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Background: The blood-brain tumor barrier (BTB) significantly impedes delivery of most hydrophilic molecules to brain tumors. Several promising strategies, however, have been developed to overcome this problem.
Methods: We discuss several drug delivery methods to brain tumor, including intracerebroventricular, convection-enhanced delivery, BBB/BTB disruption, and BTB permeability modulation, which was developed in our laboratory.
Results: Using immunolocalization, immunoblotting, and potentiometric studies, we found that brain tumor capillary endothelial cells overexpress certain unique protein markers that are absent or barely detectable in normal capillary endothelial cells. We biochemically modulated these markers to sustain and enhance drug delivery, including molecules of varying sizes, selectively to tumors in rat syngeneic and xenograft brain tumor models. We also demonstrated that the cellular mechanism for vasomodulator-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles that transport therapeutic molecules across the BTB.
Conclusions: Other methods to deliver drugs across the BTB are effective but have severe drawbacks. Our strategy targets BTB-specific proteins to increase antineoplastic drug delivery selectively to brain tumors with few or no side effects, thus increasing the possibility of improving brain tumor treatment.
The cerebral microvessels and capillaries that form the blood-brain barrier (BBB) protect the brain, but they also pose an obstacle to the delivery to the brain of small and large therapeutic molecules. In fact, Pardridge reported that the BBB blocks delivery of more than 98% of central nervous system (CNS) drugs. As large water-soluble molecules (eg, therapeutic humanized monoclonal antibodies) are developed for the treatment of neurological diseases, the challenge to deliver them across the BBB has assumed critical importance. This article focuses on the biochemical modulation of the blood-brain tumor barrier (BTB), which surrounds brain tumors and has key characteristics that differentiate it from the BBB, as a strategy to enhance anticancer drug delivery to brain tumor. Our research has also shed light on the properties of the abnormal BBB, which results from damage caused by cerebral ischemia and other neurological disorders, yet is still somewhat different from the BTB.
Every year in the United States, approximately 25,000 new primary brain tumor and more than 200,000 secondary (metastatic) brain tumor cases are reported. For the most part, even after surgery to remove a malignant brain tumor, brain cancer recurs, severely shortening life expectancy. Conventional treatment using radiation and intravenous (IV) chemotherapy are often unsuccessful primarily because the anticancer drugs fail to cross the BTB in sufficient quantities. Therefore, understanding the BTB and the biochemical regulation of the BBB in its normal and abnormal states will be increasingly important as efforts continue to deliver therapeutic compounds to CNS targets. In particular, successful treatment of brain tumors involves efficient anticancer drug delivery to brain tumors across the BTB. Although the BTB is leaky in the tumor center, the established microvessels feeding the proliferating edge of the tumor and the brain adjacent to the tumor are nearly as impermeable as the BBB. Therefore, the BTB still poses a major hurdle to anticancer drug delivery to tumors. Over the past 10 years, several promising strategies have been developed to open the BTB to increase anticancer drug delivery to brain tumors. In this article, we review the advantages and disadvantages of the major drug delivery methods.
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