The Challenge of the Blood-Brain Barrier

Neuwelt, Edward A.

doi:10.1007/978-1-4613-0701-3_1

Cited by 16 publications

(9 citation statements)

References 41 publications

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“…For example, (1) a marked increase in brain and CSF concentrations of MTX were documented after BBBD with IA chemotherapy administration (Kroll & Neuwelt, 1998; Neuwelt, 1989; Neuwelt, Frenkel, Rapoport, & Barnett, 1980), (2) disruption of the BBB provides global delivery throughout the disrupted hemisphere, but delivery is variable depending on the brain region and the type and size of tumor, (3) vascular permeability to small molecules such as MTX, as well as large molecules such as mAbs, is increased maximally by 15 min after mannitol infusion, and (4) BBB permeability rapidly decreases, returning to preinfusion levels within 2 h after BBBD.…”

Section: Discussionmentioning

confidence: 99%

Delivery of Chemotherapeutics Across the Blood–Brain Barrier

Doolittle

Muldoon

Culp

et al. 2014

Advances in Pharmacology

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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.

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Section: Discussionmentioning

confidence: 99%

Delivery of Chemotherapeutics Across the Blood–Brain Barrier

Doolittle

Muldoon

Culp

et al. 2014

Advances in Pharmacology

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“…Ross et al (5) have also reported significant changes in tumor doubling times after direct inoculation of a tk-expressing adenovirus into intracranial gliomas. While the precise mechanism for this growth retardation by the "bystander effect" is currently unknown, some studies have suggested a role for the immune system in mediating this effect (18,19 (6,22). …”

Section: Methodsmentioning

confidence: 99%

“…Intraarterial (i.a.) administration of hypertonic mannitol leads to a reversible and transient opening of the BBB (6). We have previously demonstrated the feasibility of global delivery of a variety of agents including antibodies, chemotherapeutic drugs, and imaging agents throughout the cerebral hemisphere after osmotic modification of the BBB (6,8).…”

mentioning

confidence: 99%

“…The scheme of using retroviral vector packaging cell lines to transfer HSV-tk to brain tumor cells has recently been approved for use in human subjects following the encouraging results of preliminary in vitro and animal experiments. Antitumor activity has been observed, but gene delivery was observed only 5-25 cell diameters from the injection site.tt Our laboratory has been studying ways of facilitating greater access of therapeutic agents to brain and intracerebral neoplasms by temporary osmotic opening of the blood-brain barrier (BBB) (6). The BBB is a single layer of brain capillary endothelial cells that are bound together by tight junctions, which excludes entry of blood-borne molecules >180 Da and particularly large and complex biological molecules such as viruses from the brain (6,7).…”

mentioning

confidence: 99%

“…Antitumor activity has been observed, but gene delivery was observed only 5-25 cell diameters from the injection site.tt Our laboratory has been studying ways of facilitating greater access of therapeutic agents to brain and intracerebral neoplasms by temporary osmotic opening of the blood-brain barrier (BBB) (6). The BBB is a single layer of brain capillary endothelial cells that are bound together by tight junctions, which excludes entry of blood-borne molecules >180 Da and particularly large and complex biological molecules such as viruses from the brain (6,7). Even the leaky barrier at the brain-tumor interface is relatively impermeable to such particles.…”

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confidence: 99%

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Delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood-brain barrier disruption.

Nilaver

Muldoon²,

Kroll

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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The delivery of viral vectors to the brain for treatment of intracerebral tumors is most commonly accomplished by stereotaxic inoculation directly into the tumor. However, the small volume of distribution by inoculation may limit the efficacy of viral therapy of large or disseminated tumors. We have investigated mechanisms to increase vector delivery to intracerebral xenografts of human LX-1 small-cell lung carcinoma tumors in the nude rat. The distribution of Escherichia coli lacZ transgene expression from primary viral infection was assessed after delivery of recombinant virus by intratumor inoculation or intracarotid infusion with or without osmotic disruption of the blood-brain barrier (BBB). These studies used replication-compromised herpes simplex virus type 1 (HSV; vector RH105) and replication-defective adenovirus (AdRSVlacZ), which represent two of the most commonly proposed viral vectors for tumor therapy. Transvascular delivery of both viruses to intracerebral tumor was demonstrated when administered intraarterially (i.a.) after osmotic BBB disruption (n = 9 for adenovirus; n = 7 for HSV), while no virus infection was apparent after i.a. administration without BBB modification (n = 8 for adenovirus; n = 4 for HSV). The thymidine kinase-negative HSV vector infected clumps of tumor cells as a result of its ability to replicate selectively in dividing cells. Osmotic BBB disruption in combination with i.a. administration of viral vectors may offer a method of global delivery to treat disseminated brain tumors.

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The Choroid Plexus—CSF Nexus

Johanson¹

2003

Neuroscience in Medicine

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The Challenge of the Blood-Brain Barrier

Cited by 16 publications

References 41 publications

Delivery of Chemotherapeutics Across the Blood–Brain Barrier

Delivery of Chemotherapeutics Across the Blood–Brain Barrier

Delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood-brain barrier disruption.

The Choroid Plexus—CSF Nexus

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