© 2000 by Society
© 2000 by the Society forNeuro-Oncology
The blood-brain and blood-tumor barriers: A review of strategies forincreasing drug delivery
Evanston Northwestern Healthcare, Department of Neurology;Northwestern University Medical School, Department of Neurobiology andPhysiology; and the Institute for Neuroscience, Northwestern University,Evanston, IL 60201
2 Address correspondence and reprint requests to Dennis R. Groothuis, M.D.,Evanston Hospital, 2650 Ridge Ave., Evanston, IL 60201.
Drug delivery to brain tumors has been a controversial subject. Somebelieve the blood-brain barrier is not important, while others believe it isthe major obstacle in treatment and have devised innovative approaches tocircumvent it. These approaches can be divided into two categories: those thatattempt to increase drug delivery of intravascularly administered drugs bymanipulating either the drugs or capillary permeability, and those thatattempt to increase drug delivery by local administration. Several strategieshave been developed to increase the fraction of intravascular drug reachingthe tumor, including intra-arterial administration, barrier disruption, newways of packaging drugs, and, most recently, inhibiting drug efflux fromtumor. When given intravascularly, all drugs have a common drawback: the bodyacts as a sink, and, even in the best situations, only a small fraction ofadministered drug actually reaches the tumor. A consequence is that systemictoxicity is usually the dose-limiting factor. When given locally, such as intothe cerebrospinal fluid or directly into the tumor, 100% of an administereddose is delivered to the target site. However, local delivery is associatedwith variable and unpredictable spatial distribution and variation in drugconcentration. The major dose-limiting factor of most local delivery methodswill be neurotoxicity. The relative advantages and disadvantages of thedifferent methods of circumventing the blood-brain barrier are presented inthis review, and special attention is given to convection-enhanced delivery,which has particular promise for the local delivery of large therapeuticagents such as monoclonal antibodies, antisense oligonucleotides, or viralvectors.
Received July 2, 1999; Accepted August 5, 1999
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