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Using tnf to break down the blood brain barrier and allow drugs in
SPECT detection of labelled trastuzumab at sites of metastases (arrowed)

Effective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood–brain barrier (BBB). In a ground breaking study, funded by Cancer Research UK, Oxford Scientists led by  Daniel Antony and Nicola Sibson have found a way of delivering drugs more effectively to tumours in the brain. The team included scientists from the Gray Institute for Radiation Oncology and Biology, the Department of Pharmacology and Department of Oncology.

Writing in the Journal of the National Cancer Institute, Connell et al., described how they utilized TNF receptor expression on vascular endothelium associated with brain metastases to selectively disrupt the BBB in these regions. Mice with experimentally induced brain metastases were treated with low dose TNF and subsequently 111 Indium labelled trastuzumab, also known as herceptin, (111In-BnDTPA-Tz); which does not normally cross the BBB.

Selective permeabilization of the BBB at the sites of metastases was determined using gadolinium-enhanced T1-weighted MRI and confirmed histochemically.  Brain uptake of 111In-BnDTPA-Tz was determined using in vivo single photon emission computed tomography (SPECT). Isolated regions of increased SPECT signal were evident within the brain and associated histologically with sites of metastases. The team confirmed their results in an alternative model of metastases using a human breast cancer derived cell line MDA231BR-GFP. 

Nicola Sibson, said: “Treatments that work very well against the original site of the cancer lose their effectiveness when the cancer spreads to the brain – as these drugs are prevented from getting to the tumour because of the blood-brain-barrier. A number of attempts have been made to open up the BBB but they’ve all struggled because they’re either not specific enough to open the BBB only at the site of the tumour or not effective enough to allow the drug across to kill the cancer.”

The findings need to be confirmed in models that more closely reflect the situation in human cancer.  However, they provide hope that the technique will enhance our ability to deliver anticancer drugs and diagnostic imaging agents to the brain.