OxCD3: Oxford Centre for Drug Delivery Devices

Lead Research Organisation: University of Oxford
Department Name: Engineering Science

Abstract

The greatest challenge in oncological drug delivery is achieving successful penetration and distribution of the therapeutic agent throughout the tumour: billions of pounds have been spent to date in deploying biochemical approaches in an attempt to solve what is essentially an engineering problem, namely the transport of therapeutics from the blood stream to reach every cancer cell.

OxCD3 will seek to transform both clinical and industry practice in drug delivery by demonstrating the value and feasibility of engineering approaches, involving a combination of stimulus-responsive nanocarriers and medical devices already in clinical use, for improved tumour uptake and therapeutic outcome. The Programme Grant will enable the creation of a sustainable, world-unique multi-disciplinary environment for combinational engineering of biology, chemistry and medical devices to improve drug delivery under a single roof. It is also expected to create a unique training environment for the next generation of young scientists working on combination therapies and biomedical nanotechnology, by providing direct exposure to regulatory and manufacturing issues encountered when translating laboratory research into production and clinical practice.

A unique feature of the Centre is the capability to design both devices and drug delivery vehicles under a single roof. In the first 5 years, under EPSRC funding, up to 3 carefully selected "Device+Drug" exemplars will be manufactured to GMP, ready for Phase I clinical trials, to provide compelling evidence of feasibility to industrial partners and clinicians; in the next 5 years, a private-public partnership will be built to complete clinical trials of these exemplars using therapeutics of strategic significance to the pharmaceutical industry; beyond 10 years, full industrial sponsorship of the OXCD3 is anticipated, which will focus on addressing next-generation challenges in drug delivery (beyond cancer) in partnership with industry and clinicians. The transformative aim over 50 years is to position the UK as the world leader for multi-disciplinary drug delivery development, complementing its existing position as a drug discovery leader, from design to manufacture and clinical trials.

Planned Impact

The proposed programme grant spans two of EPSRC's core strategic areas, "Healthcare Technologies" and "Manufacturing the Future" and will be key in providing the UK with a world-leading position in the exploding fields of targeted drug delivery and nanotechnology biomanufacturing. In addition to academic excellence in addressing the greatest challenge in oncological drug delivery (achieving tumour penetration), its aim is to provide the underlying science and manufacturing know-how that will enable successful delivery of existing and future anti-cancer agents, transforming both UK healthcare and UK industry.

True impact in biomedical engineering and drug delivery is achieved in one of three, often interlinked ways: translation from bench to bedside through clinical trials and demonstration of therapeutic efficacy; dissemination of transformative science and techniques through high-impact peer-reviewed publications for uptake by the academic and industrial communities; and commercialization of new advances, either through licensing to existing manufacturers or through the formation of new spin-out companies.
The impact of major advances in drug delivery has historically been limited by three factors:
(i) Scale-up: most innovative drug carrier manufacturing techniques developed in the laboratory are poorly suited to large-scale manufacturing, and often overlook the constraints of manufacturing to GMP as needed for clinical trials, thus requiring major and costly redevelopment before clinical trials and uptake by industry.
The OXCD3 difference: Involve the Clinical Biomanufacturing Facility from day one, so that laboratory techniques are selected from an early stage to be compatible with GMP scale-up.
(ii) Non-anticipation of regulatory hurdles, particularly for complex combinational products: the choice of drug vehicle materials and of the type of excitation required for device-triggered release will greatly affect the cost and complexity of experimentation and biocompatibility studies required for regulatory approval to enter the clinic.
The OXCD3 difference: Involve clinicians and a qualified pharmacist (QP) with direct experience of managing drug, device and combinational trials from day one,
(iii) Excessively long timescale to first-in-man trials:
The OXCD3 difference: Deliver not only transformative science but also three exemplars already manufactured to GMP ready for a clinical trial by the end of the funding period.

Publications

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Ackerman NL (2018) Targeted alpha therapy with Pb or Ac: Change in RBE from daughter migration. in Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB)

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Bavelaar BM (2018) Subcellular Targeting of Theranostic Radionuclides. in Frontiers in pharmacology

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Bavelaar BM (2018) Subcellular Targeting of Theranostic Radionuclides. in Frontiers in pharmacology

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Beguin E (2019) Comparing Strategies for Magnetic Functionalization of Microbubbles. in ACS applied materials & interfaces

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Bhatnagar S (2016) Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines. in Journal of controlled release : official journal of the Controlled Release Society

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Bhatnagar S (2016) Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines. in Journal of controlled release : official journal of the Controlled Release Society

 
Description The Oxford Centre for Drug Delivery Devices (OxCD3) launched on the 23rd July 2014 to address one of the greatest challenges in oncology: achieving successful penetration and distribution of the therapeutic agent throughout the tumour.

