Using pulsed ultrasound to optimise drug delivery to brain tumours

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Published: 4 Feb 2016
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Dr Kévin Beccaria - Hôpital Necker, Paris, France

Dr Beccaria talks to ecancertv at Children with Cancer UK’s workshop on Drug Delivery in Paediatric Brain Tumours in London, UK.

In the interview he discusses how local delivery of pulsed ultrasound could help optimise drug delivery across the blood-brain barrier (BBB).

Dr Beccaria notes there have been many preclinical studies showing that the technology works and that the first clinical trial assessing BBB disruption with an implantable ultrasound device is now underway in adults with glioblastoma.

Many approaches have been proposed to open the blood-brain barrier and intra-arterial drugs, laser. All of these approaches have disadvantages – either toxicity, either diffuse and not focalised opening of the blood-brain barrier. The main advantage of focussed ultrasound opening of the blood-brain barrier is that, as I said, it’s a focussed opening so we can target a volume, a tumour or cavity, surgical cavity, and it has been shown that this is possible with few or no side effects.

How has the effect of pulsed ultrasound been tested to date?

Many preclinical studies on animals, on rats, mice, non-human primates, and in only one study that is being occurred in humans, actually in Paris. So many preclinical studies that have shown that the technique is possible, the technique is safe probably, probably safe. But now we have to go to the human clinics.

How is the ultrasound delivered?

There are two main techniques: you can deliver ultrasound through the bone because the main challenge with ultrasound in neuro-oncology is the problem of the skull because we know that to not cross the skull, the bone interface induces distortion, absorption of the ultrasound. So many teams have worked on delivering ultrasound through the bone with very complex. In my team we designed with a neurosurgeon in La Pitié-Salpêtrière Hospital in Paris, designed an implantable device that can be implanted into the skull so that we do not mind with the skull. We directly deliver the ultrasound on the brain parenchyma and it’s a classical ultrasound device.

What is the mechanism of action?

Ultrasound is delivered in conjunction with microbubbles, an intravenous injection of microbubbles. Microbubbles in the ultrasound beam are going to vibrate and this physical mechanism induces stimulation of the endothelial cells that constitute the blood-brain barrier. The first consequence is the opening of tight junctions that are very tight junctions between endothelial cells that are the particularity of the blood-brain barrier that impedes any drug to cross the blood-brain barrier. So opening of the tight junctions, it has been shown that it induces transcytosis, opening of cells with channels into the cells, and with high intensity ultrasound it can damage the blood-brain barrier, opening a large opening into the blood-brain barrier. But it’s almost opening of the tight junctions and transcytosis.

Can you tell us more about the implantable device you have developed?

This device has been designed to be useful for neurosurgeons. So it’s a small device that is about 1cm diameter and some 1.5cm deep that can be implanted in the classic bore hole that we do as neurosurgeons when we operate skulls. This device is totally MRI compatible so that we can survey, we can check patients with MRI without any interaction. This device can be implanted very simply during any surgical procedure including with local anaesthesia. It’s implanted only into the skull in and then it’s totally under the skin. The connection is a transcutaneous connection that can be done with a simple connection through the skin without any pain and when we want. So that the objective is to synchronise the opening of the blood-brain barrier with ultrasound to the chemotherapy protocol so that we can open the blood-brain barrier when we want during some hours and then diffuse the chemotherapy by intravenous injection. Because in this kind of technique the blood-brain barrier disruption is trenchant, it’s some hours, and then the disruption disappears and the blood-brain barrier closes.

What experience have you had with using the device to date?

We have 17 people that have been tested to date but the results are not official, the study is being done so that I cannot say more about this.

Would this approach be used in adults only or is it appropriate for use in children?

No, this technique, this approach, would be used in children as well and we would like, in my department, to use this technique in children in the next months. Implantation of the device can be done in adults, in children without any difference and as we can do the opening of the blood-brain barrier either on general anaesthesia or under local anaesthesia it can be done in children without any difficulty.

What about the safety of the approach, particularly in children?

The safety is being assessed, actually, with the phase I trial that is being occurred in Paris. But what we know is that from the preclinical studies that have been done in mice, in non-human primates, in dogs, in rats, is that with this approach the opening of the blood-brain barrier only induces some microvascular opening and microvascular haemorrhages, extravasation of some erythrocytes, blood cells, into the brain parenchyma. Some papers have shown that repeated disruption of the blood-brain barrier does not induce more side effects than single sessions. Some have assessed EEG modifications, metabolism modifications, behavioural modifications and we, up to date, have not seen any side effect about all of this with this technique. So it seems to be safe but the next protocols we will confirm it.

What’s the next step?

First to close, to finish the protocol that is being assessed in Paris actually with adults. We would like to first complete preclinical studies with new drugs, with drugs that are efficient on in vitro on high grade gliomas or DIPG for children for example. The next step is to open a new protocol, a phase I trial in children to check toxicity of this technique and check the feasibility of the technique in children. To envisage a secondary phase III/IV trial to try to evaluate the effect of the technique on gliomas, on DIPG, other brain tumours.

What is your take-home message?

The technique seems to be very encouraging, encouraging because it seems to have few side effects and with the technique we will be able, if it works, to deliver drugs focally with targeting and when we want by synchronising the technique with the standard chemotherapy protocols. I think that we have to encourage clinical trials with this technique because it seems to be a nice technique.