Transient and controllable opening of the blood-brain barrier to cytostatic and antibiotic agents by alkylglycerols in rats

The blood-brain barrier hinders progress in the chemotherapy of brain tumor s due to insufficient penetration of anticancer drugs into the brain tissue . Short-chain alkylglycerols affect the physicochemical proper ties of biol ogical membranes. The enhancement of the blood-brain barrier permeability b y intra-arterial administration of alkylglycerols was investigated in tumor -free and C6 astroglioma bearing rats. The antineoplastic agents cisplatin and methotrexate and the antibiotics vancomycin and gentamicin were selecti vely injected into the right internal carotid artery in the absence and pre sence of various alkylmono-, alkyldi-, and alkyltri-glycerols. In normal ra ts the intra-arterial administration of the drugs without alkylglycerols re sulted in low drug concentrations in brain tissue. In the presence of alkyl glycerols (0.01-0.3 M) a reversible (within minutes) and concentration-depe ndent enrichment of the coinjected agents was found, preferentially in the ipsilateral hemisphere. The extent of drug accumulation in the brain was mo dified by changes in the chemical structure of the alkylglycerols. The effe ct increased with the chain length of the alkyl group, decreased with the n umber of glycerols, and varied from 2- to more than 230-fold compared to co ntrols. In rats with C6 tumors 1-O-pentylglycerol increased the delivery of methotrexate 18-fold in the tumor, 28-fold in the surrounding brain, 18-fo ld in the contralateral brain, and 19-fold in the cerebellum compared to co ntrols with methotrexate in the absence of pentyl-glycerol. In conclusion, the intra-arterial administration of alkylglycerols represents a novel and well controllable method for enhanced drug delivery to the brain and to bra in tumors.