The effect of hyperosmotic blood—brain barrier disruption on blood‐to‐tissue transport in ENU‐induced gliomas

Abstract

Hyperosmotic blood—brain barrier disruption transiently increases the rate of blood‐to‐tissue transport of water soluble compounds to normal brain and has been used in brain tumor patients to increase the delivery of chemotherapeutic drugs. This method remains controversial; debate concerns the extent to which it increases drug delivery to brain tumors. Ethylnitrosourea (ENU)‐induced gliomas in rats have the lowest rate of blood‐to‐tissue transfer of the water‐soluble compound alpha‐aminoisobutyric acid of all experimental brain tumor studied to date. To gain further understanding about the effect of hyperosomotic blood—brain barrier disruption in brain tumors, we measured the unidirectional blood‐to‐tissue transfer constant of alpha‐aminoisobutyric acid in ENU‐induced brain tumors in rats after hyperosmotic disruption. Hyperosmotic blood—brain barrier disruption with 1.6 osmolar mannitol resulted in an averaged whole‐tumor transfer constant of 0.013 ± 0.003 (standard error) mL/(g/min), compared to a transfer constant of 0.007 ± 0.002 mL/(g/min) for ENU‐induced gliomas in the contralateral undisrupted hemisphere, a difference that was not significant. In contrast, hyperosmotic blood—brain barrier disruption produced a large and significant increase in the transfer constant of alpha‐aminoisobutyric acid in tumor‐free cortex (from 0.002 ± 0.001 to 0.05 ± 0.011 mL/{g/min}) and in tumor‐free corpus callosum (from 0.001 ± 0.003 to 0.017 ± 0.005 mL/{g/min}). Hyperosmotic blood—brain barrier disruption does not appear to be an efficient method with which to increase the rate of delivery of water‐soluble drugs to brain tumors but does result in a significant increase in the delivery rate of these drugs to normal brain tissue.