Shuttling through the Blood Brain Barrier using Carbon Nanoneedles

Lead Research Organisation: King's College London
Department Name: Pharmaceutical Sciences

Abstract

A significant proportion of the population are affected by diseases of the brain, many of which have limited drug treatment. Such diseases are often difficult to clinically diagnose and treat due to the limitations of brain access. One of the principle obstacles in drug development is brain delivery of the drugs or imaging agents, that can treat the disease or enhance its diagnosis. Recently, ultra small tubular like nanomaterial made of carbon called carbon nanotubes has been developed which could serve as "rafts" that could help transport drugs into the brain or could facilitate imaging of the brain. However, at present there is lack of information about the ability and mechanisms by which these nanotubes can penetrate into the brain through the blood brain barrier. This project will utilise a cellular model of this tight membrane to investigate how these nanotubes cross the endothelial brain membrane and whether they affect its integrity.

Technical Summary

Targeted drug delivery across the blood brain barrier (BBB) to the central nervous system is a large challenge for the treatment of neurological disorders. Drug delivery systems that cross the BBB without disrupting it would also have many applications for brain cancer diagnostic and other diseases, e.g. Alzheimer's disease. There still remains a pressing need for improved nanoparticle delivery systems to target drugs across the BBB. Functionalized carbon nanotubes (CNTs) are receiving increasing attention as vehicles for the delivery of diagnostic and therapeutic agents. The delivery properties of CNTs derive from the potential to deliver a drug by heterogeneously functionalizing their surface and also their ability to traverse the plasma membrane, promoting the cellular uptake of small molecules. However, there is essentially no mechanistic data at the level of individual CNTs to characterise their fundamental interaction with endothelial cells or how this interaction is modified by CNT surface chemistry and targeting to specific BBB receptors such as transferrin receptor or low density lipoprotein receptor-related protein 1. This project aims towards the evaluation of the BBB penetration capacity of novel f-CNT carriers using an in vitro BBB model employing porcine brain endothelial cells (PBECs) chosen due to its high transendothelial electrical resistance when cultured as a monolayer without astrocytes (>300 ohm.cm2) and good expression of the most important drug efflux transporters and P-glycoprotein. f-CNT will be fluorescently labelled or conjugated to a radioactive tracer to allow for qualitative and quantitative measurement of uptake or BBB permeation. Insights into these mechanisms will be essential to guide the development of CNT vectors to deliver drugs across the BBB to the central nervous system for the treatment of neurological disorders.

Planned Impact

This project will have an impact in academia and industry and will address all those interested in brain delivery, blood brain barrier biology and nanomedicine. Such a collaborative project promises to bring about a long-term benefit to the development of UK and European science and its clinical translation. It is relevant to pharmaceutical and medical companies interested in developing novel therapeutic approaches to the brain. The research aims to improve and expand brain delivery options to enhance the quality of life for UK and European citizens. It has the potential to contribute to knowledge transfer among the different national and European collaborators who are experts in their field. The development of nanopharmaceuticals is an emerging multidisciplinary area and research within a multidisciplinary team is mandatory for progress in the field. It is expected that a number of additional national, EU or independently funded collaborative projects will follow the developments achieved by this project. After fundamental understanding of how permeation processes take place, future funding for further clinical testing and commercialisation of the novel nanotube-based brain delivery systems along will be sought along with an industrial partner. Two highly skilled PDRA researchers will result from this work, ripe for employment in pre-clinical, clinical, industrial, or academic sector.

Publications

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Bai J (2016) Real-time monitoring of magnetic drug targeting using fibered confocal fluorescence microscopy. in Journal of controlled release : official journal of the Controlled Release Society

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Costa PM (2016) Functionalised carbon nanotubes: From intracellular uptake and cell-related toxicity to systemic brain delivery. in Journal of controlled release : official journal of the Controlled Release Society

 
Description Angiopep peptide conjugating to CNT increased the brain uptake and resulted in glioma targeting in mouse brain following intravenous injection.
Exploitation Route Further incorporation with therapeutic agents using the developed nanocarrier system can be explored for glioma therapy.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description BBSRC Spark Impact
Amount £10,000 (GBP)
Funding ID N/A 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2015 
End 04/2016
 
