̽��ֱ�� of Cambridge - radiotherapy

“Trojan horse” treatment could beat brain tumours

tdk25 — Wed, 13 Aug 2014 07:00:12 +0000

A “Trojan horse” treatment for an aggressive form of brain cancer, which involves using tiny nanoparticles of gold to kill tumour cells, has been successfully tested by scientists.

̽��ֱ��ground-breaking technique could eventually be used to treat glioblastoma multiforme, which is the most common and aggressive brain tumour in adults, and notoriously difficult to treat. Many sufferers die within a few months of diagnosis, and just six in every 100 patients with the condition are alive after five years.

̽��ֱ��research involved engineering nanostructures containing both gold and cisplatin, a conventional chemotherapy drug. These were released into tumour cells that had been taken from glioblastoma patients and grown in the lab.

Once inside, these “nanospheres” were exposed to radiotherapy. This caused the gold to release electrons which damaged the cancer cell’s DNA and its overall structure, thereby enhancing the impact of the chemotherapy drug.

̽��ֱ��process was so effective that 20 days later, the cell culture showed no evidence of any revival, suggesting that the tumour cells had been destroyed.

While further work needs to be done before the same technology can be used to treat people with glioblastoma, the results offer a highly promising foundation for future therapies. Importantly, the research was carried out on cell lines derived directly from glioblastoma patients, enabling the team to test the approach on evolving, drug-resistant tumours.

̽��ֱ��study was led by Mark Welland, Professor of Nanotechnology at the Department of Engineering and a Fellow of St John’s College, ̽��ֱ�� of Cambridge, and Dr Colin Watts, a clinician scientist and honorary consultant neurosurgeon at the Department of Clinical Neurosciences. Their work is reported in the Royal Society of Chemistry journal, Nanoscale.

“ ̽��ֱ��combined therapy that we have devised appears to be incredibly effective in the live cell culture,” Professor Welland said. “This is not a cure, but it does demonstrate what nanotechnology can achieve in fighting these aggressive cancers. By combining this strategy with cancer cell-targeting materials, we should be able to develop a therapy for glioblastoma and other challenging cancers in the future.”

To date, glioblastoma multiforme (GBM) has proven very resistant to treatments. One reason for this is that the tumour cells invade surrounding, healthy brain tissue, which makes the surgical removal of the tumour virtually impossible.

Used on their own, chemotherapy drugs can cause a dip in the rate at which the tumour spreads. In many cases, however, this is temporary, as the cell population then recovers.

“We need to be able to hit the cancer cells directly with more than one treatment at the same time” Dr Watts said. “This is important because some cancer cells are more resistant to one type of treatment than another. Nanotechnology provides the opportunity to give the cancer cells this ‘double whammy’ and open up new treatment options in the future.”

In an effort to beat tumours more comprehensively, scientists have been researching ways in which gold nanoparticles might be used in treatments for some time. Gold is a benign material which in itself poses no threat to the patient, and the size and shape of the particles can be controlled very accurately.

When exposed to radiotherapy, the particles emit a type of low energy electron, known as Auger electrons, capable of damaging the diseased cell’s DNA and other intracellular molecules. This low energy emission means that they only have an impact at short range, so they do not cause any serious damage to healthy cells that are nearby.

In the new study, the researchers first wrapped gold nanoparticles inside a positively charged polymer, polyethylenimine. This interacted with proteins on the cell surface called proteoglycans which led to the nanoparticles being ingested by the cell.

Once there, it was possible to excite it using standard radiotherapy, which many GBM patients undergo as a matter of course. This released the electrons to attack the cell DNA.

While gold nanospheres, without any accompanying drug, were found to cause significant cell damage, treatment-resistant cell populations did eventually recover several days after the radiotherapy. As a result, the researchers then engineered a second nanostructure which was suffused with cisplatin.

̽��ֱ��chemotherapeutic effect of cisplatin combined with the radiosensitizing effect of gold nanoparticles resulted in enhanced synergy enabling a more effective cellular damage. Subsequent tests revealed that the treatment had reduced the visible cell population by a factor of 100 thousand, compared with an untreated cell culture, within the space of just 20 days. No population renewal was detected.

̽��ֱ��researchers believe that similar models could eventually be used to treat other types of challenging cancers. First, however, the method itself needs to be turned into an applicable treatment for GBM patients. This process, which will be the focus of much of the group’s forthcoming research, will necessarily involve extensive trials. Further work needs to be done, too, in determining how best to deliver the treatment and in other areas, such as modifying the size and surface chemistry of the nanomedicine so that the body can accommodate it safely.

