Chemotherapy system proves successful in pre-clinical study

A chemotherapy delivery system that combines ultrasound and MRI has been shown to increase dosage to tumours while potentially limiting harmful side effects.

The technology has been in development by Philips Electronics and Eindhoven University of Technology for around three years, but it is the first time this particular technique has been demonstrated in a pre-clinical, proof-of-concept study.

Chemotherapy is still part of the treatment regime for around half of all cancer patients. Once administered, the chemotherapy drugs circulate freely in the bloodstream and attack rapidly dividing cells, including cancer cells.

However, they also attack normal healthy dividing cells, such as those in bone marrow and the digestive tract, causing side effects ranging from anaemia (reduced red-blood-cell count) and neutropenia (reduced white-blood-cell count) to bleeding and an increased risk of opportunistic infections.

Chemotherapy is also complicated by the fact that tumours are not homogenous in their blood supply and, as a result, drugs are not taken up evenly, with poorly perfused regions receiving suboptimal doses. This is believed to be one of the reasons why tumours sometimes re-grow after what at first appears to be successful therapy.

The research group, led by Holger Grüll of Eindhoven, developed a prototype system to try and mitigate some of these pitfalls.

First, cancer patients would undergo an MRI scan to localise the exact size and location of the tumour. Based on the scans, the tumour is then heated using a high-intensity focused ultrasound (HIFU) beam to around 42oC with a precision of +/-0.8oC. MRI can also sense internal temperature changes.

Patients are then injected with tiny temperature-sensitive particles called liposomes that contain the chemotherapy drug and an MRI contrast agent.

These liposomes travel throughout the body in the bloodstream but crucially only release their payload when they arrive at the tumour, which is at a higher temperature than the rest of the body. The liposomes remain sealed and stable in other parts of the body that are at the normal temperature of 37oC.

In addition, contrast agent is released along with the drug, allowing the direct measurements and feedback of drug uptake in the tumour and surrounding tissue.

Matthew Harris from Philips Research explained that this is one of the key strengths of the system.

‘In some tumours, you have a centre part that is no longer supplied with blood, and so the chemotherapy cannot reach that part and cannot kill it,’ he said. ’It takes the body months to break down the dead tumour cells — but the centre can be revitalised and start spreading again.

‘The trouble is that you can’t tell this until months later when the tumour has shrunk after the dead cells have cleared. With this [system], you’re able to visualise which parts of the tumour have been reached immediately after treatment.’

In such a situation, oncologists would consider alternative therapies to try and kill off the remaining tumour.

The prototype system is based on a Sonalleve 3-Tesla MRI-HIFU scanner — a commercially available product that is currently used to treat uterine fibroids, a non-cancerous but painful growth experienced by some women. In this case, the MRI scanner locates the fibroids and literally ‘cooks them’ to 60–70oC in a process called ablation. This differs from the ‘mild hyperthermia’ used in the current application.

In the pre-clinical study, which was performed on rats, uptake of the anti-cancer agent doxorubicin was found to be increased by between two- and five-fold in induced tumours compared with regular chemotherapy delivery.

The most recent collaborative work is part of the EU-funded (Framework 7) European Research project ‘Sonodrugs’.

Another arm of this research looks at sonoporation, which also combines ultrasound and MRI, but to burst microbubbles at the site of drug delivery.