Comparison of various methods for delivering radiolabeled monoclonal antibody to normal rat brain.
Different methods were evaluated for delivering iodine-125 monoclonal antibodies (Mab's) to the central nervous system in 40- to 99-gm Fischer rats. By evaluating interhemispheric, interregional, and brain:blood ratios of Mab's, the efficacy of intracarotid (IC) or intravenous (IV) administration of Mab's with and without prior IC perfusion with 0.9% NaCl (normal saline, NS), 1.4 M mannitol, or 1.6 M arabinose, or of femoral artery perfusion with 1.4 M mannitol was evaluated. No difference was seen between IC and IV administration of Mab's with or without prior perfusion. Intracarotid perfusion with hyperosmolar agents was required to disrupt the blood-brain barrier (BBB) and to significantly elevate brain levels of Mab's. The brain and blood levels of Mab's were elevated in all regions of the brain following hyperosmolar BBB disruption. However, the levels were significantly higher in the ipsilateral hemisphere, with cross-over occurring primarily in the vascular distribution of the contralateral anterior cerebral artery. Intracarotid hyperosmolar perfusion produced 450% to 500% increases in ipsilateral and 240% to 280% increases in contralateral hemispheric brain:blood Mab ratio levels compared to those achieved with NS perfusion. For IC perfusion of mannitol or arabinose, flow rates ranging from 0.017 to 0.052 ml/sec were equally effective in disrupting the BBB. Insignificant morbidity and mortality rates were noted up to 2 weeks following BBB disruption. Additional ligation of major extracranial branches of the external and internal carotid arteries prior to IC perfusion did not result in a selective increase in hemispheric Mab levels. Temporally, following hyperosmolar BBB disruption, brain:blood Mab ratios remained elevated bilaterally at 7 days after Mab delivery, with the ipsilateral hemispheric levels remaining significantly elevated compared with the contralateral hemispheric levels until Day 5, when the ratio returned to the nonperfused range. Catheterization was required in the small animals and was performed under magnification in 10 to 20 minutes, with less than an 8% overall morbidity and mortality. The methodology developed should prove helpful in delivery of Mab's or other agents in rat tumor models and experimental models for other disease entities.
Bullard, DE; Bourdon, M; Bigner, DD
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