Sonali Setua, a PhD student who worked on the project, said: “It was hugely satisfying to chase such a challenging goal and to be able to target and destroy these aggressive cancer cells. This finding has enormous potential to be tested in a clinical trial in the near future and developed into a novel treatment to overcome therapeutic resistance of glioblastoma.”

Welland added that the significance of the group’s results to date was partly due to the direct collaboration between nanoscientists and clinicians. “It made a huge difference, as by working with surgeons we were able to ensure that the nanoscience was clinically relevant,” he said. “That optimises our chances of taking this beyond the lab stage, and actually having a clinical impact.”

̽��ֱ��full research paper can be found at: http://dx.doi.org/10.1039/c4nr03693j

A smart technology which involves smuggling gold nanoparticles into brain cancer cells has proven highly effective in lab-based tests.

By combining this strategy with cancer cell-targeting materials, we should be able to develop a therapy for glioblastoma and other challenging cancers in the future

Mark Welland

M Welland

A cancer cell containing the nanoparticles. ̽��ֱ��nanoparticles are coloured green, and have entered the nucleus, which is the area in blue

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Project to improve radiotherapy planning

amb206 — Mon, 30 Jan 2012 09:54:10 +0000

Radiation therapy (radiotherapy) is an essential part of cancer treatment and is used in the treatment of 40 per cent of all patients who are cured of their disease. All radiotherapy treatments work by the application of ionising radiation to malignant cells in tumours. ̽��ֱ��free radicals released by this process damage the DNA of the exposed tissue, killing off the cancerous cells. By targeting the radiation to the tumour, the damage to surrounding healthy tissue is minimised.

Modern radiotherapy machines can now deliver highly targeted radiotherapy treatment. However, the use of high precision radiotherapy techniques is extremely demanding in terms of hours spent, from the physician who defines the tumour target and healthy tissues, to the physicist who has to calculate a plan of optimum beam angles and trajectories for the treatment, and the radiographer, who must ensure that the treatment is delivered accurately to the target every day during a six or seven week course of radiotherapy.

Accel-RT is an innovative partnership between oncologists, physicists and computer scientists at the Universities of Cambridge and Oxford. Over the next three years the collaborators will develop software tools and processes that will speed up the process of planning of radiotherapy. Once completed, free software tools will be available to radiotherapy treatment centres. These tools will increase patient access to high precision radiotherapy by reducing the bottle-necks in the clinical workflow. ̽��ֱ��system will operate as a 'virtual oncologist', observing what the oncologist is treating and using novel search algorithms to recall similar cases from a clinical archive. Models of tissue structures will be used to help outline normal tissue automatically, as well as to track the movement of these structures during the course of radiotherapy treatment.

Accel-RT is being funded by the Science and Technologies Facilities Council (STFC), through its Innovations Partnership Scheme, and will benefit from the support of Siemens Healthcare, a leading supplier of imaging technology and radiotherapy treatment devices throughout the world.

̽��ֱ��key players in the project are established leaders in their fields. At the ̽��ֱ�� of Cambridge, Dr Neil Burnet has been an 'early adopter' of novel radiotherapy technologies at Addenbrooke's, from the commissioning of the first in-house 3D computerised treatment planning system, through to the evaluation of the TomoTherapy image guided intensity modulated radiotherapy system conducted for the Department of Health. At Oxford ̽��ֱ��, Professor Jim Davies and his team from the Department of Computer Science have experience in the handling of 'smart' data systems - using metadata elements to allow data to be searched and processed in more intuitive ways.

Professor Andy Parker and his team at the High Energy Physics group in Cambridge have extensive experience in the storage and handling of large quantities of image data, and the use of grid computing techniques to accelerate this process. "In essence, Accel-RT is helping to identify tumours and surrounding organs during the planning and delivery of radiotherapy treatment. Tracking the change in position and volume of these structures is a complex problem. To perform these calculations in real time for a single patient would require up to 16 Teraflops of processing power – approximately 100 times the power of a standard PC workstation,” said Professor Parker, who is Professor of High Energy Physics at the Cavendish Laboratory and Principal Investigator for Accel-RT.

For more details about the project, and to register for project news emails, go to www.accelrt.org.

A collaborative project between physicists, oncologists and computer scientists at Oxford and Cambridge Universities, launched last month, will develop improved tools for the planning of high precision radiotherapy. Accel-RT will also help overcome time constraints that currently limit the use of complex radiotherapy treatment.

̽��ֱ��system will operate as a 'virtual oncologist', observing what the oncologist is treating and using novel search algorithms to recall similar cases from a clinical archive.

Andy Parker

Neil Burnet

Image-guided intensity modulated RT plan for a patient with a spinal tumour. ̽��ֱ��radiation dose is shaped away from the kidneys (yellow outlines) and the spinal nerve roots (inside the green outline). ̽��ֱ��colour wash represents radiation dose

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