Doped Titania for Cancer Therapy

Rates of cancer mortality have remained virtually unchanged since the 1950's while death rates from heart disease and stroke have dropped significantly. Surgical treatments are often limited by physical access to the tumour, and are usually augmented by other therapies due to the large risk associated with remaining malignant cells after removal of the main tumour. Chemotherapeutic approaches have extremely unpleasant side effects and cancerous cells often become resistant
to the drugs and at present the efficacy of radiation therapy is limited by damage to healthy tissue and associated sideeffects. Nanoparticulates provide a better penetration of therapeutic and diagnostic substances within the body, at a
reduced risk in comparison to conventional therapies.

We have designed a system based on the semiconductor, titanium dioxide (titania), which exhibits a high photoactivity which generates Reactive Oxygen Species (ROS) upon excitation of valence band electrons to the conduction band by absorption of photons. As such titania nanoparticles, especially those of the anatase crystallographic phase may be used for ultraviolet light stimulated ROS production for photodynamic therapy (PDT). The penetration depth of light limits this technique to tumours on, or just under, the skin. We have generated nanoparticles which have been designed to optimize the interaction of the titania with X-rays, a more deeply penetrating energy source. The nanoparticles have been doped with elements which have been selected to absorb the maximum energy from a typical medical X-ray with a broad emission spectrum centred around 60keV. This allows the nanoparticle ROS treatment to be extended to deep tissue and large tumours which could not be treated by photodynamic therapy.

The doped TiO2 nanoparticles have been coated with silica to improve biocompatibility and have been shown to passively enter cells in monolayer culture. In the absence of irradiation there is no significant decrease in cell viability illustrating the
bio-compatibility of the particles. Excitation of the nanoparticles by X-rays has been demonstrated in vitro to generate ROS
and exposure of the cells containing nanoparticles to X-ray results in generation of cell-damaging ROS from the titania.
Preclinical trials have tested the efficacy of the particles against xenografts of lung non-small cell carcinoma. Tumours which were injected with the nanoparticles prior to irradiation were shown to be half the size of those treated with radiotherapy alone.

The aim of the current study is to improve the efficacy of the nanoparticles and to scale-up the synthesis to produce a
commercially viable product with a clear supply chain.

The particles will be synthesized using flame spray pyrolysis; a technique developed by Johnson Matthey. The nanoparticles made at lab-bench scale are polycrystalline and approximately 65nm. Attempts will be made to produce single crystal nanoparticles which are less likely to suffer losses of energy within the particle and therefore produce ROS with greater efficiency. The distribution of rare earth ions will also be assessed and methods developed to produce a highly uniform distribution of ions. Furthermore, the combination of rare earth dopants will be investigated and the nanoparticulate diameter modified since the production of smaller particles may allow access in to the nucleus with resulting increases in efficacy.

The scale-up of the nanoparticles will ensure the reproducible production of a homogeneously doped nanoparticle with a
uniform biocompatible coating and particulate size control. This will enable translation of the technology to Pharma and reduce the time taken to reach the clinic.

Cancer was estimated to cost the world economy over US$3 Trillion in economic losses from premature death and disability in 2009. This represents the single largest drain on Nations' economies compared to all other causes of death.

Despite surgery, radiation and chemotherapy treatments, cancer is one of the principal causes of death in developed countries, accounting for 25% of mortalities in the UK. Of the 30-40% of the population which will develop cancer, at least half will require radiotherapy at some time during their illness. Improving the effectiveness of radiotherapy would have a substantial impact on cancer cures in the UK.

In the UK, a six week wait for radiotherapy is typical and is directly related to the level of resource provision. Six weeks is the approximate doubling time of many tumours. Overall relative improvement of around 25% could be achieved by providing adequate radiotherapy facilities. Nanoparticle augmented radiotherapy would enhance the effectiveness of each fraction of radiotherapy therefore requiring fewer fractions per patient. This in turn would reduce the burden on hospital facilities, reducing waiting times therefore permitting earlier treatments which inherently increases survival, increasing patient compliance, resulting in an overarching impact on the cancer cure rate and associated impact on the National Health Service. Alternatively, nanoparticle augmented radiotherapy can enable lower doses of radiotherapy to give the same efficacy at the tumour site. This will result in fewer side effects such as skin damage, and fertility issues. In addition, recalcitrant tumours which would require radiation doses too high to be tolerated by healthy cells could potentially be treated due the increased selective absorption.

It is expected that the demand for cancer treatment is increasing by 3-4% per year as a result of an ageing population and improved early detection systems.

A patent landscaping and IP market assessment (1851 Technology Ltd.) was commissioned as part of an EPSRC pathways to impact award. This was used to gauge the opportunities for radiotherapy nanohealth technology. The specific patent landscape relating directly to the field showed a sparsely populated niche, leaving an obvious business opportunity to be availed of, given the right technology.

We would therefore expect that the success of this project would make an attractive commercial proposition. It would also create a supply chain for nanotherapeutics and make an important contribution to European economic growth and employment.