Pipe-line for rapid screening and rational improvement of nanoparticles for cancer imaging and therapy

Heavy ion beam radiotherapy has been shown to be a highly effective way to treat many types of cancer, both in Japan and Germany. However, this approach requires large, expensive facilities of a kind not currently foreseen in the UK. There are two reasons for this approach being so effective:

i) Because the ions in these beams deposit most of their energy just before they come to rest, they can be used to pick out each part of the tumour in turn, with the patient suffering much lower side effects than those associated with traditional approaches, i.e. their effect is highly targeted.
ii) Each ion in the beam gives a 'punch' to the cells it passes through just before it stops. This punch is much more intense and highly focused than photons used in traditional radiotherapy. This localised punch can knock out even the most resistant cell.

In summary, these heavy ions deliver a series of 'targeted punches' right to the diseased cells. Carefully designed gold nanoparticles have the potential to offer both of these benefits, delivering this same series of targeted punches at traditional radiotherapy centres such as those we have across the UK. Whilst offering a realistic and economic alternative to heavy ion therapy they can also offer additional benefits.

To realise this approach, these particles would be given a chemical 'cloak' that will allow them to pass through the patient's body to the tumour. They would also be given a chemical 'key' which will recognize and preferentially allow them to enter the diseased cells. They might also be given other keys to pass into critical regions of the cell (e.g. the nucleus). Once inside the diseased cells, their presence can be detected in a CT scan to show where the tumour is located. Furthermore, during traditional radiotherapy (using linacs), they can take a large fraction of the energy in the X-ray beam and turn it into the same kind of highly focused punch that has proved so effective in ion beam radiotherapy, destroying the cancerous cells while leaving the healthy ones largely unaffected.

We have revealed the mechanism whereby these nanoparticles give the same punch as the heavy ions used so successfully in Germany and Japan. We also have developed a technique to rapidly image them within cells. The particular feature of our imaging approach is that it measures the presence of the gold core directly rather than some other tag which has been placed upon it. This is important because the tag can detach giving misleading results in other approaches.

The next step in making this therapy effective is to try gold nanoparticles of various sizes, various 'cloak' constructions and equipped with different 'keys' with a view to optimizing their uptake into cancerous cells whilst minimizing it for healthy cells. We will develop a pipeline built around our new imaging technique to assess the degree of uptake and localization of the gold nanoparticles, thereby assessing their suitability. Furthermore, our imaging technique can be used to show if the gold nanoparticles are clumping together in the cells (a common problem). Using this pipeline we will rapidly determine the optimum size of the gold nanoparticles, suitable cloaking constructions and a set of 'keys' to provide entry into the diseased cells. Furthermore, we will extend the imaging technique to image live cells as they take up the nanoparticles, providing very useful information for improving their design in a rational way.

The optimized nanoparticle designs coming from the pipeline will be suitable to be taken forward into bigger research projects and clinical trials where their full potential for treating various cancers will be determined. Hence, this project will act as a springboard from which an entirely new approach to treating cancer will emerge.

Who will benefit from this research?
A large fraction of the population will benefit from this research. Cancer, the second most common form of death after cardiovascular disease, is a major European health concern. In 2006, 3.1 million new cases were diagnosed and 1.7 million deaths were attributed to cancer within Europe [Ferlay et al, Annals Oncol, 18, 581 (2007)]. With the ageing European population current estimates predict that, even with no change in incidence rates, the number of cases will increase by 20% by 2020 while the World Health Organisation predicts 13.2 million people will die from cancer in 2030. Around 50% of patients receive radiotherapy as part of their cancer treatment and it is second only to surgery in its ability to cure cancer [Delaney et al, Cancer 104, 1129 (2005)]. However, radiotherapy is limited by the need to minimize the dose delivered to the surrounding healthy tissue to prevent harmful effects of exposure.

How will they benefit from this research?
This research will provide a pipeline for rapid screening and development of a range of functionalized gold nanoparticles each optimized to treat one or more cancer types. The same functionalized nanoparticle can perform a dual role. It can act as a contrast enhancing agent, thereby improving cancer diagnostics and tumour demarcation when used in conjunction with existing CT scanners. It can also act to enhance the biological effect of radiation during radiotherapy in a manner which will affect the tumour but leave the healthy tissue largely unaffected. Hence, it is expected that these agents will lead to higher cure rates for a significant fraction of the population.

We have demonstrated that these nanoparticles act through the same mechanism as is used in heavy ion therapy [McMahon et al, Nature Scientific Reports, 1 DOI:10.1038/srep00018 (2011)] and that this benefit can be realised using standard hospital Linacs [McMahon et al, Radiotherapy & Oncology 100 412-416 (2011)]. Hence, the nanoparticles will be able to treat the radioresistant tumours (e.g. glioma) for which heavy ions have shown success. Combining these benefits with the local targeting of the gold, to be delivered through this project, will provide candidate agents to deliver the healthcare benefits only currently available through a few heavy ion therapy centres to patients at existing clinical therapy centres worldwide.