Delivering drugs better - using sound

Supplementary content information

Professor Constantin Coussios and colleagues on using ultrasound to deliver drugs much closer to tumours and other targets in the body

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Constantin Coussios – Professor of Biomedical Engineering, University of Oxford [CC]

I first became involved with High Intensity Focus Ultrasound (HIFU) in 2004 when I moved to Oxford. One can actually focus sound in the same way as one can focus light. What you actually are dealing with is an ultrasound transducer, loud speaker in effect, which has got a certain shape that allows us to bend the sound onto a specific location onto a region about the size of a grain of rice, at an almost arbitrary depth within the body. We are gradually moving towards and pioneering the ability to do the drug delivery not with a high powered loud speaker, but something that looks much closer to a diagnostic ultrasound device, so something that is simpler, lighter, safer for the patient and more readily available to hospital units around the world. Where the ultrasound hits cancerous tissue tiny bubbles are actually created and excited by the ultrasound and as these bubbles pulsate they act as micro-pumps that help push the drug into the tumour.

Dr Robert Carlisle – University Lecturer, Institute of Biomedical Engineering [RC]

One of the biggest challenges in delivering chemotherapeutic drugs is that when we inject them intravenously they immediately disperse into all our organs and tissues and this gives us very nasty side effects. So what we want is a much more targeted way of delivering drugs so they get to the tumour and don't hit our normal healthy tissue.

[CC]

The farthest cancer cell from a blood vessel has been reported to be about 150 microns, this is .15 of a millimetre so when delivering a drug what you want is to make sure that it actually exceeds .15 of a millimetre travel distance from the nearest blood vessel. No one has ever previously demonstrated the ability to deliver drugs that far. What we have demonstrated for the first time is that with the addition of ultrasound and cavitation we can deliver drugs as far as .2 or even .25 millimetres from the nearest blood vessel.

Fergus Gleeson – Consultant Radiologist, Oxford University Hospitals [FG]

If you imagine the sun and you focus it on a leaf, with a magnifying glass, it burns a hole in the leaf by concentrating the sun's rays. High Intensity Focused Ultrasound (HIFU) works in exactly the same way. What we intend here is to raise the temperature of the body, but not nearly enough to cause a burn, just enough to release the drug when it is in its capsule.

[RC]

This drug formulation contains a very conventional and old chemotherapeutic agent within a sphere of what we call lipid and cholesterol. Lipid and cholesterol is essentially what is in butter and just like butter the formulation we use in response to being heated, melts and loses its structure and in doing so the drug is released.

[CC]

Typically when a drug is injected into a patient, less than half a per cent of that total drug dose will actually make it to the target tumour. Using the thermal and mechanical effects of ultrasound, that drug dose recovered can be as much as 25 per cent.

We are about to initiate this summer a first in man trial of ultrasound and harm/stroke delivery for cancer, whereby patients will be treated in Oxford. Patients who have metastatic liver disease will be given this thermo sensitive liposome which will be non-invasively triggered using a clinical and high intensity focus ultrasound device.

[FG]

Once we have managed the trial and shown it works, then there are other drugs which could be put in the lipids. There are other tumours, renal tumours, tumours in the abdomen, they can be soft tissue tumours, so it will open up a complete new branch of therapy.

[CC]

It is the very first time that these strategies are being tried in man and we are very excited if some of the benefits that we have been seeing in pre-clinical models, the much higher concentration of drug accumulated in the tumour and the ability to achieve drug delivery on demand, are actually realised in humans, it will most probably change the face of oncology for decades to come.