Targeted drug delivery for inflammatory bowel disease utilising exosome-based technology.

Inflammatory bowel disease (IBD) can result in debilitating physical and psychosocial symptoms for patients and affect society through loss of schooling, absenteeism, and health-care costs. More than 6.8 million people are estimated to be living with IBD worldwide. IBD comprises of ulcerative colitis (UC) and Crohn's disease (CD), two chronic, relapsing disorders of the gastrointestinal tract. In UC, inflammation is continuous and widespread and disturbs the superficial mucosal layer of the large intestine or the colon. CD on the other hand is characterized by deeper and more erratic inflammation that can occur throughout the entire digestive tract.

First-line treatment strategies involve the use of small molecule therapeutics, including 5-aminosalicylates, corticosteroids, systemic immunomodulators and JAK inhibitors. However, due to the limited efficacy of these modalities, extensive effort has been put into developing novel biologics for the treatment of IBD, such anti-TNF-alpha and anti-integrin antibodies. The drawback of these systemic treatment strategies are the serious and sometimes fatal, adverse effects. These factors, coupled with complex dosing regimens, contribute to poor patient adherence that is in turn associated with poor clinical outcomes, increased healthcare costs, and increased rates of hospitalization and relapse.

Various nano-based drug formulations have been used to improve the therapeutic efficacy and safety of chemical and biomolecular drugs. However, clinical translation of these systems is limited by their rapid clearance from the body, and the cytotoxicity of the materials used. Consequently, an endogenous nanoparticle that has been receiving increasing attention is exosomes; these are nanometre-sized lipid-bilayer-enclosed extracellular vesicles, which are released by cells to shuttle lipids, proteins and nucleic acids to neighbouring cells. Exosomes have distinct advantages over synthetic nanoparticles, such as their small size for penetration into deep tissues, limited immunogenicity, slightly negative zeta potential for long circulation, high delivery efficiency and natural targeting abilities. So far, genetic, anticancer and anti-inflammatory drugs have been successfully delivered by exosomes. In these cases, exosomes enhance the transfection efficiency of cytotoxic drugs and reduces their side effects, as well as protecting these fragile molecules from drug clearance. They are also characterised by a negative zeta-potential charge which enables them to interact with the positively charged inflamed inflammatory bowel disease tissue, making them ideal carriers for targeted oral drug delivery.

This innovative project aims to formulate drug-loaded exosomes for targeted oral drug delivery to inflamed bowel tissue. We will isolate exosomes by size exclusion chromatography and differential centrifugation methods. The exosomes will then be characterised by dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and western blotting. In-vitro and in-vivo transfection studies will be completed and an assessment of the effect of gastrointestinal mucus on the exosomes will be performed. The exosomes will be loaded with a drug cargo by electroporation and the characterisation assays repeated. They will finally be tested in-vivo for therapeutic efficacy.

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.