Imaging, Nuclear Targeting and Modulation of DNA Damage Responses by Polyfunctionalized Nanoparticles in Tumour Cells

Lead Research Organisation: University of Birmingham
Department Name: Clinical and Experimental Medicine

Abstract

Looking small thinking big - what is nanotechnology? One of the definitions of nanotechnology describes it as:
?The design, characterization, production, and application of structures, devices, and systems by controlled manipulation of size and shape at the nanometer scale (atomic, molecular, and macromolecular scale) that produces structures, devices, and systems with at least one novel/superior characteristic or property.? There are quite a few other definitions as well and some confusion about what nanotechnology really means. In simple terms we can say that nanotechnology is a science of small bits of man-made materials that are about thousand to ten thousand times smaller than the thickness of human hair. The ?man-made? is important because otherwise all natural molecules and material particles would have to be included. What is also important is that these small bits of material can gain very unusual and unique properties, not found in the bigger pieces. Our research is trying to exploit these new qualities of the old materials to improve the health prospects of cancer patients. We shall change the surface properties of tiny gold and platinum spheres made in our laboratory in such a way that will allow them to find,enter and mark cancer cells so X-rays machines and other scanners used in diagnostic procedures can better see them. They will also have the ability to amplify the effects of radiation used for treating tumours and to knock-down cancer cell defences against it. Does it mean then that small is always beautiful? Not really. As much as these new tiny nanoparticles can gain the unique properties that are desirable and useful, in the same way their new qualities can be unexpectedly harmful. We shall investigate these potentially harmful effects in normal human cells, so we can select the particles that would have the most potent effects on the cancer cells whilst being the least harmful to surrounding normal cells.

Technical Summary

Nanotechnology represents the area of science focused on the manipulation of atoms and molecules that leads to new structures in the nanometer scale range. These structures often gain unique and unexpected properties. In cancer nanotechnology the focus is on development of nanoscale devices that can diagnose, deliver therapeutic agents, and monitor cancer treatment progress. The early and efficient detection of small cancer (and, possibly, pre-cancerous) lesions remains the most important goal of diagnostic imaging. Increasing target selectivity is critical for nanovectors acting as carriers for both imaging and therapeutic payloads. Ideally, any imaging or therapeutic system would be exclusively targeted to the tumour cell clusters or tumour cell vasculature, preferably with the ability to do so at early stages of malignant transformation. Effective as all the individual approaches might be by themselves, we believe that the greatest gains will be achieved by their synergistic combination. The past decades had seen an outstanding progress in our understanding of the fundamental cancer biology, but this development was not accompanied by comparable advances in the clinic. For example the radiation therapy in humans benefited much more from the technical progress and computerization rather than from knowledge-based manipulation of the biological responses of cancer cells to therapeutic radiation. In this proposal, we introduce the development of novel, multi-functional nanocariers that would translate our understanding of DNA damage responses and new nano-imaging technologies into more efficient ways of diagnosis and treatment of cancer. Our strategy is to design and test multifunctional gold and platinum nanoparticles with following desired properties:

? Potential for in vivo imaging of targeted tumour cells
? Increased target selectivity for cancer cells
? Capability to increase the dose efficacy of radiotherapy and ability to inhibit DNA damage responses in targeted cells

In line with the MCMB Committee?s recommendations regarding our previous, more extensive, application, this is a proof-of-principle streamlined research proposal that will focus on the development of prototype polyfunctional nanoparticles with selected properties followed by testing predicted specificity of biological responses in vitro only.

