Hybrid Lipid - Inorganic nanoparticles for drug delivery to the brain

Drug delivery to the brain is challenging and relies on crossing a semipermeable membrane known as the blood-brain barrier (BBB). The BBB is an endothelial cell monolayer that separates the blood from the cerebral central nervous system (CNS). This tight junction in the BBB presents a physical barrier to the permeability of the majority of drugs from the blood to the CNS when administered intravenously. Oxidative stress plays a significant role in the pathology of multiple neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease and stroke. Certain inorganic nanoparticles (NPs) are powerful antioxidants with robust activity and it was recently shown that they are promising candidates for novel therapy of neurodegenerative diseases involving oxidative stress that can neutralize several important pathological reactive oxygen species that can lead to neurodegeneration. Whilst they show great therapeutic promise, their small size (3-4 nm) means they are rapidly cleared from the body, accumulate in the liver and spleen, are unable to reach the brain and show off-target toxicity. Lipid nanoparticles (LNPs) are a promising noninvasive strategy to protect drug payload and toxicity, and have been employed as delivery vehicles to treat many diseases such as cancer and recently in two COVID vaccine formulations. They can enhance penetration into the brain and although they show superior performance there are limited number of studies. LNPs offer advantages over current nanoformulations, including favourable drug payloads due to their high internal surface area, simple preparation protocols, superior ease of conjugation, biodegradability/ biocompatibility, and the ability to encapsulate hydrophobic and hydrophilic cargo. The aim of this project is to create colloidally stable soft matter formulations that encapsulate inorganic NPs into various novel LNPs (100-200 nm) developed in our labs. These hybrid lipidinorganic NPs will be characterized using Dynamic Light Scattering, Small Angle X-ray Scattering and cryo-TEM and long term stability studies. Encapsulation and release of the inorganic NPs will be assessed spectroscopically. The inherent heterogeneity within a nanomedicine formulation can lead to a range of behaviours and properties that influence the overall functionality of the product. We will investigate the heterogeneity of these soft matter formulations by asymmetric flow field flow fractionation (AF4) to separate LNPs into distinct subpopulations based on their size and shape, which are characterised by in-line multi-angle light scattering, UV-Vis spectroscopy and dynamic light scattering. The fractionated LNP subpopulations will also be characterized off-line to elucidate heterogeneities in drug-loading and release, which is crucial for performance.

1. PEOPLE. The SOFI2 CDT will have varied economic and societal impacts, the greatest of which will be the students themselves. They will graduate with a broad and deep scientific education as well as an entrepreneurial mind-set combined with business awareness and communication skills. The training programme reflects the knowledge and skills identified by industry partners, the EPSRC, recent graduates and national strategies. Partners will facilitate impact through their engagement in the extensive training programme and through the co-supervision of PhD projects. Responsible Innovation is embedded throughout the training programme to instil an attitude towards research and innovation in which societal concerns and environmental impact are always to the fore. The team-working and leadership skills developed in SOFI2 (including an appreciation of the benefits that diversity brings to an organisation and how to foster an atmosphere of equality and inclusion) will enable our graduates to take on leadership roles in industry where they can, in turn, influence the thinking of their teams.

2. PROJECTS. The PhD research projects themselves are impact pathways. Approximately half the projects will be co-sponsored by external partners and will be aligned to scientific challenges faced by the partner. Even projects funded entirely by the EPSRC/Universities will have an industrial co-supervisor who can provide advice on development of impact. The impact workshops and Entrepreneur in Residence will additionally help students to develop impact from their research, while at the same time developing the mind-set that sees innovation in invention.

3. PUBLIC. The public benefits from innovation that comes from the research in the CDT. It also benefits from the training of a generation of researchers trained in RI who seek out the input of stakeholders in the development of products and processes. The public benefits from the outreach activities that enable them to understand better the science behind contemporary technological developments - and hence to make more informed decisions about how they lead their lives. The younger generations benefit from the excitement of science that might attract them to higher education and careers in STEM subjects.

4. PARTNERSHIPS. SOFI2 involves collaborative research with >25 external partners from large multinationals to small start-ups. In addition to the results of sponsored projects and the possibility of recruiting SOFI2 students, companies benefit from access to training resources, sharing of best practice in RI and EDI, access to the knowledge of the SOFI2 academics and sharing of expertise with other partners in the SOFI2 network. This networking is of particular benefit to SMEs and we have an SME strategy to facilitate engagement of SMEs with SOFI2. SME representation on the Management and Strategic Advisory Boards will support the SME strategy.

CPI/NFC is a key partner both for delivery of training and to connect SOFI2 research, students and staff to a wide network of companies in the formulated products sector.

The unusual partnership with the Leverhulme Research Centre on Forensic Science may lead to a stronger scientific underpinning of forensic evidence with positive impacts on the legal process and the pursuit of justice.

5. PRODUCTS. Partner companies identify areas of fundamental and applied science of interest to them with the knowledge that advances in these areas will help them to overcome technological challenges that will lead to better products or new markets. It is an expectation that scientific discoveries made within the CDT will drive new products, new markets and potentially new companies. SOFI2 CDT seeks also to develop innovative training materials, for example, in RI and in data analytics and AI (in collaboration with the Alan Turing Institute), from which other CDTs and training organisations can benefit.