Keith L Black1, Nagendra S Ningaraj. 1. Maxine Dunitz Neurosurgical Institute and Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Abstract
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.
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.
Authors: M Grabacka; P Waligorski; A Zapata; D A Blake; D Wyczechowska; A Wilk; M Rutkowska; H Vashistha; R Ayyala; T Ponnusamy; V T John; F Culicchia; A Wisniewska-Becker; K Reiss Journal: J Physiol Pharmacol Date: 2015-04 Impact factor: 3.011
Authors: Nichole A Pianovich; Mathew Dean; Adam Lassak; Krzysztof Reiss; Branko S Jursic Journal: Bioorg Med Chem Date: 2017-08-12 Impact factor: 3.641