Publications

10 25 50
 
Description Citation in the ESRF future developments review
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
Impact The nanoimaging program has been identified as a priority in the future planned expansion of ESRF
 
Description ESRF Project grant
Amount £37,323 (GBP)
Organisation European Synchrotron Radiation Facility 
Sector Academic/University
Country European Union (EU)
Start 09/2009 
End 05/2010
 
Description ESRF project grant
Amount £44,788 (GBP)
Organisation European Synchrotron Radiation Facility 
Sector Academic/University
Country European Union (EU)
Start 09/2010 
End 04/2011
 
Description MRC Follow on Fund
Amount £75,550 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2013 
End 04/2014
 
Description project grant/Birmingham Children's Hospital Research Fund
Amount £50,461 (GBP)
Organisation Queen Elizabeth Hospital Birmingham Charity (QEHB) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2009 
End 03/2010
 
Description project grant/Birmingham Children's Hospital Research Fund
Amount £37,323 (GBP)
Organisation European Synchrotron Radiation Facility 
Sector Academic/University
Country European Union (EU)
Start 03/2009 
End 03/2010
 
Title Synchrotron X-ray imaging of nanoparticles in cells 
Description A unique method had been developed for the intracelular imaging of internalized nanoparticles using hard X-ray probe 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact A novel method in the development of nanovectors for use in medicine and biotechnology 
 
Description Collaboration with a partner in NHS 
Organisation University Hospitals Birmingham NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Access to facilities, poject development
Collaborator Contribution Project development, joint grant applications
Impact joint grant application submitted
Start Year 2010
 
Description Collaboration with the Industrial Partner 
Organisation Johnson Matthey
Country United Kingdom 
Sector Private 
PI Contribution Project development, access to the facilities,
Collaborator Contribution access to the facilities, intelectual input to the project development
Impact A large joint project grant application under MICA scheme
Start Year 2010
 
Description Intenational collaboration and Horizon 2020 proposal submitted 
Organisation University of Turin
Country Italy 
Sector Academic/University 
PI Contribution Project proposal for Horizin 2020 programme
Collaborator Contribution Project proposal submitted for Horizon 2020 programme
Impact Multidisciplinary proposal to Horizon 2020 programme: Title of Proposal: Neutron Capture Therapy (NCT): a non-conventional radiotherapy for the treatment of Malignant Pleural Mesothelioma based on a theranostic approach using Gd/B multimodal probes. Acronym: MesoTHER Physics Chemistry Medicine Biology
Start Year 2014
 
Description International collaboration 
Organisation European Synchrotron Radiation Facility
Department Nanoimaging Group ESRF
Country France 
Sector Academic/University 
PI Contribution training of staff, intelectual input
Collaborator Contribution research program extension
Impact 20879836 Two successful project grant applications to ESRF A new research grant application to MRC submitted Our nanoparticle imaging work at European Synchrotron Research Facility (ESRF) had been chosen as one of the strategic highlights for the year 2010: www.esrf.eu/UsersAndScience/Publications/Highlights/2010 and selected as strategic future priority. The
Start Year 2009
 
Description International collaboration 
Organisation Joseph Fourier University
Department Grenoble Institute of Neuroscience INSERM (U836)
Country France 
Sector Multiple 
PI Contribution Access to facilities, intelectual input
Collaborator Contribution access to facilities, intelectual input
Impact joint grant application
Start Year 2010
 
Description International consortium for Horizon 2020 programme 
Organisation National Institute for Nuclear Physics
Country Italy 
Sector Academic/University 
PI Contribution Horizon 2020 project proposal
Collaborator Contribution Multidisciplinary Horizon 2020 project proposal
Impact Horizon 2020 proposal submitted: Title: Cell-targeted radiotherapy with accelerator produced neutrons Acronym: RACER - Radio frequency ACcelerator-based facility for cancER Medicine Physics Chemistry Biology
Start Year 2014
 
Description The Brain Tumour Charity Quest for Cures Initiative Programme grant application 
Organisation European Synchrotron Radiation Facility
Department Nanoimaging Group ESRF
Country France 
Sector Academic/University 
PI Contribution Leading applicant and coordinator
Collaborator Contribution Co-applicants
Impact programme grant application
Start Year 2016
 
Title Targeted nanoparticles for cancer imaging and therapy 
Description Precious metal based functionalized nanoparticles for cancer treatment and imaging 
IP Reference WO2013/179014 
Protection Patent application published
Year Protection Granted
Licensed No
Impact Commercial licensing under negotiations
 
Description Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact A talk had been delivered to a private sector company interested in collaboration

A joint grant application under the MICA scheme with this industrial partner
Year(s) Of Engagement Activity 2010