A new approach selectively permeabilizes the blood-brain barrier (BBB) at sites of brain metastases, even those 200 times smaller than currently detectable in the clinic. This newly published approach to deliver drugs to brain metastases uses tumor necrosis factor (TNF), which is a human proinflammatory cytokine that had previously been shown to be able to disrupt the BBB in rat brains.
Although some breast cancer drugs can penetrate the BBB, they have not been very effective against brain metastases, whereas other more effective antibreast cancer drugs cannot penetrate the BBB at all.
The researchers, led by DPhil student John Connell of the CRUK/MRC Gray Institute for Radiation Oncology and Biology, Churchill Hospital in Oxford, United Kingdom, 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 revealed on MRI, the researchers injected the mice with TNF or its analog, lymphotoxin (LT), and, after 2 to 24 hours, they injected the radiolabeled antibreast cancer drug, trastuzumab.
Radiolabeled trastuzumab was detected at the cerebral metastases in the brains of the mice that had been treated with TNF, whereas the drug was excluded from metastases in the control mice that had been treated with saline solution. The same effect was observed in brain metastases of mice injected with human breast cancer cells. Importantly, blood-brain barrier permeability lasted long enough to allow delivery of the drug, peaking at 6 hours and lasting 24 hours. This study was study published in the Journal of the National Cancer Institute (2013; doi:10.1093/jnci/djt276).
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.” They noted, however, that although TNF was effective in mice, variability in TNF receptors in humans could have different effects, and so this new technique must be validated in clinical trials.