The Centre's research spans 4 work packages (WPs), each led by at least one physical and one medical investigator, and resourced with two post-doctoral fellows and 2-3 doctoral (DPhil) students.
o WP1 (Coussios, Seymour, Carlisle) exploits cavitating nanoparticles for ultrasound-enhanced delivery of biologics.
o WP2 (Carlisle, Vallis) develops liposomal encapsulation technologies for ultrasound-enhanced delivery of radiopharmaceuticals.
o WP3 (Cleveland, Rabbitts) investigates the use of shock waves for delivery across the cell membrane.
o WP4 (Stride, Sibson) is concerned with combining magnetic and ultrasound approaches for brain theranostics.
Exploitation Route Active collaborations under CDAs and MTAs with pharma partners (GSK, Medimmune, AstraZeneca) to identify how to take these advances into the clinic over the next 3 years
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://www.drugdelivery.org
 
Description Invitation to discuss Secretary of Business, Energy and Industry Strategy how government can support growth of biomedical engineering businesses
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Scientific Advisory Board NORMOLIM; the Norwegian Molecular Imaging Infrastructure
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Bloodwise (formerly known as Leukaemia & Lymphoma Research)
Amount £1,400,000 (GBP)
Organisation Bloodwise 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 02/2019
 
Description CRUK Pioneer Award
Amount £200,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2016 
End 06/2018
 
Description Chromosomal translocation genes and their protein interactions in cancer
Amount £2,223,000 (GBP)
Funding ID MR/J000612/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description EPSRC Responsive Mode
Amount £1,100,000 (GBP)
Funding ID EP/R013624/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 08/2018 
End 07/2021
 
Description Marie Sklodowska-Curie Individual Fellowship
Amount € 184,000 (EUR)
Funding ID 654985 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2015 
End 03/2017
 
Description NIH - OXCAM scholarship
Amount $200,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 09/2019 
End 08/2021
 
Description Pancreatic Cancer Research Fund
Amount £180,000 (GBP)
Organisation Pancreatic Cancer Action (PCA) 
Sector Charity/Non Profit
Country Unknown
Start 06/2017 
End 06/2019
 
Description Rosalind Franklin Institute
Amount £3,500,000 (GBP)
Organisation Research Complex at Harwell 
Sector Public
Country United Kingdom
Start 03/2019 
End 02/2023
 
Description Royal Commission for the Exhibition of 1851 - industrial fellowship
Amount £120,000 (GBP)
Organisation Royal Commission for the Exhibition of 1851 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2021
 
Description Seeding Drug Development Award
Amount £3,825,714 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2012 
End 02/2017
 
Description Wellcome Trust SI Award
Amount £2,345,550 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2012 
End 02/2019
 
Description Delivery of liposomal mRNA 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We have identified novel methods of delivering liposomal mRNA to cells using shock waves and ultrasound
Collaborator Contribution We have been provided with a proprietary mRNA liposomal formulation and expertise on how to quantify mRNA delivery.
Impact There are no published outputs yet.
Start Year 2016
 
Description High-speed imaging of ultrasound-enhanced drug delivery and associated mechnanisms 
Organisation University of Twente
Department Physics of Fluids
Country Netherlands 
Sector Academic/University 
PI Contribution We have designed, manufactured and supplied novel vehicles for ultrasound-mediated drug delivery, expertise in real-time cavitation detection, and a member of staff for up to 10 weeks to help conduct experiments in Twente.
Collaborator Contribution Access to a world-unique ultra-high-speed camera (Brandaris) and access for up 10 weeks to an expert researcher to setup and conduct the experiments.
Impact In vitro methods to study bubble-cell interactions: Fundamentals and therapeutic applications. G Lajoinie, I De Cock, CC Coussios, I Lentacker, S Le Gac, E Stride, M Versluis Biomicrofluidics 10 (1), 011501 (2016)
Start Year 2014
 