Description CRUK KHP Centre Development Fund
Amount £10,000 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 12/2018
 
Description China Scholarship Council Postdoctoral Fellowship
Amount £60,000 (GBP)
Organisation University of Leeds 
Department China Scholarship Council
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 09/2018
 
Description KC Wong Postdoctoral Fellowship
Amount £58,000 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2017
 
Description Katip Celebi Newton Fund
Amount £264,338 (GBP)
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2017 
End 05/2019
 
Description Marie Sklodowska-Curie individual Fellowships
Amount € 183,455 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 10/2017 
End 09/2019
 
Description New Ideas Awards
Amount £98,000 (GBP)
Organisation The Brain Tumour Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2017 
End 06/2018
 
Description Newton Bhabha
Amount £12,800 (GBP)
Funding ID N/A 
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2015 
End 12/2015
 
Description Newton-Bhabha Fellowship
Amount £10,200 (GBP)
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 08/2017
 
Description Newton-Musharafa Fellowship
Amount £20,000 (GBP)
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 03/2020
 
Description Sir Henry Wellcome Postdoctoral Fellowship
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Research Training Fellowship
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 09/2018
 
Description UKEIRI-DST
Amount £22,128 (GBP)
Funding ID UKIERI-DST-2014-15-09 
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 03/2016
 
Description Marie Curie Actions ITN FP7 PEOPLE 
Organisation Marie Sklodowska-Curie Actions
Country Global 
Sector Charity/Non Profit 
PI Contribution In vivo biodistribution and tumour therapy studies of samarium filled carbon nanotubes in mice.
Collaborator Contribution Synthesis, functionalisation and characterisation of samarium filled carbon nanotubes.
Impact N/A
Start Year 2012
 
Description Microfluidics-based BBB 
Organisation National Chung-Hsing University
Department Department of Mechanical Engineering
Country Taiwan, Province of China 
Sector Academic/University 
PI Contribution Our support include providing the brain cells to establish the blood-brain barrier cell model, help in the design and analysis of experiments, and contribution to iterative refinement of the programme needed to generate the most reliable information about the behaviour of the delivery vehicles at the blood-brain barrier.
Collaborator Contribution Develop and standardise the novel microfluidic-based blood-brain barrier device which is designed for high-throughput drug screening. Key advances include real-time monitoring of BBB integrity and measurement of drug permeability.
Impact Multi-disciplinary collaboration: Engineering, Neuronal science, Pharmaceutics and Nanomedicine.
Start Year 2017
 
Description UKEIRI-DST 
Organisation Dibrugarh University
Country India 
Sector Academic/University 
PI Contribution This scheme is established between KCL (UK partner) and Dibrugarh University (India) to work on the project entitled "Development of biodegradable CNS-targeted nanoparticles as a novel therapeutic approach in chemotherapy of Neuro-AIDS". KCL contribution has been to train young researchers on optimisation of the nanoparticles formulation, radiolabeling, testing blood brain barrier crossing in vitro and in vivo, in addition to tumour accumulation studies in mice.
Collaborator Contribution They provided solid lipid nanoparticles to our team and also will host 3 members of UK team to visit their lab.
Impact N/A
Start Year 2015
 
Title Nanoparticles 
Description The discovery cover a type of polymeric nanoparticles containing high amounts of magnetic nanoparticles for the purpose of magnetic targeting of anticancer drugs to solid tumours. The nanoparticles could be used for therapy and/or imaging. 
IP Reference GB1520637.8 
Protection Patent application published
Year Protection Granted 2015
Licensed No
Impact Too early.
 
