DELIVERY OF VITAL DRUGS TO THE BRAIN FOR THE TREATMENT OF BRAIN-TUMORS

The brain entry of many clinically valuable drugs is restricted by the blood-brain barrier, even during pathological conditions when the integrity of this barrier may become partially reduced. In this article, we describe the factors which, combined, determine the amount of a drug that enters and is maintained in brain following its systemic administration. These factors include, (i) the plasma concentration-time profile of the drug, (ii) its binding affinity and binding off-rates to plasma proteins and tissues, (iii) the permeability of the drug at the blood-brain barrier, and (iv) the rate of cerebral blood flow. We describe how drug uptake into brain changes during pathological conditions, specifically in the presence of a brain tumor. The problems of brain tumor treatment (surgery, radiation therapy and chemotherapy) are reviewed and the delivery of drugs into microenvironments within brain tumors and surrounding brain are described. Finally, we report our studies on two techniques to enhance the uptake of drugs, biological response modifiers and proteins such as monoclonal antibodies into brain and brain tumors. The first involves the transient and innocuous opening of the blood-brain barrier by a 20 second infusion of a hyperosmotic sugar solution, either mannitol or l-arabinose, into the carotid or vertebral arteries. This allows the brain uptake of a compound to be increased by up to 100-fold. We describe studies undertaken to characterize this technique prior to its clinical use, and its value, when combined with non-neurotoxic anticancer agents, in the treatment of patients with primary and metastatic brain tumors. The second technique to improve delivery of drugs into brain involves the chemical modification of specific moieties on drugs. We describe our studies with the anticancer alkylating agent chlorambucil, in the development of lipophilic derivatives of potential clinical value for brain tumor treatment. © 1990.