DISTRIBUTION OF MACROMOLECULAR DYES IN BRAIN USING POSITIVE PRESSURE INFUSION - A MODEL FOR DIRECT CONTROLLED DELIVERY OF THERAPEUTIC AGENTS

BACKGROUND Direct infusion of therapeutic agents into the brain is a n ovel technique that has the potential for bypassing the blood-brain ba rrier and delivering high concentrations of therapeutic agents into th e brain parenchyma. We have developed a model to characterize the dist ribution of Evans Blue (MW 960) and Blue Dextran (MW 2 x 10(6)) in rat brain using a positive pressure infusion system. METHODS Evans Blue a nd Blue Dextran were infused in volumes of 20, 40, 60, 100, 140, and 1 80 mu L into the caudate putamen of female Fischer rats over a period of 2 h with rates of infusion varying between 0.167 mu L and 1.5 mu L/ min. During the infusions, the pressure generated in the infusion syst em and intracranial pressure were measured using a fiberoptic pressure monitoring system. After infusions, the volumes of distribution of th e dye molecules were measured from 3-mm thick sections using video mic roscopy and computer image analysis. Histologic changes during the inf usion were studied using snap freezing and hematoxylin/eosin staining of cryosections. RESULTS Volumes of distribution for Evans Blue were g reater than those for Blue Dextran. There was extensive spread of each dye in the ipsilateral hemisphere and also across the corpus callosum to the opposite hemisphere. Infusion/interstitial pressures peaked du ring the first 5 min of the infusion period, after which pressures dro pped to a plateau value that remained relatively constant during the r emainder of the infusion. Histologic findings suggest that this phenom enon is an important transition process that is likely to play a role in the pattern of distribution of macromolecules infused by this techn ique. No marked changes in intracranial pressure were noted during the infusion procedure. CONCLUSIONS Direct positive pressure infusion int o the brain has great potential in the treatment of brain tumors and o ther central nervous system disorders using both high and low molecula r weight compounds (immunotoxins, protein conjugates, pharmacologic ag ents, oligonucleotides, and viral vectors). (C) 1998 by Elsevier Scien ce Inc.