Description 11th European and Global Summit for Clinical Nanomedicine (CLINAM) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A few people from my group including myself attended this annual conference focusing on developing nanomecines for clinical translation. We presented our work in different research topics either by oral or poster presentations. I gave a talk entitled 'Magnetic Drug Targeting: Preclinical in Vivo Studies, Mathematical Modelling, and Extrapolation to Human'. My post doc LiZhou Xu gave a talk entitled 'Optical Tracking of siRNA Encapsulated Exosomes in Cancer Models in Vitro and in Vivo'. My post doc Julie Wang gave a talk entitled 'Imaging Carbon Nanotubes: Journey from Basic Understanding of the Carrier Biodistribution to Alzheimer's disease Monitoring'. My post doc Adam Walter had a poster presentation entitled Sugarfunctionalised and Farred Fluorescence Emitting Graphene Oxide for Antigen Delivery and Monitoring. My PhD student Farid Faraquhad a poster presentation with the title 'Membrane Radiolabelling of Exosomes for Comparative Biodistribution Analysis in Immunocompetent and Immunodeficient Mice - a Novel and Universal Approach'.
Year(s) Of Engagement Activity 2018
URL https://www.clinam.org/
 
Description 11th Global Drug Delivery and Formulation Summtt 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was an invited speak in the Panel discussion and gave a talk entitled 'Designer Nanomedicine for Cancer Therapy'.
Year(s) Of Engagement Activity 2020
URL https://www.ddfevent.com/
 
Description AICR Open Day @ Kings College London 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Supporters
Results and Impact I gave a presentation on the research carried out from my group. In the hands-on session, my research team demonstrated how to purify nanoparticles by the size and provided a microscope for cancer tissue observation.

Numerous attendees of the event commented that the quality of the research presented, the enthusiasm of participants and the overall positive buzz made it an enjoyable afternoon. Undergraduate students in particular contributed to the day and felt the importance of research which they never realised before.
Year(s) Of Engagement Activity 2013
 
Description Bilkent University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker, "Rationale Design of Nanocarriers for Brain and Cancer Targeting", Bilkent University, Ankara, Turkey (Host: Dr Dönüs Tuncel)
Year(s) Of Engagement Activity 2018
 
Description CBTDDC 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Round table discussion, "Nanomedicine at King's", Children's Brain Tumour Drug Delivery Consortium (CBTDDC) Workshop (Host: Prof. David Walker)
Year(s) Of Engagement Activity 2018
URL http://www.cbtddc.org/workshop/index.aspx
 
Description COST Action TD1004 Annual meeting in Belgrade, Serbia, 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact My PhD students Naomi Hodgins and Jie Bai gave 2 talks:

1. The effect of Liposomal Zoledronic acid on the Biodistribution of ?d T cells in different tumour models".
2. Multi-modal imaging of magnetic nanocapsules in tumours

Talks attracted interest and stimulated questions that are helpful for their PhD project.

EU contribution and further opportunities to Horizon 2020 funding
Year(s) Of Engagement Activity 2015
 
Description International Conference of the Faculty of Pharmacy, Ain Shams University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I am an invited speaker (Host: Dr. Nadia Hamdy). The title of my talk is "Magnetic Drug Targeting".
Year(s) Of Engagement Activity 2018
 
Description Interview for London Centre for Nanotechnology 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact An interview was taken in my lab to mark King's joining with the London Centre for Nanotechnology (LCN) to use the power of nanotechnology to confront global healthcare, energy and environmental challenges. The film has been publicised at LCN August New (https://etio.wistia.com/medias/11jsmp8kd9).
Year(s) Of Engagement Activity 2018
URL https://www.london-nano.com/news-events/kings-college-london-joins-powerhouse-nanotechnology-researc...
 
Description London Centre for Nanotechnology Welcome KCL 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The London Centre for Nanotechnology (LCN) is a UK-based multidisciplinary research enterprise operating at the forefront of science and technology that was founded in 2003 by University College London and Imperial College London. King's College London is now joining this venture. Each of these institutions is a world leader in Nanoscience and our purpose is to solve global problems in data driven economy, healthcare, energy and environment through the application of nanotechnology. With King's joining the LCN, the most talented researchers will be working in Central London and using cutting edge equipment. Collaborations will have the opportunity to flourish and pioneering discoveries have the potential to be made.

To celebrate joining the LCN, King's College London is hosting a launch event on the 3rd September 2018 in the Great Hall at our historic Strand Campus. My group as a partner of the LCN has an exhibition to showcase our work.
Year(s) Of Engagement Activity 2018
URL https://www.london-nano.com/news-events/kings-college-london-joins-powerhouse-nanotechnology-researc...
 
