title: Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances.
abstract: The blood-brain barrier (BBB) limits drug delivery to brain tumors. We utilize intraarterial infusion of hyperosmotic mannitol to reversibly open the BBB by shrinking endothelial cells and opening tight junctions between the cells. This approach transiently increases the delivery of chemotherapy, antibodies, and nanoparticles to brain. Our preclinical studies have optimized the BBB disruption (BBBD) technique and clinical studies have shown its safety and efficacy. The delivery of methotrexate-based chemotherapy in conjunction with BBBD provides excellent outcomes in primary central nervous system lymphoma (PCNSL) including stable or improved cognitive function in survivors a median of 12 years (range 2-26 years) after diagnosis. The addition of rituximab to chemotherapy with BBBD for PCNSL can be safely accomplished with excellent overall survival. Our translational studies of thiol agents to protect against platinum-induced toxicities led to the development of a two-compartment model in brain tumor patients. We showed that delayed high-dose sodium thiosulfate protects against carboplatin-induced hearing loss, providing the framework for large cooperative group trials of hearing chemoprotection. Neuroimaging studies have identified that ferumoxytol, an iron oxide nanoparticle blood pool agent, appears to be a superior contrast agent to accurately assess therapy-induced changes in brain tumor vasculature, in brain tumor response to therapy, and in differentiating central nervous system lesions with inflammatory components. This chapter reviews the breakthroughs, challenges, and future directions for BBBD.
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Doolittle
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA; Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Muldoon
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Aliana Y
authors.initials: AY
authors.lastname: Culp
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA; Department of Neurosurgery, Oregon Health and Science University, Portland, Oregon, USA; Office of Research and Development, Department of Veterans Affairs Medical Center, Portland, Oregon, USA. Electronic address: neuwelte@ohsu.edu.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Neuwelt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003287:Contrast Media / Q000493:pharmacokinetics; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism; D008279:Magnetic Resonance Imaging
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media
keywords: Blood–brain barrier; Blood–brain barrier disruption; Chemoprotection; Monoclonal antibody; Neuroimaging; Primary central nervous system lymphoma