Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by
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BioMed Central
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Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life Hemant Sarin*1,2, Ariel S Kanevsky2, Steve H Fung3, John A Butman2, Robert W Cox4, Daniel Glen4, Richard Reynolds4 and Sungyoung Auh5 Address: 1National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA, 2Radiology and Imaging Sciences Program, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA, 3Neuroradiology Department, Massachusetts General Hospital, Boston, Massachusetts 02114, USA, 4Scientific and Statistical Computing Core, National Institute of Mental Health, Bethesda, Maryland 20892, USA and 5Biostatistics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA Email: Hemant Sarin* - [email protected]; Ariel S Kanevsky - [email protected]; Steve H Fung - [email protected]; John A Butman - [email protected]; Robert W Cox - [email protected]; Daniel Glen - [email protected]; Richard Reynolds - [email protected]; Sungyoung Auh - [email protected] * Corresponding author
Published: 13 May 2009 Journal of Translational Medicine 2009, 7:33
doi:10.1186/1479-5876-7-33
Received: 25 March 2009 Accepted: 13 May 2009
This article is available from: http://www.translational-medicine.com/content/7/1/33 © 2009 Sarin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas. Methods: Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadoliniumdiethyltriaminepentaacetic acid (Gd-DTPA), a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1st bolus
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