Fluorescence Lifetime Imaging of New Functional Biomaterials for Non Invasive Early Tumour Diagnosis

Early diagnosis and treatment of cancer prior to metastasis has a significant impact on patient survival. This project will demonstrate novel luminescent optical imaging agents that could lead to safe, extremely accurate, non-invasive and affordable early diagnostics of cancers which are difficult to access non-invasively due to limited light penetration through tissues such as the alimentary tract.
Our RCaH-MGU-Bath collaboration will utilize our joint expertise in chemistry, biophysics and bioimaging in vitro and in vivo to exploit unique nanomaterials. We will attach tumour targeting peptides and commercial antibodies for cancer cell markers (Abcam) to near-infrared emitting luminescent nanoparticles (synthesised at Bath and also those available via the project partner, Intrinsiq Materials Ltd). These conjugates will be investigated at Bath and at the RCaH for selective delivery to cancer cells, uptake, toxicity, in vitro and in vivo optical imaging using multiphoton fluorescence imaging, lifetime imaging and in vivo bioluminescence.
Jointly with our project partners (Abcam Plc, Intrinsiq Materials Ltd and Nikon Bioimaging UK) we will develop a design and testing integrated technology for the nanoparticles to attract investment for early cancer diagnostic by novel imaging agents. This will open up an opportunity to validate this technology which will allow us to tap into the $3.3 billion medical diagnostics market upon completion of the project. A deeper understanding of interactions between nanoparticles and cancer cells and a full investigation into their chemical biology will also emerge as a result, which is crucial to the delivery of new, marketable, diagnostic tools.
The state-of-the-art relies on the use of organic molecules as imaging agents that normally suffer from short emission lifetime and poor photostability or use of quantum dots, which are of high cost and biologically toxic. We will carry out the first benchmark study of toxicity, in vitro targeting of cancer cells and in vivo bioluminescence imaging. This project will deliver the imaging probe as a result of the close collaboration between synthetic chemists, imaging technologist, chemical biologists and cell biologists. We will demonstrate that near-IR emitting nanoparticles (NPs), functionalized with peptides and antibodies can be applied to the medical diagnostics market by overcoming disadvantages of existing fluorophores e.g. quantum dots (cost and toxicity) and organic fluorophores (short life span).
This project can pave the way to address the unmet clinical need for future endoscopes operating in the NIR regime and adapted to bypass tissue autofluorescence. It can also lead to the development of new medical diagnostic tools in future developments with colleagues in the Biosensing Network at Bath and with the clinical collaborators from the Cancer Research at Bath network.

Soft tissue imaging techniques have revolutionised diagnostic medicine and contributed greatly to our understanding of physiology at the molecular level. New chemical and spectroscopic tools have proved particularly powerful in moving microscopy from the age of stains to that of molecular probes that can image physiological processes in real time. During this past decade, the laser microscope laboratory at RAL (now at the state-of-the art RCaH) has provided a national facility that has driven innovation in the development of time-gated microscopy and multi-photon imaging. The LSF and MRC MGU at the Harwell Oxford site have provided a meeting point for interdisciplinary science, allowing physical scientists and biomedical scientists to work with one another and forge new collaborative partnership. This proposal focuses on the development of unique biomolecule/nearIR emitting nanoparticle hybrids with long lived excited states (Bath) and their biological testing (RAL). Here, we set out a research programme that permits (a) the development of nanophosphorescent probes probes provided by our industrial partner (Intrinsiq Materials) which proceeds hand in hand with the development of nearIR tagged core-shell nanoparticles developed at Bath, and their functionalisation with commercial antibodies (known, as well as new ones under development by Abcam) for cancer targetting; and (b) the evaluation of the effectiveness of both in the study of real biological problems related to the non-invasive diagnosis of tumours. This national facility is the ideal place in which such new techniques can be developed, evaluated, established in the community and eventually commercialised. We will use state of the art optical imaging technology and targeting biomolecules to probe selective cancer cells responses to imaging nanoparticles, an essential requirement for the effective non-invasive diagnostics of the future.
The impact on our understanding of the biological processes involved in targeted delivery will be immediate, and of academic as well as societal. It will pave the way for new instrumentation, e.g. with Gilden Photonics and the group of Prof Tony James Bath, for sensing applications and in endoscopes operating in nearIR. In the short term the impact of this work will be realised in the research reagents market including manufacturers and suppliers of reagents (particularly Intrinsiq and Abcam). In the medium to longer term the improvements afforded by these new materials have the potential to result in significant advances in our understanding of mechanisms of disease and in underpinning earlier and more accurate detection and monitoring of medical conditions with consequential benefits for patient health and quality of life.
Commercial and Economic: For the project partners the novel nanomaterials proposed here can address a £2 billion medical diagnostics market.
This project addresses a key need in diagnostics and imaging technologies of relevance to healthcare and healthcare industry. Pharmaceutical and biotech companies will benefit from being able to apply more accessible, advanced diagnostics techniques in drug discovery programmes such as new target identification, biomarkers imaging (e.g. Cancer) leading to new or improved therapeutic treatments, identification of new disease biomarkers, and development of targeted treatments and more rapid patient profiling and quicker administration of specific treatments (e.g improved cancer diagnosis, personalised treatments). For the Department of Health and NHS and clinicians this has advantages for healthcare delivery (see pathways to impact).
Impact on science: New materials with controlled optical properties and biocompatibility will lead to applications beyond the currently proposed research direction and will enhance our fundamental knowledge of nanomedicines design.
Environmental: Our NPs will provide means to limit the use of toxic metals (e.g. Cd in quantum dots) in imaging