Description University of Twente 
Organisation University of Twente
Department Developmental BioEngineering (Twente)
Country Netherlands 
Sector Hospitals 
PI Contribution my team has provided materials and expertise for the fabrication of drug loaded microbubbles and nanoparticles for initiating cavitation as well as microfluidic systems
Collaborator Contribution The University of Twente has provided us with access to their unique high speed imaging facility to study various phenomena related to ultrasound mediated cavitation. They have hosted several of our researchers over a series of visits.
Impact V. Pereno, M. Aron, O.Vince, C. Mannaris, A. Seth, M. de Saint Victor, G. Lajoinie, M. Versluis, C. Coussios, D. Carugo, E. Stride. Layered acoustofluidic resonators for the study of the physical and biological effects of acoustic cavitation. Biomicrofluidics 12: 034109 (2018) G. Lajoinie, J. Lee, P. Kruizinga, J. Owen, G. van Soest, N. de Jong, E. Stride and M. Versluis. Laser driven resonance of microbubbles: experimental study. J. Acoust. Soc. Am. 141: 4832-4846 (2017) G. Lajoinie, E. Linnartz, P. Kruizinga, G. van Soest, E. Stride and M. Versluis. Laser driven dynamics of optically absorbing microbubbles: a theoretical and numerical study. J. Acoust. Soc. Am. 141 (4), 2727-2745 (2017) J. Kwan, G. Lajoinie, N. de Jong, E. Stride, M. Versluis, C. Coussios. Ultra High Speed Dynamics of Micron- Sized Inertial Cavitation from Nanoparticles. Physical Review Applied 6:044004 (2016). J. Kwan, G. LaJoinie, E., M. Versluis, and Constantin Coussios. Bubble dynamics of inertial cavitation from nanoparticles. The 14th International Symposium on Therapeutic Ultrasound, Utrecht, The Netherlands 15th-18th April 2015 all interdisciplinary: Engineering, Physics, Oncology, Imaging
Start Year 2015
 
Title TarDox 
Description Non-invasive targeted doxorubicin delivery from thermosensitive liposomes using high-intensity focussed ultrasound in cancer patients with metastases to the liver. This is a first-in-man trial enabled by the work carried out under my Challenging Engineering award and supported by the Oxford Centre for Drug Delivery Devices (OxCD3) and the Oxford BRC (NIHR) . 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Ten patients were successfully treated between 2016 and 2018 and the outputs of the trial were reported in Lancet Oncology (2018) and Radiology (2019) 
URL https://clinicaltrials.gov/ct2/show/NCT02181075
 
Description Expert comment for BBC news; press release on focused ultrasound blood-brain barrier (BBB) opening (Nov 2015) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I was asked to provide an expert opinion on recent findings from a group in the United States in which they demonstrated focussed opening of the blood-brain barrier in primary brain tumours.
Year(s) Of Engagement Activity 2015
 
Description MRC Festival of Medical Research 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact The MRC festival is a one week travel around public spaces in towns around Oxford. The idea is to reach out to people who live too far away to come to us. And to put ourselves in the way of people who might not come to a science event - we're setting up shop in supermarkets, shopping centres and markets. It was very successful last year with nearly 1000 people talking to us over the week.
Year(s) Of Engagement Activity 2017
 
Description MSc and DTC Lectures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Regular lectures on brain imaging in cancer and neurosciences to Doctoral Training Course and M.Sc. students, which sparked questions and discussion as well as interest in entering research within this field of research. Outcome is often one or more students joining the group for either M.Sc. or D.Phil. projects.

Development of collaborations and numerous examples of interest in applying our VCAM-targeted technology in different patients groups from paediatrics to head injury.
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Mercedes Family Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Manned a stall at the Mercedes family day for CRUK, explaining aspects of cancer research within the Institute. Lots of people participated and were very engaged and interested in the research being done.
Year(s) Of Engagement Activity 2017
 
Description Staff talk for CRUK at Mercedes-Benz Grand Prix 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation of CRUK funded work at Mercedes-Benz as CRUK is their nominated charity. Many of the audience (approx 100) found resonance with the topic (brain cancer) and commented afterwards that they were interested and excited to hear what research is being done.
Year(s) Of Engagement Activity 2017
 
Description Super Science Saturday 
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 Public engagement event at the Natural History Museum in Oxford - 2 postdocs participated in sharing our research with the public.
Year(s) Of Engagement Activity 2017
 
Description Talk at Founders Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The talk was supposed to raise awareness about the role of engineering approaches in healthcare, specifically cancer treatment. It has generated significant media interest and contacts from industrial and medical practitioners.
Year(s) Of Engagement Activity 2018
URL https://www.havaslynx.com/founders-forum-health-tech-2018/