this might be BIG---if it works similarly in humans!!!! selective BBB permeability

[Lani]

BBB=BLood-brain barrier

If it works should allow brain mets to be diagnosed much earlier when they are much smaller and for treatments which can cross the BBB to get at them

Technique Allows Anti-Breast Cancer Drugs to Cross Blood-Brain Barrier
[Journal of the National Cancer Institute]

Some breast cancer drugs can penetrate the blood-brain barrier (BBB), but they have not been very effective against brain metastases, whereas other, more effective anti-breast cancer drugs cannot penetrate the BBB at all. In a study published October 9 in the Journal of the National Cancer Institute, researchers used a new approach to selectively permeabilize the BBB at sites of brain metastases, even those 200 times smaller than currently detectable in the clinic.

To facilitate drug delivery to brain metastases, John Connell of the CRUK/MRC Gray Institute for Radiation Oncology and Biology, Churchill Hospital, Oxford, UK, and colleagues utilized the human pro-inflammatory cytokine, tumor necrosis factor (TNF), which they had previously shown could disrupt the BBB in rat brains.

The researchers first verified the expression of TNF receptors in mouse as well as human brain metastases by immunohistochemistry. They then induced brain metastases in mice by injection of mouse breast carcinoma cells labeled with green fluorescent protein. After metastases were detected by MRI, the researchers injected the mice with TNF or its analog, lymphotoxin (LT) and 2-24 hours later, the radiolabeled anti-breast cancer drug, trastuzumab.

Radiolabeled trastuzumab was detected at the cerebral metastases in mouse brains that had been treated with TNF, whereas the drug was excluded from metastases in control mice treated with saline solution. The same effect was observed in brain metastases of mice injected with human breast cancer cells. Importantly, BBB permeability lasted long enough to allow delivery of the drug, peaking at 6 hours and lasting 24 hours.

The authors conclude that the work represents ".a novel approach to facilitating the delivery of therapeutic and diagnostic agents to cerebral metastases by exploiting a previously unknown phenotype of the vasculature of brain metastases." Connell et al. note, however, that although TNF was effective in mice, variability in TNF receptors in humans could have different effects and that this new technique must be validated in clinical trials.

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Selective Permeabilization of the Blood–Brain Barrier at Sites of Metastasis
John J. Connell, Grégoire Chatain, Bart Cornelissen, Katherine A. Vallis, Alastair Hamilton, Len Seymour, Daniel C. Anthony and Nicola R. Sibson
+ Author Affiliations

Affiliations of authors: CRUK/MRC Gray Institute for Radiation Oncology and Biology, Churchill Hospital, Oxford, UK (JJC, GC, BC, KAV, AH, NRS); Department of Pharmacology (JJC, AH, DCA) and Department of Oncology (JJC, GC, BC, KAV, AH, LS, NRS), University of Oxford, Oxford, UK.
Correspondence to: Daniel C. Anthony, PhD, Experimental Neuropathology, Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK (e-mail: daniel.anthony@pharm.ox.ac.uk).
Received March 11, 2013.
Revision received August 30, 2013.
Accepted September 6, 2013.
Abstract

Background Effective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood–brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilizing the BBB at sites of cerebral metastases.

Methods BALB/c mice were injected intracardially to induce brain metastases. After metastasis induction, either tumor necrosis factor (TNF) or lymphotoxin (LT) was administered intravenously, and 2 to 24 hours later gadolinium- diethylenetriaminepentaacetic acid, horseradish peroxidase, or radiolabeled trastuzumab (111In-BnDTPA-Tz) was injected intravenously. BBB permeability was assessed in vivo using gadolinium-enhanced T1-weighted magnetic resonance imaging and confirmed histochemically. Brain uptake of 111In-BnDTPA-Tz was determined using in vivo single photon emission computed tomography/computed tomography. Endothelial expression of TNF receptors was determined immunohistochemically in both mouse and human brain tissue containing metastases. Group differences were analyzed with one-way analysis of variance followed by post hoc tests, Wilcoxon signed rank test, and Kruskal–Wallis with Dunn’s multiple comparison test. All statistical tests were two-sided.

Results Localized expression of TNF receptor 1 (TNFR1) was evident on the vascular endothelium associated with brain metastases. Administration of TNF or LT permeabilized the BBB to exogenous tracers selectively at sites of brain metastasis, with peak effect at 6 hours. Metastasis-specific uptake ratio of 111In-BnDTPA-Tz was also demonstrated after systemic TNF administration vs control (0.147±0.066 vs 0.001±0.001). Human brain metastases displayed a similar TNF receptor profile compared with the mouse model, with predominantly vascular TNFR1 expression.

Conclusions These findings describe a new approach to selectively permeabilize the BBB at sites of brain metastases to aid in detection of micrometastases and facilitate tumor-specific access of chemotherapeutic agents. We hypothesize that this permeabilization works primarily though TNFR1 activation and has the potential for clinical translation.

© The Author 2013. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.