Raman Nanotheranostics - RaNT - developing the targeted diagnostics and therapeutics of the future by combining light and functionalised nanoparticles

Lead Research Organisation: University of Exeter
Department Name: Physics and Astronomy

Abstract

The rapidly emerging field of 'Nano-Theranostics' is widely expected to have a significant impact on healthcare in the next decade and beyond. Theranostics is the combination of therapy and diagnosis. It aims to identify diseases and treat them in a single, effective non-surgical procedure. Our recently developed gold nano-technologies allow unprecedented accuracy in identifying diseases such as cancers measured at depths of centimetres inside the body using only light. Furthermore, light can then also be used to trigger the gold particles to destroy the diseased cells or tissues identified using this method in a controlled, safe and targeted fashion.

Numerous diseases would benefit from new methods to provide early accurate diagnosis, with effective localised treatment tailored to each patient and non-invasive monitoring of treatment progress. Existing diagnostic techniques do not manage to measure the early changes in the makeup of abnormal cells - whilst they are still in the body with sufficient accuracy or sensitivity. In cancers the molecular changes found within the cells and tissues are the downstream effects of genetic mutations driving the tumour development. A novel method to identify these early changes within the body, without removing tissue, and to use them to target treatment or monitor progression is our objective, delivering tangible benefits in patient outcome and costs.

We will also develop a novel approach for assembling tiny gold nanoparticle clusters to enable their effective optical readout and to pass safely through the body and target diseased cells of interest. These clusters will be coated in a proven biocompatible wrapping which enhances transport across biological barriers, and modified to enable them to be attracted selectively to diseased cells. Most importantly we bring together the unique capabilities: to read out multiple signals non-invasively from clusters at depths of many cm; to build safe clusters which will self-disintegrate over time (eg hours) into smaller safe units that can be excreted from the body; to tune the size and contents of these constructs to enable light to trigger a therapeutic response, via heating or drug delivery; and to provide real-time in-vivo readout of the local temperature within the tissue during treatment to maximise its effectiveness and minimise collateral damage to healthy tissue.

Furthermore, the proposed Nano-Theranostic approach will deliver the ability to detect and localise many different diseases via a single nano-construct. This utilises functionalised gold nanoparticles to produce specific spectroscopic signatures (via surface enhanced Raman - SERS) from reporter molecules illuminated with low intensity, safe, near-infrared laser light from outside the body. This opens the way for real-time identification and localisation, within the body, of distinct expressions of disease, by targeting numerous specific molecular targets simultaneously. The near-infrared light is barely absorbed in tissues and cells and is non-cancerous (unlike UV light), thus facilitating the possibility of safe, regular non-invasive monitoring of treatment or progression of disease.

In the near future, patients will have effective and limited treatments selected specifically for their needs, to maximise the therapeutic value of any necessary treatment and prevent the application of any unnecessary, and potentially harmful through side effects, therapy. This has the potential to lead to not only increased survival rates, but increased quality of life for those likely to be offered major treatments in current clinical system and also potentially save many £100Ms across the UK each year on ineffective treatments.

We constitute a team of world leading experts in complementary research fields to facilitate a number of significant advances impacting on healthcare of the future.

Planned Impact

The major impact from this PG will be to establish a platform healthcare technology, in a significant area of increasing clinical need, to provide stratified diagnosis and therapy in a single modality. It will have the significant potential to improve patient outcomes (lower mortality/less aggressive treatments); reduce dramatically the financial burden of healthcare and provide a catalyst for UK novel healthcare technology industries. This will be achieved by developing industry and healthcare partnerships to develop solutions for specific disease targets that will be first tested in pre-clinical studies and lead to full in vivo clinical trials.

Here we propose to develop an advanced diagnostic platform addressing the critical clinical needs of the next generation of healthcare, combining non-invasive in-vivo detection and diagnosis of disease with targeted, light-mediated therapeutics and real-time treatment monitoring. The initial targets of this novel approach will be subsurface cancers and their associated metastases; such as breast, prostate, head and neck cancers and associated metastases (secondary cancers). This will be achieved by bringing together several unique technologies, established by the applicants in their respective fields, who have already evidence of collaborating. These when integrated will yield exceptionally high added value providing the capability of delivering Raman Nanotheranostics in a safe, effective and minimally invasive (non-surgical) manner.

