Modulation of brain tumor capillaries for enhanced drug delivery selectively to brain tumor.
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.
Black
Keith L
KL
Maxine Dunitz Neurosurgical Institute and Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Ningaraj
Nagendra S
NS
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001920:Bradykinin / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D017869:Cyclic GMP-Dependent Protein Kinases / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D045462:Endothelium-Dependent Relaxing Factors / Q000008:administration & dosage; D006801:Humans; D007263:Infusions, Parenteral / Q000379:methods; D017572:Leukotriene A4 / Q000008:administration & dosage; D009569:Nitric Oxide / Q000008:administration & dosage; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D014665:Vasodilator Agents / Q000008:administration & dosage
D000970:Antineoplastic Agents; D045462:Endothelium-Dependent Relaxing Factors; D017572:Leukotriene A4; D015221:Potassium Channels; D014665:Vasodilator Agents; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D001920:Bradykinin