Development of Theranostic Nanoparticles; MRI-responsive, thermosensitive drug carriers activated by MRg FUS for local tumour drug release

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry

Abstract

Our proposed research program is concerned with how to mobilize physical science and engineering innovation in nanoparticle drug carrier design from basic science laboratory to medical application. In order to do this, Prof Miller's chemistry team (Imperial) with expertise in nanoparticle technologies, will collaborate closely with Dr Maya Thanou's pharmaceutical sciences team (Kings) in the design, formulation and characterization of MRI-responsive thermosensitive drug carrier nanoparticles (theranostic ABC nanoparticles) that have the capacity to accumulate in cancerous lesions (fibroids or tumours), in real time post administration in vivo (as observed by MRI). Thereafter, we will collaborate with and make use of the expertise of the research teams of Prof Gedroyc and Dr Stebbing (Imperial, Medicine) to demonstrate that these nanoparticles can then be activated by means of magnetic resonance guided focused ultrasound (MRgFUS) to release drug locally at sites of nanoparticle accumulation within the relevant lesion. This combined process should be able to deliver a powerful anti-cancer effect that also improves radically on local drug bioavailability (specific only to tumours) and drug efficacy while minimizing systemic drug toxicity. Nanoparticle modelling and fluid dynamics studies will then be performed by the team of Prof Xu (Imperial, Chemical Engineering) in order to improve our understanding of the delivery barrier and drug release and uptake process. Thereafter we shall seek to take this understanding to optimize MRgFUS-activated theranostic nanoparticle mediated drug delivery of actives in vivo provided by our healthcare partner Antisoma. We anticipate that Antisoma and our other healthcare partners [the Focused Ultrasound Surgery (FUS) Foundation and MacMillan Nurses] will assist us with the commercialization process thereafter including providing some of their novel anti-cancer compounds for local delivery, to increase efficacy and decrease toxicity.

Planned Impact

The proposed research program aims at the development of theranostic nanoparticles for Cancer. Cancer is one of the mostly frequent life threatening diseases. There are more than 293,000 new cases of cancer (excluding non-melanoma skin cancer) diagnosed each year in the UK, and more than 1 in 3 people will develop some form of cancer during their lifetimes. For the first time in the UK, researchers from two leading institutes of teaching and research (Imperial College London and Kings College London) that represent three discrete disciplines (Medicine, Engineering and Chemistry) propose to form a partnership with a London stock exchange-listed biotech company (Antisoma Ltd), a global biomedical charitable foundation (the Focused Ultrasound Surgery Foundation [FUS Foundation]), and a leading UK provider of Cancer care (MacMillan Nurses) to develop and apply smart nanotechnology for the advanced treatment of Cancer. The project aims to enhance the quality of life of all those who suffer from Cancer. Direct beneficiaries: Output and outcomes from the proposed research program will directly benefit the non-academic partners involved with this project. 1 Antisoma; a biotechnology company specialising in the development of novel drugs for the treatment of cancer. The output and outcomes from the proposed research program are certain to be of interest and benefit to big Pharma companies too. 2) The FUS Foundation as a non-commercial collaborator will also immediately benefit from the output and outcomes of the proposed research program. 3) The MacMillan Nurses will benefit through being seen to be a leading medical exponent and champion for leading edge smart nanotechnologies for Cancer treatment. Indirect beneficiaries: Indirectly, 1) data generated will assist in the development of even further novel nanotechnologies for Cancer in a novel area of Cancer research (Nanooncology) 2) millions of cancer patients world-wide will benefit from the development of routine detection and treatment of small size tumours and their metastases without the need for operation, hospitalization and with minimal adverse effects from chemotherapy. The approached described in our proposed research program should be so specific that Cancer lesions will be treated while neighbouring healthy tissues can remain completely unaffected. Consequently the output and outcomes from the proposed research program should substantially improve the effectiveness of cancer chemotherapeutic treatments and provide a substantially enhanced management of the disease. Therefore, the benefits to cancer patients and the NHS should be obvious. Moreover, such smart, drug delivery nanotechnologies applied to Antisoma drugs will position Antisoma with the opportunity to develop new highly competitive cancer therapies and take a position in novel smart, drug delivery nanotechnologies that could render potentially wider ground-breaking changes in cancer therapy, thereby boosting substantially the global competitiveness of this (and potentially other) UK based biotech companies specialising in cancer therapies. All this will all be made possible by the actions of a dedicated core academic team (headed by Prof Miller of Imperial College) carrying out the proposed research program with the assistance and collaboration of the key healthcare partners (Antisoma, FUS Foundation and the MacMillan Nurses) working together in a disciplined process of regular reporting, monitoring, discussing, guiding and advice giving in order to keep the proposed research program to plan. Antisoma will assist with links and networking with other biotech and pharma working in the area of Cancer therapies, and has the means for commercial development of the output and outcomes from the current proposed research program. Clinical enthusiasm for smart nanotechnologies will be boosted in collaboration with the FUS Foundation and MacMillan Nurses who will open the door to the Oncology community.