Description Max-Planck Institutes for Chemistry (MPIC) and for Polymer Research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker, "Applications of Nanomedicines in Pancreatic Cancer", Max-Planck Institutes for Chemistry (MPIC) and for Polymer Research (MPIP), Mainz, Germany. (Host: Prof. Volker Mailaender)
Year(s) Of Engagement Activity 2018
 
Description Midatech Pharma 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Industrial seminar, "From Nanocarrier Design to Cell Trafficking and In Vivo Biodistribution", Midatech Pharma, UK (Host: Dr Kelly Conlon)
Year(s) Of Engagement Activity 2018
 
Description NanoFar Autumn School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact My PhD student Naomi Hodgins attended this Autumn School workshop and had a poster presentation entitled 'Novel ErbB targeted liposomes encapsulating zoledronic acid for breast cancer immunotherapy'.

EU contribution.
Year(s) Of Engagement Activity 2013
 
Description NanoFar Autumn School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact My PhD student Jie Bai attended this Autumn School workshop and presented a poster entitled 'Polymeric Nanocapsule for Triple-modal Imaging as A Theranostic System in Cancer Therapy'. She was awarded the Best Poster prize.

EU contribution.
Year(s) Of Engagement Activity 2013
 
Description Nanomedicine Summer School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The Marie Curie Early Stage Researcher, Dr Rebecca Klippstein, presented her work entitled 'Assesment of candidate drugs and cell lines for nanoparticle specific tumour targeting'.

EU contribution
Year(s) Of Engagement Activity 2013
 
Description Nanomedicine Summer School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Elzbieta Pach, a Marie Curie Early Stage Researcher, of my collaborator Dr Ballesteros in Spain, gave a presentation entitled 'Electron Microscopy Studies of Carbon Nanocapsules for Targeted Delivery of Radioactivity' based on our joint project. Laura Cabana, a PhD student of my collaborator Dr Tobias in Spain, gave a presentation entitled 'Multi-Walled Carbon Nanotubes with different lengths decorated with SPION' based on our joint project. The Marie Curie Early Stage Researcher, Maxime Bourgognon, from my group gave a presentation entitled 'The shortening of SPION-MWNTs enhances their biocompatibility and MR properties'.

EU contribution.
Year(s) Of Engagement Activity 2013
 
Description Pancreatic Cancer Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker, "Applications of Nanomedicines in Pancreatic Cancer", Pancreatic Cancer Symposium, Guy's Cancer centre, KCL. (Host: Dr Claire Wells)
Year(s) Of Engagement Activity 2018
 
Description Queen's University Invited Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact I gave a talk on "Uptake of chemically functionalised nanotubes across the blood brain barrier at Queen's University, Belfast. I was invited by Prof. Ryan Donnelly the leader of the Research Seminar Programme at Queen's.

They invite leading scientists from across the globe to visit the University and give a seminar on their work. Over the past few years, other renowned speakers like Richard Guy, Kevin Shakesheff, Clive Wilson and Robert Lochhead (inventor of Carbopol®, designed surfactant formulations for management of the oil spill in the gulf of New Mexico and heat-resistant camouflage for soldiers in Iraq and Afghanistan) speak about their research.


The talk stimulated discussions and initiated collaborations between the 2 universities.
Year(s) Of Engagement Activity 2014
 
Description School seminar Cardiff University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I was an invited speaker (Host: Dr Youcef Mehellou, School of Pharmacy, Cardiff University) to give a talk entitled "Rationale Design of Nanocarriers for Brain and Cancer Targeting".
Year(s) Of Engagement Activity 2019
 
Description Science and Technology Exchange Programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was an invited speaker to give a keynote lecture entitled "Presenting a Successful Model of Muslim Women Involved in the Field of Science and Technology World-Wide". Host: Science Technology Exchange Programme (STEP association), Tehran
Year(s) Of Engagement Activity 2019
 
Description Women in Science Symposium, King's College London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact I was an invited speak in this College event in celebrating the International Women's Day. The talk of my title is 'Challenges and Opportunities for Women in Science'
Year(s) Of Engagement Activity 2020