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 novel technique that has the potential for bypassing the blood-brain barrier and delivering high concentrations of therapeutic agents into the brain parenchyma. We have developed a model to characterize the distribution 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 and Blue Dextran were infused in volumes of 20, 40, 60, 100, 140, and 180 microL into the caudate putamen of female Fischer rats over a period of 2 h with rates of infusion varying between 0.167 microL and 1.5 microL/min. During the infusions, the pressure generated in the infusion system and intracranial pressure were measured using a fiberoptic pressure monitoring system. After infusions, the volumes of distribution of the dye molecules were measured from 3-mm thick sections using video microscopy and computer image analysis. Histologic changes during the infusion were studied using snap freezing and hematoxylin/eosin staining of cryosections. RESULTS Volumes of distribution for Evans Blue were greater 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 during the first 5 min of the infusion period, after which pressures dropped to a plateau value that remained relatively constant during the remainder of the infusion. Histologic findings suggest that this phenomenon is an important transition process that is likely to play a role in the pattern of distribution of macromolecules infused by this technique. No marked changes in intracranial pressure were noted during the infusion procedure. CONCLUSIONS Direct positive pressure infusion into the brain has great potential in the treatment of brain tumors and other central nervous system disorders using both high and low molecular weight compounds (immunotoxins, protein conjugates, pharmacologic agents, oligonucleotides, and viral vectors).