Publications

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Cong Liu (2012) An integrated systems-based modelling framework for investigating the effect of anticancer drugs on solid tumors in American Institute of Chemical Engineers Annual Meeting, Pittsburgh, US,

 
Description We have developed a variety of drugs that incorporate anticancer chemotherapeutic agents which are not active in the body when given in these new formulations, but which can be released and activated at the chosen site of action by non-invasive focussed ultrasound heating within the body. We have proved that we can release such combinations using heat from focused ultrasound which is delivered completely noninvasively. We have proven that such drug release has significant anti-tumour activity within the body when it is delivered under these circumstances and the work has also optimised the delivery to local tumours in the body so that we can achieve very substantial increases in drug concentration in tumours in comparison to conventionally delivered chemotherapy.
Exploitation Route These new combinations need to be tested in early human studies in the 1st instance once early toxicity and safety results have been carried out . Early human work will have to be carried out carefully to demonstrate that cell death can be induced in a controlled manner at the desired site of action in the body. This process is currently in development with our collaborators and partners.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description King's Commercialization Institute
Amount £120,000 (GBP)
Organisation King's College London 
Department King's Commercialisation Institute
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 08/2015
 
Description Kings comemercialisation 2015
Amount £96,000 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 11/2015 
End 12/2016
 
Description UK-China Scholarships for Excellence programme
Amount £120,000 (GBP)
Organisation University of Sheffield 
Department UK-China Scholarships for Excellence Programme
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 07/2017
 
Title Mathematical models of local heat sensitive drug delivery 
Description New mathematical models have been developed for: (i) the transport and uptake of doxorubicin-encapsulated thermosensitive liposomes (TSL) in solid tumours; (ii) bioheat transfer in solid tumour incorporating heating by high-intensity focused ultrasound (HIFU). 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact The mathematical models can be used to (i) optimize the heating schedule for TSL-mediated delivery of doxorubicin activated by HIFU; (ii) evaluate the effects of delivery schedule, TSL-related transport properties and doxorubicin release rate on anticancer efficacy for a specific tumour. 
 
Title Near infrared optical fluorescence guidance of focused ultrasound results 
Description The use of infrared optical fluorescence probes linked to delivered liposome heat sensitive drug combinations allows a demonstration of uptake in tumours. The tumours may be visualised simply and subsequent tumour behaviour post drug release can be visually assessed. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2012 
Provided To Others? Yes  
Impact The vivid demonstration of results that this technique allows and the rapidity of imaging assessment that it permits has allowed our group to obtain further funding at this stage from the Kings College London commercialisation group. 
 
Description Commercialisation of focused ultrasound drug compounds 
Organisation GlobalAcorn
Country United Kingdom 
Sector Private 
PI Contribution Basic research work in this field
Collaborator Contribution Involvement and development in the future commercialisation of the results of the basic work and in potential of large-scale manufacture
Impact No outcomes as yet but intellectual property issues are currently being filed
Start Year 2012
 
Description Drug activation by focused ultrasound 
Organisation InSightec
Country Israel 
Sector Private 
PI Contribution Exchange of methodology information for basic research utilising animal models in focused ultrasound mediated drug delivery
Collaborator Contribution Contribution of technological information about basic focused ultrasound methodologies and ultrasound transducer methodologies
Impact No outcomes yet
Start Year 2011
 
Description Sonoporation project collaboration 
Organisation University of Dundee
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Exchange of information for carrying out the methodology of drug activation in animals and its visualisation
Collaborator Contribution Involvement in the SONOPILL project funded by EPSRC
Impact No outcomes as yet. Work is proceeding in collaboration with University of Dundee
Start Year 2011