Nano4CaRE (Nanoparticles for Cancer Radiotherapy Enhancement)
Despite significant advances in diagnosis and treatment, cancer represents the second most important cause of death and morbidity in Europe, with more than 3.7 million new cases and 1.9 million deaths each year. Moreover, although cancer can occur at any age, it is much more common in older people and the risk of developing cancer increases significantly over the age of 50.
The causes of cancer are multi-factorial and the most common treatments include combinations of surgery, radiotherapy and chemotherapy. Acquired drug resistance and acute side effects are the major drawbacks of chemotherapy. Similarly, radiotherapy also results in significant side effects and damage to surrounding tissues. These problems have led researchers to investigate the targeting of chemotherapy drugs or compounds capable of absorbing X-rays (known as radiosensitisers) to cancer cells with the aim of increasing the effectiveness of the therapeutic agent and reducing its side effects.
Nanotechnology, the study and application of materials at atomic and molecular scales, offers exciting opportunities to transform the diagnosis and treatment of cancer through innovative therapeutic application of nanomaterials. Triphenylphosphonium (TPP) cations are known to be preferentially accumulated by the mitochondria of cancer cells and research at SHU and the OU has demonstrated that attachment of TPP-groups to gold nanoparticles (AuNPs) facilitates their selective accumulation into cancer cells (SHU) and selective toxicity towards cancer cells (OU). Thus, acute 3 hr exposure of HSC3 human oral squamous cell carcinoma cells to 30 g/ml TPP-AuNPs resulted in over 90% death in clonogenic assays, while identical treatment of normal human HaCaT keratinocytes resulted in no toxicity. At the OU, X-ray irradiation of 10g/ml TPP-AuNP-exposed HSC3 cells demonstrated weak radiosensitisation, with increased selectivity for cancer cells.
Multiscale molecular dynamics simulations at the OU revealed that lowering the ligand density on AuNPs, to a point where water molecules can freely diffuse to the AuNP surface, substantially improves radiosensitisation [Haume 2018 DOI: 10.1140/epjd/e2018-90050-x]. Therefore, in this Nano4CaRE application, we will determine the optimum TPP density of these promising anti-cancer AuNPs to yield a powerful cancer- selective chemo-radiosensitiser.
Despite recent advances in cell biology, the effectiveness of most nanoparticle-based cancer therapies are determined in 2D cell culture models. However, in a living organism the cellular environment is a 3D system. Consequently, there is growing interest in investigating the interaction of nanoparticles with 3D in vitro models. As part of a separate project, Dr Cross has developed 3D cancer models that can be used to assess several parameters of nanoparticle cancer therapeutics. Inclusion of immune cells in this model would improve its resemblance to in vivo tumours, which interact with immune cells to prevent immune surveillance and destruction of the tumour.
Dr Leyland brings expertise of immunotherapies for cancer and is currently investigating the immuno-inhibitory mechanisms of cancer and co-cultures of immune cells and cancer cells, which will be combined with Cross’s model. The behaviour of nanoparticle-based cancer therapeutics and radiosensitisers under these more realistic conditions has never been explored previously and represents a major advantage of this project.