Osmotic blood-brain barrier disruption. Computerized tomographic monitoring of chemotherapeutic agent delivery.

Neuwelt, Edward A.; Maravilla, Kenneth R.; Rapaport, Samuel I.; Hill, S. A.; Barnett, Peggy A.

doi:10.1172/jci109509

Cited by 139 publications

(78 citation statements)

References 10 publications

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“…This is usually done with a highly concentrated ($25%) solution of D-mannitol, a hypertonic agent that causes temporary and reversible disruption of the BBB. 55 A few protocols exist that inject mannitol intravenously through the femoral or the tail vein, 56 or intra-arterially through the common 1,2 or the external carotid artery. 3,4 After BBB disruption and upon brain stimulation, Mn 2þ accumulates in active regions on a short time scale (minutes), but as in the case of systemic administration discussed above, once accumulated it does not leave the regions for several hours.…”

Section: Activity-induced Manganese-enhanced Mri (Aim-mri)mentioning

confidence: 99%

Manganese‐enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations

et al. 2004

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Manganese-enhanced MRI (MEMRI) is being increasingly used for MRI in animals due to the unique T 1 contrast that is sensitive to a number of biological processes. Three specific uses of MEMRI have been demonstrated: to visualize activity in the brain and the heart; to trace neuronal specific connections in the brain; and to enhance the brain cytoarchitecture after a systemic dose. Based on an ever-growing number of applications, MEMRI is proving useful as a new molecular imaging method to visualize functional neural circuits and anatomy as well as function in the brain in vivo. Paramount to the successful application of MEMRI is the ability to deliver Mn 2þ to the site of interest at an appropriate dose and in a time-efficient manner. A major drawback to the use of Mn 2þ as a contrast agent is its cellular toxicity. Therefore, it is critical to use as low a dose as possible. In the present work the different approaches to MEMRI are reviewed from a practical standpoint. Emphasis is given to the experimental methodology of how to achieve significant, yet safe, amounts of Mn 2þ to the target areas of interest.

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Section: Activity-induced Manganese-enhanced Mri (Aim-mri)mentioning

confidence: 99%

Manganese‐enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations

et al. 2004

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“…Many available drugs with the potential to treat these diseases are not effectively delivered to the brain due to the physical hindrance and efflux transporters imposed by the BBB. There have been numerous attempts to overcome the hindrance of drug delivery by the BBB that include physical disruption of the BBB, drug modification for easier passage across the BBB, and intrathecal injection of drugs into the brain (7)(8)(9)(10). However, these approaches have suffered from shortcomings, including toxicity, decreased drug efficacy, and invasiveness, that can result in permanent brain damage.…”

Section: Introductionmentioning

confidence: 99%

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

Kim¹,

Bynoe²

2016

Journal of Clinical Investigation

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The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer's disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a timedependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.

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“…The BBBD process has been largely characterized in preclinical and clinical studies. [6][7][8][9][10][11] It is now used in the clinic regularly in some clinical centers with a demonstrated safety profile, and clear evidence of a therapeutic value. 12 The procedure has been shown to increase the survival of newly diagnosed GBM patients, with a median survival of 32.2 months.…”

Section: Introductionmentioning

confidence: 99%

Impact of Drug Size on Brain Tumor and Brain Parenchyma Delivery after a Blood–Brain Barrier Disruption

Blanchette

Tremblay

Lepage

et al. 2014

J Cereb Blood Flow Metab

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Drug delivery to the brain is influenced by the blood-brain barrier (BBB) and blood-tumor barrier (BTB) to an extent that is still debated in neuro-oncology. In this paper, we studied the delivery across the BTB and the BBB of compounds with different molecular sizes in normal and glioma-bearing rats. Studies were performed at baseline as well as after an osmotic BBB disruption (BBBD) using dynamic contrast-enhanced magnetic resonance imaging and two T 1 contrast agents (CAs), Magnevist (743 Da) and Gadomer (17,000 Da). More specifically, we determined the time window for the BBB permeability, the distribution and we calculated the brain exposure to the CAs. A different pattern of accumulation and distribution at baseline as well as after a BBBD procedure was observed for both agents, which is consistent with their different molecular size and weight. Baseline tumor exposure was threefold higher for Magnevist compared with Gadomer, whereas postBBBD tumor exposure was twofold higher for Magnevist. Our study clearly showed that the time window and the extent of delivery across the intact, as well as permeabilized BTB and BBB are influenced by drug size.

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Osmotic blood-brain barrier disruption. Computerized tomographic monitoring of chemotherapeutic agent delivery.

Cited by 139 publications

References 10 publications

Manganese‐enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations

Manganese‐enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

Impact of Drug Size on Brain Tumor and Brain Parenchyma Delivery after a Blood–Brain Barrier Disruption

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