The current treatment of malignant diffuse gliomas with combined radiation and chemotherapy is limited and often results in high rates of persistent and recurrent disease with poor survival. Inadequate delivery across the blood-brain barrier (BBB) has been identified as a significant factor contributing to the failure of systemic chemotherapy for malignant brain tumors. The properties of the BBB that shield the brain from deleterious agents are thus the same that prevent drugs from treating disease. The primary goal of this work is to manipulate the molecular structure of the BBB to enhance drug delivery into a brain tumor. It was recently shown that targeted suppression of claudin 5, an endothelial cell specific tight junction protein on the BBB, following injection of siRNA targeting claudin 5, caused both a transient and size-selective increase in paracellular permeability of the BBB (Campbell et al, J Gene Med, 2008). Many preclinical studies testing molecular therapeutics and chemotherapeutics rely on xenograft tumor models to predict tumor response and survival. Preliminary work in the PI's laboratory demonstrated a preferential tumor microvessel vulnerability to the siRNA targeting claudin 5 compared to adjacent normal microvessels. The working hypothesis is that this novel strategy of targeting claudin 5 in vivo will preferentially target brain tumor microvessels and result in a transient tumor selective opening of the BBB, also referred to as the blood-tumor barrier. To better characterize the molecular and functional changes with this approach, we propose to test the following: 1) characterize the temporal course of modulation of BBB permeability;2) determine the molecular pore size threshold in the tumor microvessels and extent of various sized tracers into the perivascular space using intravital cranial window microscopy;and 3) test this approach to augment the delivery of known antitumor agents. Using this novel molecular approach, these important studies will lay the foundation for future translational studies to better deliver chemotherapeutics into malignant brain tumors and the surrounding microenvironment. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Pag1e
Virtually all malignant gliomas in children recur even after the most aggressive combination therapy, usually at the original site of presentation. Poor drug delivery is one of the important features which is responsible for treatment failure and recurrence. The studies outlined here in mice will set the stage for future treatment strategies and test a novel molecular strategy to selectively open the tumor barrier to enhance the delivery of chemotherapy agents into the brain and avoid systemic toxicity.
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