Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas

Matsukado, Koichiro; Sugita, Michiaki; Black, Keith L.

doi:10.1016/s0006-8993(97)01502-3

Cited by 58 publications

(40 citation statements)

References 31 publications

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“…However, increased transport across the BTB mediated by bradykinin and RMP-7 is transient (f15 minutes) and dependent on bradykinin-2 receptor expression in individual brain tumors (40). Moreover, the dose-limiting side effect of hypotension from both compounds has discouraged their clinical use (12).…”

Section: Discussionmentioning

confidence: 99%

Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

Yin

Xiao

Konda

et al. 2008

Clinical Cancer Research

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Purpose:The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability.We investigated the effects of NO donors, L-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats. Experimental Design:The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and L-arginine. BTB permeability, defined by the unidirectional transport constant, K i , for [ 14 C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, L-citrulline, and cGMP in the tumor and normal brain tissue were measured. Results: Oral administration of L-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (K Ca ) channel that is a cGMP pathway effector.The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, L-citrulline, a byproduct of NO formation from L-arginine, and cGMP were enhanced in the tumor tissue by oral administration of L-arginine and/ or hydroxyurea. Conclusions: Oral administration of L-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.

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Section: Discussionmentioning

confidence: 99%

Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

Yin

Xiao

Konda

et al. 2008

Clinical Cancer Research

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“…64,65 Intra-arterial administration of bradykinin and its stable analog RMP-7 (Cereport; Alkermes, Inc., Cambridge, MA, USA) to rats caused an increase in carboplatin penetration into the brain. 66 RMP-7 has been used in clinical trials for brain tumors along with carboplatin; however, clinical trials have been stopped at the level of Phases II and III due to its low efficacy, resulting from high concentrations of the antitumor preparation in the brain but not in the tumor. 67,68 In addition, it was reported that Cereport can be attached to the surface of a nanocarrier (liposome or polymeric nanoparticle), facilitating CNS penetration of drugs such as amphotericin B, stavudine, delavirdine, and saquinavir.…”

Section: Biological Stimulimentioning

confidence: 99%

Nanoscale drug delivery systems and the blood–brain barrier

Alyautdin¹,

Khalin²,

Nafeeza³

et al. 2014

IJN

121

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The protective properties of the blood–brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain’s vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual’s age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.

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“…Intracarotid administration of hyperosmotic solutions like mannitol 10 or vasodilators like bradykinin 11 transiently increases BBB permeability and aids drug delivery to the CNS. These methods, however, are invasive procedures that require general anesthesia and can have side effects.…”

Section: Introductionmentioning

confidence: 99%

Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier

Xiang¹,

Liu²,

Yang³

et al. 2014

IJN

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Methotrexate (MTX) is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%±0.86%, and their size (2.64±0.93 μm in diameter) was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood–brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3±2.4 μg/g) > unmodified ZHIFUXIAN + MTX + ultrasound (18.6±2.2 μg/g) > MTX alone (6.97±0.75 μg/g) > MTX-liposome-coupled microbubbles (2.92±0.39 μg/g). Therefore, treatment with MTX-liposome-coupled microbubbles and ultrasound resulted in a significantly higher brain MTX concentration than all other treatments ( P <0.01). These results suggest that MTX-liposome-coupled microbubbles may hold great promise as new and effective therapies for primary central nervous system lymphoma and other central nervous system malignancies.

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Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas

Cited by 58 publications

References 31 publications

Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

Nanoscale drug delivery systems and the blood–brain barrier

Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier

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Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas

Cited by 58 publications

References 31 publications

Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

Nanoscale drug delivery systems and the blood&ndash;brain barrier

Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood&ndash;brain barrier

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Product

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About

Nanoscale drug delivery systems and the blood–brain barrier

Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier