A small animal radiation research and multi-spectral optoacoustic tomography facility for advancing the physics and engineering of novel radiotherapy

Lead Research Organisation: Institute of Cancer Research
Department Name: Division of Radiotherapy and Imaging

Abstract

BACKGROUND
Radiotherapy (RT) is one of the most efficient tools in cancer treatment, and clinical RT is evolving considerably with technological advances in delivery and treatment planning. A key component of modern RT is enhanced image guidance, needed for precise tumour targeting, therapy monitoring and therapy assessment. To achieve the best care for patients with cancer receiving RT, developments are needed to optimise the physics and technology of image guidance. This should include the exploitation of new discoveries in targeted drugs and nanoparticles that increase tumour sensitivity to radiation, and of synergisms between RT and other physical therapies such as high intensity focused ultrasound (HIFU), hyperthermia and ultrasound (US) microbubble damage to tumour vasculature. These novel approaches to image guided RT must first be investigated in a preclinical setting before the most promising techniques can be translated to clinical studies. For this work, the integration of the best preclinical therapy with the best preclinical imaging will play a crucial role.

To replicate the sophistication of clinical radiation treatment methods for preclinical research requires significant technological advances to systems such as the small animal radiation research platform (SARRP), including the integration of reliable methods for image guidance. US imaging methods, including multispectral optoacoustic tomography (MSOT), offer the potential for improved and complementary image guidance capability relative to existing methods based on x-ray, nuclear medicine (NM) and magnetic resonance (MR) imaging.

RESEARCH
We aim to (a) develop an integrated SARRP-MSOT image guided preclinical RT facility and (b) use it to aid the development and optimisation of novel imaging methods and probes, and new therapeutic synergisms, to either evaluate or enhance effects of radiation on cancer cells. Over a five year period, 7 physics teams will conduct research in the following areas.

The SARRP will be modified for co-registration with MSOT and for preclinical tumour treatment using the most advanced methods employed clinically, under image guidance. We will develop methods for accurate determination of applied radiation dose and integrate a special x-ray detector for quantitative computed tomography able to distinguish tissue types and detect dose-enhancing nanoparticles.

We will investigate possibilities to exploit therapeutic synergisms by integrating US therapy with the SARRP. We will modify the MSOT device for US microbubble imaging, using MSOT imaging of blood supply and oxygenation to optimise RT and US treatment combinations, investigating the use of US microbubbles to enhance RT, and developing dose parameters for combined physical therapies.

Imaging techniques and probe chemistry will be developed and optimised for MSOT prediction of enhancement of targeted radiosensitisation, indication of prognosis and assessment of tumour response. Performance will be compared with NM probes and MR imaging techniques.

Methods for US guidance of advanced RT treatments will be optimised by developing co-registration of US images with NM, MR and MSOT images that predict radiosensitivity, and developing and evaluating US-based motion compensated dose delivery and imaging to identify the distribution of viable tumour cells as treatment progresses to facilitate treatment adaptation to avoid relapse.

Finally, cross-institutional collaborative research in the above and other areas will be fostered by making the integrated facility available to external users and by running workshops for sharing technical and scientific information, and planning, executing and reporting on joint studies.

Planned Impact

The primary non-academic beneficiaries, in the longer term, will be cancer patients. Research and development with the MSOT system will provide sophisticated, novel, imaging techniques and imaging probes that will allow a better understanding of tumour behaviour and response to treatment. MSOT, with its high resolution, whole body 3D, real-time imaging of molecular and functional information, is the most suitable imaging tool for combining with the SARRP in the preclinical research described in this proposal. Because of its limited penetration depth, however, it will not always be the most suitable tool for clinical application. The research will therefore act to inform development for eventual translation to clinical application with chemical probes and image information either directly, as clinical optoacoustic imaging for appropriately superficial organs or those accessible by endoscopy, or indirectly, albeit at lower resolution, by using radiolabelled equivalent probes for nuclear medicine imaging or equivalent image biomarkers employing MRI. This is one of a number of reasons why the proposed research includes cross-modality image registration, image fusion and multiparametric image analysis. The SARRP will allow the pre-clinical testing of new image guided radiotherapy (RT) techniques whether on their own, or in combination with other treatment modalities, enabling their optimisation and comparison with established methods before they are implemented for the benefit of patients. Such implementation holds considerable potential for collaboration with industry. The pre-clinical research enabled by the use of these two pieces of equipment will lead to improved diagnosis, more effective RT treatments, and better treatment monitoring. Siting the devices at The Institute of Cancer Research will have obvious benefits. The tie up between the ICR and the Royal Marsden NHS Foundation Trust ensures rapid translation of new ideas into the clinic, the two organisations having an excellent track record of industry collaboration and commercialisation of inventions in both imaging and RT with companies such as Elekta, Philips, Seimens, and Zonare. The preferred MSOT provider, iThera, has an interest in clinical translation of the research findings and to assist with this has offered to contribute (see quotation) an open system with research access and a hand-held hemispherical array, with engineering support. The SARRP supplier, Xstrahl, has made equivalent undertakings to assist the research. Both suppliers also represent excellent routes for direct commercialisation in the preclinical research industry. The proposed implementation of IMRT and VMAT on the SARRP, will ensure the clinical relevance of the research and opportunities for rapid translation to the clinic. In modern RT the emphasis is on integration of diagnosis and therapy to provide treatments that are personalised for each patient. Users from outside the ICR, who will have access to this equipment, have similar goals. The development of patient specific biomarkers for disease, and of RT treatment plans that follow individual tumour contours more closely, and follow functional and molecular information that defines the biologically important target, are essential for this strategy. Investigation of these areas will be greatly enhanced by the use of the two devices requested. The users of the equipment will thus be excellently placed to ensure that this research is translated as rapidly as possible into the clinic, and thus for the benefit of the patient. More effective RT treatments, in terms of optimised dose delivery, sometimes achieved by combination with radiosensitisers or synergistic treatments, will result in fewer side effects, and thus improved tumour control and greater quality of life for patients. The improved treatment monitoring techniques that may result from this work, would allow earlier re-intervention in the case of treatment failure.

Publications

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Brüningk SC (2018) A comprehensive model for heat-induced radio-sensitisation. in International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group

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Wamel AV (2016) Acoustic Cluster Therapy (ACT) - pre-clinical proof of principle for local drug delivery and enhanced uptake. in Journal of controlled release : official journal of the Controlled Release Society

 
Description This grant supported the purchase of equipment for multispectral optoacoustic tomography (MSOT) for 3D mouse spectral imaging and a small animal radiation research platform (SARRP) for delivering clinical-like radiotherapy to mice. We have developed a novel image registration method which allows MSOT images to be registered to a whole range of types of conventional ultrasound images. In using this we made the discovery that in tumours, the later conventional ultrasound contrast (microbubbles) arrives at a location within the tumour, the more likely it is that the blood at that location will be deoxygenated. In combination with the use of the SARRP, we have shown that level of blood oxygenation determined by MSOT imaging immediately before and shortly after treatment is a good predictor of tumour response to radiotherapy. Dose planning software for the SARRP is under development. We have shown that MSOT is at least as sensitive as MRI in detecting whether BRAF and HSP-90 inhibitors (new cancer therapies) have been effective in their intended interference with metabolic pathways in cancer cells. We have developed novel dye-coated phase change nanodroplets and demonstrated substantial enhancement of MSOT imaging signal, as well as multimodality imaging use of this agent. The dye-coated nanodroplets were shown in vitro capable of providing information for super-resolution imaging, unlike conventional microparticles, even when stationary (no publication yet). Gold nanorods for use in MSOT molecularly targeted imaging and therapy have been tuned using a novel laser irradiation technique that we have developed, so that they are more responsive specific to chosen optical wavelengths than raw synthesised nanorods. New work has begun: (a) in collaboration with the National Physical Laboratory investigating reporter genes to generate MSOT signals that render cells of preclinical tumour models intrinsically visible in MSOT images; iRFP720 was not successful but melanoma cells provide good signal, and (b) in collaboration with Imperial College London to investigate semiconductor polymeric nanoparticles for photoimmunotherapy with MSOT monitoring, providing preliminary evidence of a best nanoparticle for both.
Exploitation Route We will be applying for further grants to extend these pilot studies. Eventually, where appropriate, clinical trials may be planned based on further successful outcomes. Industrial collaboratiors assigned to this grant within Researchfish will be an important component of these processes.
Sectors Healthcare

