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Targeted delivery

A new minimally invasive procedure that attacks cancerous cells only at the site of diseased tissue is claimed to cause patients fewer ill effects.

A new minimally invasive procedure that attacks cancerous cells only at the site of diseased tissue is claimed to cause patients fewer ill effects.

The treatment, which is being studied by researchers at Philips Research and various academic institutions, involves injecting patients with microscopic polymer bubbles filled with anti-cancer drugs. The bubbles are then tracked in the bloodstream with ultrasound imaging and burst using a focused ultrasound pulse to release the drugs at the desired spot.

'Traditional chemotherapy is administered to every part of the body and is certainly an effective therapy for patients, but it does have side effects,' said Steve Klink, a spokesman for Philips. 'One way to reduce these is to reduce the dose,' he added.

But he added that while this may cut down on the side effects, it will also reduce the effectiveness.

Klink explained that with the new method the drugs are only administered to the region where they are needed. 'Of course, the microbubbles also reach other regions of the body as they travel through the bloodstream, but since the drugs are encapsulated in a microbubble patients will not feel any side effects.' he said.

Philips is working with several academic partners, including the University of Virginia in the US, where pre-clinical experiments are being performed on mice, and the University of Münster in Germany to refine the technology. Clinical trials, said Klink, are no nearer than five years away.

This is not the first use of microbubbles with medical ultrasound imaging. In current clinical practice, doctors use gas-filled microbubbles as contrast agents. Microbubbles can be used, for example, to highlight blood in ultrasound images because they reflect ultrasound waves better than blood or soft tissue.

This latest drug delivery technology being developed at Philips continues to use the contrast-enhancing capabilities of microbubbles so that ultrasound operators can locate tumours, which appear as dense masses surrounded by a network of small blood vessels.

The new part of the technology involves shattering the microbubble shells in the blood vessels using a focused high-energy ultrasound pulse. As a result of this, the drugs in the microbubbles are released directly inside the tumour.

Klink said the microbubbles are typically less than five microns across, which is about the size of a red blood cell, and their shell is made of polylactic acid — a biodegradable, thermoplastic polyester derived from renewable sources such as corn starch.

'We have developed a way to incorporate a liquid that contains the anti-cancer drug inside the microbubble,' he said, adding that the bubbles are only partly filled. 'We want to maintain air in them so the bubbles still retain their contrast agent capabilities. The air also allows the bubbles to burst easier.'

The bubbles are created by mixing a solution consisting of a carrier solvent, an oil that can be removed after freeze-drying, another oil with an anti-cancer drug dissolved in it and a polymer.

Inkjet droplets of this solution are dropped into water where they form into polymer capsules. The capsules are then freeze-dried, which results in polymer microbubbles filled with anti-cancer drugs and air.

Klink said the other innovation involved in the research is a computer-controlled ultrasound device that can steer and focus the microbubble-rupturing ultrasound pulses.

Philips researchers developed a special phased-array transducer that can focus ultrasound pulses into a small ellipsoidal volume up to 10cm deep in the target tissue.

In the experimental prototype developed by Philips, the phased array transducer is co-aligned with a standard clinical imaging transducer so that the ultrasound imaging and drug delivery could be performed simultaneously.

The researchers believe they may be able to make use of the way microbubbles generate their own acoustic signal when they burst. This information could help doctors tell how many microbubbles have ruptured, which could allow them to quantify and control drug dosage.

Beyond this drug delivery application, Philips researchers believe their transducer might also be optimised to produce other bio-effects such as thrombolysis (clot busting). The microbubble payload delivery system could also have applications in gene therapy.

Siobhan Wagner




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