Molecular Cancer Therapeutics Activated By Cerenkov Radiation

BACKGROUND & AIMS
Photodynamic therapy (PDT) is a cancer therapy which utilises light to selectively destroy cancer cells. A light sensitive compound, photosensitiser (PS), is administered and activated through exposure to light of a specific wavelength. This triggers a chemical reaction which produces cytotoxic reactive oxygen species (ROS) and leads to cancer cell death. At present PDT is limited to superficial cancers or cancers accessible by endoscope, as it requires an external light source. An internal source of light could overcome these limitations and allow deeper tumours to be targeted. One possible internal light source is Cerenkov radiation (CR); light generated from certain radioisotopes when particles travel faster than the speed of light in tissue. Several of these radioisotopes are already used in nuclear medicine and could be adapted through the implementation of nanomaterials to activate PSs through the CR they produce.
The goal of this research project is to develop and critically evaluate novel molecular cancer therapeutics that are activated by Cerenkov radiation, with the aim of expanding the scope of PDT. Not only does this have the potential to contribute to advancing the treatment of various cancers, but will also provide novel and insightful information to the fields of nuclear medicine and nanomaterials. The overarching aim of the project will be split into the following objectives:
1) Synthesis and characterisation of novel photoactivatable compounds and radiolabelled cancer-targeting vectors
2) Combination of radiolabelled targeting vectors and photoactivatable compounds to quantify and classify ROS production
3) Investigation of the parameters associated with the successful therapeutic application of the synthesised compounds in preclinical cell studies.
The close spatial proximity between photoactivatable and radioisotope will ensure that the CR and subsequent ROS production will be confined to cancer cells. Furthermore, the parameters associated with the successful application of these novel photoactivatables and cancer-targeting vectors, e.g. therapeutic dosing, required level of radioactivity and impact of radioactivity on compound half-life and beta particle emission will be examined.

METHODOLOGY
1) Synthesis and characterisation of novel photoactivatable compounds and radiolabelled cancer-targeting vectors
o Conjugation of nanomaterials to PSs to synthesise novel photoactivatables
o Radiolabelling of cancer-targeting vectors
o Characterisation of compounds using standard biochemical techniques

2) Combination of radiolabelled cancer-targeting vectors and photoactivatable compounds to quantify and classify ROS production
o Development and optimisation of an assay to determine optimal conditions for greatest ROS production.
o Control groups will be implemented to verify that resulting ROS is produced as a result of co-incubation rather than a reagent alone.
o Quantification and classification of ROS produced
3) Investigation of the parameters associated with the successful therapeutic application of the synthesised compounds in preclinical cell studies.
o Application of photoactivatable and radiolabelled cancer-targeting vector to human cancer cells to determine efficacy.
o Application of compounds in several cancer cell lines to determine selectivity of the observed therapeutic effect.
o Optimisation of compounds will be carried out to determine therapeutic dosing. There is also scope to investigate the impact of this novel PDT approach across a wider variety of cancer cell lines.

The CDT has five primary beneficiaries:
The CDT cohort
Our students will receive an innovative training experience making them highly employable and equipping them with the necessary knowledge and skillset in science and enterprise to become future innovators and leaders. The potential for careers in the field is substantial and students graduating from the CDT will be sought after by employers. The Life Sciences Industrial strategy states that nearly half of businesses cite a shortage of graduates as an issue in their ability to recruit talent. Collectively, the industrial partners directly involved in the co-creation of the proposal have identified recruitment needs over the next decade that already significantly exceed the output of the CDT cohort.
Life science industries
The cohort will make a vital contribution to the UK life sciences industry, filling the skills gap in this vital part of the economy and providing a talented workforce, able to instantly focus on industry relevant challenges. Through co-creation, industrial partners have shaped the training of future employees. Additional experience in management and entrepreneurship, as well as peer-to-peer activities and the beginning of a professional network provided by the cohort programme will enable graduates to become future leaders. Through direct involvement in the CDT and an ongoing programme of dissemination, stakeholders will benefit from the research and continue to contribute to its evolution. Instrument manufacturers will gain new applications for their technologies, pharmaceutical and biotech companies will gain new opportunities for drug discovery projects through new insight into disease and new methods and techniques.
Health and Society
Research outputs will ultimately benefit healthcare providers and patients in relevant areas, such as cancer, ageing and infection. Pathways to such impact are provided by involvement of industrial partners specialising in translational research and enabling networks such as the Northern Health Science Alliance, the First for Pharma group and the NHS, who will all be partners. Moreover, graduates of the CDT will provide future healthcare solutions throughout their careers in pharmaceuticals, biotechnology, contract research industries and academia.
UK economy
The cohort will contribute to growth in the life sciences industry, providing innovations that will be the vehicle for economic growth. Nationally, the Life Sciences Industrial Strategy Health Advanced Research Programme seeks to create two entirely new industries in the field over the next ten years. Regionally, medicines research is a central tenet of the Northern Powerhouse Strategy. The CDT will create new opportunities for the local life sciences sector, Inspiration for these new industries will come from researchers with an insight into both molecular and life sciences as evidenced by notable successes in the recent past. For example, the advent of Antibody Drug Conjugates and Proteolysis Targeting Chimeras arose from interdisciplinary research in this area, predominantly in the USA and have led to significant wealth and job creation. Providing a cohort of insightful, innovative and entrepreneurial scientists will help to ensure the UK remains at the forefront of future developments, in line with the aim of the Industrial Strategy of building a country confident, outward looking and fit for the future.
Institutions
Both host institutions will benefit hugely from hosting the CDT. The enhancement to the research culture provided by the presence of a diverse and international cohort of talented students will be beneficial to all researchers allied to the theme areas of the programme, who will also benefit from attending many of the scientific and networking events. The programme will further strengthen the existing scientific and cultural links between Newcastle and Durham and will provide a vehicle for new collaborative research.