniques (iopanoic acid [IPA] for computerized tomography [CT] and Gd-diethylenetriamine pentaacetic acid for magnetic resonance [MR] imaging) were developed and investigated for their usefulness as surrogate tracers during convective distribution of a macromolecule. The authors infused albumin-linked tracers into the cerebral hemispheres of monkeys and measured the volumes of distribution by using CT and MR imaging. The distribution volumes measured by imaging were compared with tissue volumes measured using quantitative autoradiography with [14C]bovine serum albumin coinfused with the surrogate tracer. For in vivo determination of tracer concentration, the authors examined the correlation between the concentration of the tracer in brain homogenate standards and CT Hounsfield units. They also investigated the long-term effects of the surrogate tracer for CT scanning, IPA-albumin, on animal behavior, the histological characteristics of the tissue, and parenchymal toxicity after cerebral infusion.


CONCLUSIONS
Distribution of a macromolecule to clinically significant volumes in the brain is possible using convection. The spatial dimensions of the tissue distribution can be accurately defined in vivo during infusion by using surrogate tracers and conventional imaging techniques, and it is expected that it will be possible to determine local concentrations of surrogate tracers in voxels of tissue in vivo by using CT scanning. Use of imaging surrogate tracers is a practical, safe, and essential tool for establishing treatment volumes during high-flow interstitial microinfusion of the central nervous system.
Nguyen
Tung T
TT
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke; National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
Pannu
Yashdip S
YS
Sung
Cynthia
C
Dedrick
Robert L
RL
Walbridge
Stuart
S
Brechbiel
Martin W
MW
Garmestani
Kayhan
K
Beitzel
Markus
M
Yordanov
Alexander T
AT
Oldfield
Edward H
EH
D000418:Albumins / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D003287:Contrast Media / Q000493:pharmacokinetics; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D007480:Iopanoic Acid / Q000493:pharmacokinetics; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D009994:Osmolar Concentration; D012709:Serum Albumin / Q000493:pharmacokinetics*; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
D000418:Albumins; D003287:Contrast Media; D012709:Serum Albumin; C058946:albumin-(gadolinium-DTPA); D012710:Serum Albumin, Bovine; D007480:Iopanoic Acid; D019786:Gadolinium DTPA