 
Description 2016 Tools and Resources Development Fund 1 (TRDF1)
Amount £149,523 (GBP)
Funding ID BB/P027466/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start  
 
Description Novel semiconducting nanoparticles for photoacoustic monitoring of photoimmunotherapy
Amount £30,000 (GBP)
Organisation Institute of Cancer Research UK 
Sector Academic/University
Country United Kingdom
Start 11/2019 
End 10/2020
 
Description Photoacoustic imaging for optimisation of CAR-T cell cancer therapy, iCASE studentship with NPL and University of Surrey
Amount £150,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2020 
End 09/2024
 
Description Photoacoustic imaging for optimisation of CAR-T cell cancer therapy, matching studentship with NPL funded by Institute of Cancer Research and University of Surrey
Amount £160,000 (GBP)
Organisation University of Surrey 
Sector Academic/University
Country United Kingdom
Start 10/2020 
End 09/2024
 
Title Heated Bed 
Description We developed a heated-bed to obtain optimal positioning of mice exposed to CSI regime. Medulloblastoma CSI clinical relevant regime was performed using MVC and an arc field in brain and 2 arcs field in spine. 
Type Of Material Improvements to research infrastructure 
Year Produced 2018 
Provided To Others? No  
Impact Improved position of the animal. Improved animal welfare. 
 
Description Combined MR-SARRP (with AspectImaging) 
Organisation Aspect Imaging
Country Israel 
Sector Private 
PI Contribution Research will be undertaken to develop MR-guided small animal radiation therapy methods
Collaborator Contribution Provision of high throughput, 1T, small animal MRI system and technical assistance to register to the small animal radiotherapy system (SARRP) provided by Xstrahl.
Impact None yet
Start Year 2016
 
Description Development and evaluation of MSOT (with iThera Medical) 
Organisation iThera Medical
Country Germany 
Sector Private 
PI Contribution Intellectual input and expertise, funding, staff, technical development of hardware, software and methodology, evaluation experiments.
Collaborator Contribution Open access to system hardware, usage advice and expertise, student supervision, free research hardware.
Impact Publications, to date only in the form of conference presentations.
Start Year 2015
 
Description Development and testing tumour cell lines for photoacoustic reporter gene signal (Xinya Hong) 
Organisation Zhongshan Hospital of Xiamen University
Country China 
Sector Hospitals 
PI Contribution Provision of experimental facilities for cell culture and preclinical photoacoustic imaging using multispectral optoacoustic tomography (MSOT), and training in their use with an introduction to and guidance on scientific research practice.
Collaborator Contribution Execution of preliminary experiments using expression of iRFP720 and melanin reporter genes for MSOT imaging.
Impact Preliminary findings for iRFP720 were negative but melanoma cells test positive for MSOT signal and, for the latter, signal strength was highly dependent on the cell culture technique.
Start Year 2019
 
Description Dye and nanoparticle coated microdroplets and microbubbles as photoacoustic imaging contrast agents (with Imperial and Oxford) 
Organisation Imperial College Healthcare NHS Trust
Country United Kingdom 
Sector Hospitals 
PI Contribution Intellectual input, development of experimental imaging methodology, conducting imaging experiments.
Collaborator Contribution Intellectual input, development of methodology for synthesising novel contrast agents, carrying out the synthesis and characterisation of the agents.
Impact No outputs yet.
Start Year 2015
 
