Blood-Brain Barrier Disruption Chemotherapy

The efficacy of chemotherapy for malignant brain tumors has in general been disappointing, due in part to the limited passage of many systemically administered agents from the blood to the brain. The blood–brain barrier (BBB) excludes molecules from the brain based on electric charge, lipid solubility, and molecular weight. The goal of chemotherapy administered in conjunction with blood–brain barrier disruption (BBBD) is maximizing drug delivery to the brain, while preserving neurocognitive function and minimizing systemic toxicity. Translational blood–brain barrier (BBB) pre-clinical and clinical studies at Oregon Health & Science University (OHSU) evaluate the toxicity and antitumor efficacy of chemotherapeutics, chemoprotectants, and monoclonal antibodies (mAbs) as well as novel therapeutics and imaging agents. Thiols may permit increased dose intensity of agents administered in conjunction with BBBD. A current program focus is thiol chemoprotection against the hearing and bone marrow toxicity that is caused by platinum chemotherapy. In the clinic, BBBD has shown promising results in chemosensitive brain tumors such as primary central nervous system lymphoma (PCNSL) and offers a new strategy for global delivery of chemotherapy to tumors, such as anaplastic oligodendroglioma and central nervous system metastases. Current and future clinical studies include delivery of monoclonal antibodies across the BBB.