We will make use of the EPSRC translation toolkit, benefitting patients and UK academia. A major impact on the UK economy will also be accrued. (Cancer diagnosis and therapy is expected to cost >£15B by 2021.) The new platform technology may also be applicable elsewhere - eg in glucose detection, infectious diseases, Alzheimer's and other degenerative diseases.

This is a highly challenging programme with high level risks balanced by exceptionally high benefits to the society if delivered as proposed. The risks are mitigated by bringing together world-leading experts to deliver each of our pillar technologies, through carefully coordinated sub-programmes, followed by careful integration. Each element of this programme will facilitate breakthroughs, stimulating the nascent field in numerous ways with extra added value stemming from their integration into a unique diagnostic-therapy.

The programme partners will establish a Clinical Collaborator Group to provide insight to key clinical needs and an International Advisory Board to provide advice on identifying and translating new clinical technologies into commercial products for the benefit of patients. One of the major outputs of this programme will be to ensure we develop realistic future healthcare technologies, by use of our IAB, public engagement events - discussing patient's views on use of nano-technologies, outlining their potential - and careful health economic evaluation (cost/benefit analysis) of the technologies versus specific clinical needs.

The PI and CIs have experience of translating technologies from bench to bedside and are aware of the need to de-risk the concepts and technologies we develop to ensure industrial support is forthcoming to drive it to the market in a timely manner.

Ultimately patients will benefit from better clinical decisions being taken, with enhanced knowledge provided by the direct measure of the tissue composition and associated physiology. The health service will benefit by having to provide less secondary procedures and clinics in addition to potentially reducing the need for radical cancer treatments in those with early lesions. The commercial sector and UK plc will benefit from the implementation of such methods (and associated spin offs).

Publications

10 25 50
 
Title Raman Nanotheranostics - A vision for future healthcare 
Description A short animation developed with a professional animator to introduce the concept and vision of the Raman Nanotheranostics programme to a wider audience including members of the public and patient groups. 
Type Of Art Film/Video/Animation 
Year Produced 2020 
Impact Raising the profile of the RaNT Programme amongst the general public. Further impact is expected as the animation is used more widely during planned engagement activities. 
URL https://rant-medicine.com/
 
Title The signaller 
Description It is the cover art to accompany a review article in the journal Chemical Science. Titled the signaller, it is designed to communicate how gold nanoparticles are helping to make non-invasive optical diagnostics a reality for future clinical practice. It specifically reflects the application of the Raman Nanotheranostic Programmes surface enhanced spatially offset Raman spectroscopy (SESORS)-based technology. 
Type Of Art Artwork 
Year Produced 2020 
Impact Published on the front cover of the journal Chemical Science. Generating additional interest in the work of the RaNT Programme. 
URL https://rant-medicine.com/rant-on-cover-of-chemical-science/
 
Description 1) We have identified that sufficient signals can be generated from nanoparticles in vivo using SESORS methodologies.
2) These NPs also convert optical energy into heat efficiently. Further work to optimise these approaches will continue.
3) Novel nanoconstructs have been developed and tested using various methodologies - demonstrating both heating and SERS signals.
4) NP can be detected at depths of many cm using SESORS approaches.
5) Biocompatibility and in vivo testing is demonstrating potential clinical feasibility.
6) Novel read out appropaches are allowing both the depth and lateral extent of NP rich inclusions to be identified using transmission Raman geometries alone.
Exploitation Route Developing and exploring novel nanomedicine techniques.
Sectors Education,Healthcare,Manufacturing, including Industrial Biotechology

URL http://rant-medicine.com
 
Description Exeter Biomaterials Optical Characterisation Suite - EBOC
Amount £632,086 (GBP)
Funding ID EP/V034251/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 11/2020 
End 05/2022
 
Title Data for Metasurfaces atop Metamaterials: Surface Morphology Induces Linear Dichroism in Gyroid Optical Metamaterials 
Description Data from all the figures in this paper. Please see the README file (Dataset.pdf) for descriptions of each subfolder. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
 
Title Research data supporting "Controlling Optically-Driven Atomic Migration Using Crystal-Facet Control in Plasmonic Nanocavities" 
Description Research data contain the measurements of surface enhanced Raman spectroscopy and dark-field scattering of gold nanoparticles of various shapes, as described in the linked manuscript. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
URL https://www.repository.cam.ac.uk/handle/1810/308195
 