Description Dye and nanoparticle coated microdroplets and microbubbles as photoacoustic imaging contrast agents (with Imperial and Oxford) 
Organisation University of Oxford
Department Institute of Biomedical Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, development of experimental imaging methodology, conducting imaging experiments.
Collaborator Contribution Intellectual input, development of methodology for synthesising novel contrast agents, carrying out the synthesis and characterisation of the agents.
Impact No outputs yet.
Start Year 2015
 
Description Novel semiconducting nanoparticles for photoacoustic monitoring of photoimmunotherapy (Imperial College London) 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Writing a small grant proposal, making experimental measurements of quantitative photoacoustic signal level from various types of nanoparticles for combination with measurements of effectiveness of nanoparticles in generating reactive oxygen species when illuminated with IR light which is a measure of photimmunotherapeutic potential. Later, we will test in vitro and in cell culture, the therapeutic capabilities and photoacoustic imaging monitoring potential of each type of nanoparticle, and the move on to conduct similar studies in mouse models in vivo.
Collaborator Contribution Design and manufacture of various types of nanoparticles for testing as above.
Impact Preliminary seed funding of £30 split between ICR and Imperial College.
Start Year 2019
 
Description Photoacoustic imaging for optimisation of CAR-T cell cancer therapy (NPL and Univ Surrey) 
Organisation National Physical Laboratory
Country United Kingdom 
Sector Academic/University 
PI Contribution To date, this has been grant writing.
Collaborator Contribution To date, this has been grant writing.
Impact This has resulted in a successful EPSRC iCASE studentship and an additional associated studentship under iCAE-like conditions funded jointly by the Institute of Cancer Research and the University of Surrey. Students have yet to be recruited and put in post.
Start Year 2019
 
Description Photoacoustic imaging for optimisation of CAR-T cell cancer therapy (NPL and Univ Surrey) 
Organisation University of Surrey
Country United Kingdom 
Sector Academic/University 
PI Contribution To date, this has been grant writing.
Collaborator Contribution To date, this has been grant writing.
Impact This has resulted in a successful EPSRC iCASE studentship and an additional associated studentship under iCAE-like conditions funded jointly by the Institute of Cancer Research and the University of Surrey. Students have yet to be recruited and put in post.
Start Year 2019
 
Description Photoacoustic imaging of carbon nanotube constructs (KCL) 
Organisation King's College London
Department Institute of Pharmaceutical Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, research facilities, researcher time, materials
Collaborator Contribution Intellectual input, materials
Impact No outputs yet. Work in progress.
Start Year 2016
 
Description SARRP development (with Xstrahl) 
Organisation Xstrahl Ltd.
Country United Kingdom 
Sector Private 
PI Contribution All main experimental research, intellectual input, hardware and software development, development of experimental methodology.
Collaborator Contribution Engineering research support. PhD student travel award.
Impact Publications: only in the form of conference presentations to date.
Start Year 2015
 
Description Silicoated gold nanoparticles for targeted photoacoustic and x-ray imaging and radiotherapy enhancement (with University of Liverpool) 
Organisation University of Liverpool
Department Institute of Integrative Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, development of research methodology, conducting experiments.
Collaborator Contribution Intellectual input, provision of materials in the form of silica coated gold nanoparticles.
Impact No outputs yet
Start Year 2015
 
Description European MSOT user meeting 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Organiser and chairman of the European MSOT User Meeting, The Royal Marsden Conference Centre, London, UK, 16th Nov 2016
Year(s) Of Engagement Activity 2016
URL http://www.ithera-medical.com/events.html
 
Description European MSOT user meeting 2017-2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact J Bamber participated in the European MSOT User Meeting, University Hospital, Erlangen, Germany, 1st March 2018
Year(s) Of Engagement Activity 2018
URL http://www.ithera-medical.com/fileadmin/documents/OAI_Meeting_2018_-_itinerary_flyer_low.pdf