The blood-brain barrier: Bottleneck in brain drug development

Pardridge, William M.

doi:10.1602/neurorx.2.1.3

Cited by 2,153 publications

(1,231 citation statements)

References 75 publications

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“…Additional complications such as hypertension can exacerbate cerebral edema after stroke in patients with DM 23. Understanding the mechanism and consequences of BBB disruption after stroke and in particular diabetic stroke are essential to developing therapeutics 24, 25…”

Section: Blood–brain Barrier Disruption In Diabetic Strokementioning

confidence: 99%

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

Venkat

Chopp

Chen

2017

JAHA

113

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Section: Blood–brain Barrier Disruption In Diabetic Strokementioning

confidence: 99%

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

Venkat

Chopp

Chen

2017

JAHA

113

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“…Although exceptions exist, drugs that cross the BBB are typically lipid soluble, uncharged, less than 500 D, and not rapidly transported out of the CNS. 45 For example, erlotinib (Tarceva) is an efficacious drug in the treatment of non-small cell lung cancer brain metastases, with all of the aforementioned properties. 22 Designing effective drugs with all of these characteristics has been challenging, and recent efforts have focused on increasing CNS bioavailability through other means.…”

Section: Background the Blood-brain And Blood-tumor Barriersmentioning

confidence: 99%

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

Lamsam¹,

Johnson²,

Connolly³

et al. 2018

Neurosurgical Focus

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Magnetic resonance–guided focused ultrasound (MRgFUS) has been used extensively to ablate brain tissue in movement disorders, such as essential tremor. At a lower energy, MRgFUS can disrupt the blood-brain barrier (BBB) to allow passage of drugs. This focal disruption of the BBB can target systemic medications to specific portions of the brain, such as for brain tumors. Current methods to bypass the BBB are invasive, as the BBB is relatively impermeable to systemically delivered antineoplastic agents. Multiple healthy and brain tumor animal models have suggested that MRgFUS disrupts the BBB and focally increases the concentration of systemically delivered antitumor chemotherapy, immunotherapy, and gene therapy. In animal tumor models, combining MRgFUS with systemic drug delivery increases median survival times and delays tumor progression. Liposomes, modified microbubbles, and magnetic nanoparticles, combined with MRgFUS, more effectively deliver chemotherapy to brain tumors. MRgFUS has great potential to enhance brain tumor drug delivery, while limiting treatment toxicity to the healthy brain.

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“…The majority of the drugs typically used to treat metastatic brain tumors are not able to cross the blood-brain barrier (Pardridge 2005). Thus, patients with multiple brain metastases are often selected for whole brain radiotherapy (WBRT) simply because it is the only option available.…”

Section: Introductionmentioning

confidence: 99%

Investigation of Abscopal and Bystander Effects in Immunocompromised Mice After Exposure to Pencilbeam and Microbeam Synchrotron Radiation

et al. 2016

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Out-of-field effects are of considerable interest in radiotherapy. The mechanisms are poorly understood but are thought to involve signalling processes, which induce responses in non-targeted cells and tissues. The immune response is thought to play a role. The goal of this research was to study the induction of abscopal effects in the bladders of NU-Foxn1 nu mice after irradiating their brains using pencil Beam (PB) or microbeam (MRT) irradiation at the European Synchrotron Radiation Facility (ESRF) in Grenoble France. Athymic nude mice injected with F98 glioma cells into their right cerebral hemisphere 7 days earlier were treated with either MRT or PB.After recovery times of 2, 12 and 48h, the urinary bladders were extracted and cultured as tissue explants for 24h. The growth medium containing the potential signalling factors was harvested, filtered and transferred to HaCaT reporter cells to assess their clonogenic survival and calcium signalling potential. The results show that in the tumour free-mice both treatment modalities produce strong bystander/abscopal signals using the clonogenic reporter assay, however the calcium data do not support a calcium channel mediated mechanism.The presence of tumour reduces or reverses the effect. PB produced significantly stronger effects in the bladders of tumour bearing animals. We conclude that immunocompromised mice produce signals, which can alter the response of unirradiated reporter cells, however a novel mechanism appears to be involved.

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The blood-brain barrier: Bottleneck in brain drug development

Cited by 2,153 publications

References 75 publications

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

Investigation of Abscopal and Bystander Effects in Immunocompromised Mice After Exposure to Pencilbeam and Microbeam Synchrotron Radiation

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