Title Research data supporting "Detecting mid-infrared light by molecular frequency upconversion with dual-wavelength hybrid nanoantennas" 
Description This folder contains research data from every figure in the paper. Briefly, files contain the reflection of the nanoparticle-on-resonator (NPoR) in visible and mid-infrared regime. Further, we enclose experiment data of surface enhanced Raman spectroscopy (SERS) of the constructs under study, as described in the linked manuscript. Here, we perform power dependent frequency upconversion measurements while measuring SERS. We show upconversion with pump ON and OFF. Then we show detail upconversion measurements for 40 NPoRs where we focus in various Stokes and antiStokes peaks for clarity. Lastly, we examine the mid-infrared tuning dependence of the frequency upconversion. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL https://www.repository.cam.ac.uk/handle/1810/330223
 
Title Research data supporting "Eliminating irreproducibility in SERS substrates" 
Description Surface enhanced Raman spectroscopy (SERS) data from self-assembled gold nanoparticle to study how the reproducibility in SERS substrates can be improved. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL https://www.repository.cam.ac.uk/handle/1810/315936
 
Title Research data supporting "Single photon multiclock lock-in detection by picosecond time stamping" 
Description This folder contains research data of every figure in the paper. This includes histograms of the lock-in frequencies as well as time tracks of the optical signal locked-in to the laser repetition rate, the laser modulation and the sweep of a delay stage. Finally, we record time-resolved coherent anti-Stokes Raman scattering to determine the vibrational lifetime of molecules in a plasmonic nanocavity. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL https://www.repository.cam.ac.uk/handle/1810/330674
 
Description Raman Nanotheranostics 
Organisation Rutherford Appleton Laboratory
Country United Kingdom 
Sector Academic/University 
PI Contribution We collaborate on the development of Raman nanothernostics a novel Healthcare Technology to identify and treat early and later cancers throughout the body.
Collaborator Contribution Exeter leads this programme of work and the university has contributed significant resources in building and kitting out new dedicated laboratories for this work. As a partnership we each contribute a unique skill set of leading researchers combining to develop something we could not do independently.
Impact Ongoing
Start Year 2018
 
Description Raman Nanotheranostics 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We collaborate on the development of Raman nanothernostics a novel Healthcare Technology to identify and treat early and later cancers throughout the body.
Collaborator Contribution Exeter leads this programme of work and the university has contributed significant resources in building and kitting out new dedicated laboratories for this work. As a partnership we each contribute a unique skill set of leading researchers combining to develop something we could not do independently.
Impact Ongoing
Start Year 2018
 
Description Raman Nanotheranostics 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution We collaborate on the development of Raman nanothernostics a novel Healthcare Technology to identify and treat early and later cancers throughout the body.
Collaborator Contribution Exeter leads this programme of work and the university has contributed significant resources in building and kitting out new dedicated laboratories for this work. As a partnership we each contribute a unique skill set of leading researchers combining to develop something we could not do independently.
Impact Ongoing
Start Year 2018
 
Description Raman Nanotheranostics 
Organisation University of Exeter
Country United Kingdom 
Sector Academic/University 
PI Contribution We collaborate on the development of Raman nanothernostics a novel Healthcare Technology to identify and treat early and later cancers throughout the body.
Collaborator Contribution Exeter leads this programme of work and the university has contributed significant resources in building and kitting out new dedicated laboratories for this work. As a partnership we each contribute a unique skill set of leading researchers combining to develop something we could not do independently.
Impact Ongoing
Start Year 2018
 
Description Attended the Institute of Physics (IoP) - Festival of Physics at the University of Exeter 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Three members of the RaNT team engaged with young people, families and students (primary audience of the IoP event aimed at inspiring the next generation of physicists) attending the IoP Festival of Physics at the University of Exeter. We used the opportunity to begin developing an interactive narrative (including hands-on demonstrations) showcasing the fundamental science concepts behind the RaNT procedure and to practise rapid opinion canvassing. The event allowed us to establish sensible timings for elements of the narrative and gave us a list of improvements/additions to make to the setup, including the need to establish clearly defined audience flow through the stall. It also highlighted a need to have dedicated staff/space/script on the stall for opinion canvassing, whilst other members of the team deal with presenting/answering questions. These lessons will be taken forward to our next public event. This forms part of our wider plan, to gather perspectives from people that have no experience of the cancer care pathway.
Year(s) Of Engagement Activity 2021
URL https://www.iop.org/about/news/join-iop-hosted-festival-of-physics-in-exeter#gref
 
Description End-User Perspective on RaNT: People with Lived Experience of Cancer (Initial Interactions) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Our 2021 aim was to put RaNT through first contact with people who have experience of living with cancer, and to hear their thoughts and perspectives on the concept behind the research. We wanted to make sure RaNT was a desirable solution for patients, and identify any critical issues that might affect future uptake. This work would allow us to structure our approach to all future engagement with the research.
Our Communities Engagement Manager (CEM) hoped to connect with around 50 people and listen to perspectives on our 3 target cancers (breast, prostate, and head & neck).
In the end, we doubled that target, and participants generously shared their personal stories of 17 different types of cancer, including many experiences of metastases.
We've worked with 7 charities and support groups (Penny Brohn UK; Shine Cancer Support; Heads2gether; The Chestnut Appeal; Can Cope: Exmouth Breast Cancer Support Group; Prospect: Bristol & District Prostate Cancer Support Group; Somerset, Wiltshire, Avon & Gloucestershire Cancer Services), leading to in-depth phone calls, email conversations, small-group and 1-on-1 Zoom discussions with 28 individuals, and we've connected with over 70 more people through some larger, really engaging virtual meetings.
A 3-minute animation was developed in collaboration with a professional animator (Mair Perkins Ltd.), to demonstrate the concepts behind the RaNT procedure and outline a vision for how it might work in the clinic. This was played at the beginning of each session. Participants were then asked for their raw impressions without any guiding questions from the CEM. This meant that everyone began the session with the same level of information about RaNT. The open invite to respond with thoughts and queries regarding what they'd just watched resulted in a largely participant-led discussion, with the CEM stepping in only occasionally to maintain the flow of conversation and ensure that critical research questions were addressed.
The animation received very positive feedback from participants, who said how easy it was to understand what RaNT was trying to achieve. It removed the need to deliver a dense 20-30-minute introductory presentation, maximising the time available for discussion.
Around 20 hours of conversation, together with some questionnaire and written responses, are currently being collated into a qualitative report on the initial patient interaction with RaNT.
Current highlights:
People with experience of living with cancer are overwhelmingly positive about what RaNT is attempting to achieve. Critically, there were no fundamental concerns from an experienced patient perspective regarding how the technique works and how we envisage it will be applied in the clinic. We were warned however, that totally new patients with no previous experience of cancer may have different views, and we should prioritise connecting with such an audience. The CEM is currently planning events that will enable access to these groups.
Many suggested that RaNT's aim to offer treatment at the point of diagnosis could reduce the impact of being told you have cancer; the sense of immediate action could make having the disease less scary in the future. At the same time, we were cautioned about such a rapid transition from diagnosis to treatment, and will be consulting further regarding the timeline in which patients receive different information when referred to RaNT.
Our conversations highlighted the need to seek input from general practitioners and cancer nurse specialists, both very important points of contact for patients. We are now in the process of establishing relationships with representatives from both groups, in the hope of accelerating the successful clinical translation of RaNT.
The cohort also identified that RaNT could deliver an enhanced post-treatment check-up regime with potential to improve post-cancer quality-of-life. This could help ensure that the patient does not feel neglected and give them peace-of-mind that the cancer was being or had been positively managed.
Participants have identified potential positive outcomes and applications of RaNT that the research team had not previously considered. Together, we are identifying areas that require more detailed consultation, and highlighting new questions, all of which will improve the hopeful clinical translation of the RaNT technique.
Year(s) Of Engagement Activity 2021
 
Description Press release outlining the plans for the RaNT Programme 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Each partner provided press releases for inclusion in wider media across the UK.
Year(s) Of Engagement Activity 2018
URL https://www.exeter.ac.uk/news/featurednews/title_635440_en.html
 
Description Soapbox Science (Exeter) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact One of our research team participated in the Soapbox science event taking place in the Princeshay shopping centre, Exeter. Soapbox science is an outreach programme designed to promote women in science and their research. It also improves public access to science by bringing the research out to the public on the streets. Following their presentation the researcher was engaged with discussions and answering questions from members of the public indicating interest was generated in the research via the event. It also helped with understanding the sort of questions that need addressing for public audiences and in planning future events.
Year(s) Of Engagement Activity 2019
URL https://rant-medicine.com/soapbox-science-with-dr-priyanka-dey/