ULTrasound-controlled delivery technologies for IMproving oral drug Absorption, Targeting and Efficacy (ULTIMATE)

Ultrasound has shown potential to enhance buccal and rectal drug delivery through transient disruption of the barrier; however, its application in oral delivery remains largely unexplored. This innovative project will investigate the use of ultrasound stimulation, in combination with stimuli-responsive drug carriers, as a non-invasive physical intervention to reversibly disrupt the gut wall enabling spatially and temporally controlled permeation of oral APIs across biological barriers throughout the gastrointestinal tract (GIT). It is anticipated that this approach will significantly improve systemic absorption in general/specific patient populations (e.g., paediatric, geriatric, IBD).

Biologics offer promising treatments for a wide array of diseases due to their target specificity, greater efficacy and less off-target side effects compared to small molecular weight drugs. Although oral administration of these compounds is preferred to parenteral routes, development of oral biologic formulations has been hindered by their high molecular weight, limited stability and half-life, and poor epithelial permeability. For example, IBD patients have high morbidity and compromised quality of life whose treatment options include intravenous biologics (e.g., adalimumab), given at high doses to achieve therapeutically relevant mucosal levels. However, this approach can lead to loss of efficacy and development of immunogenic side effects. Local delivery of biologics via oral administration would facilitate lower doses with potentially higher efficacy and a reduced side effect profile. Despite almost a century of research and recently renewed efforts, oral biologics are still absent in the clinical setting. This highlights the significant challenges posed by the GIT barrier to their oral delivery, as well as associated inter-patient variability issues. Established chemical absorption enhancer strategies have demonstrated in vitro success, but a lack of clinical translation due to difficulties in co-localising biologic payload and enhancers.

Therefore, in the proposed research we intend to overcome these difficulties, by exploiting ultrasound as a means of localising and actively controlling drug release from carriers by remote stimulation, whilst enhancing drug penetration through the GIT barrier. Ultrasound exposure could thus increase permeation of macromolecules while allowing co-localisation of stabilising excipients and macromolecular payloads.

Ultrasound is a longitudinal pressure wave with frequencies above the upper audible limit (>20kHz). It has been applied in a variety of clinical settings, including ultrasonography, tumour ablation and lithotripsy. More recently, it has been investigated in therapeutic applications as a physical means to transiently permeabilise biological tissues and enhance penetration of bioactive compounds. In these applications, it is often applied in combination with ultrasound-responsive agents (e.g., shelled gas microbubbles or volatile nanodroplets), which can be engineered to carry different classes of bioactive and targeting moieties for localised delivery. Upon exposure to ultrasound waves, these agents undergo volumetric oscillations imparting mechanical stress on nearby biological barriers and improving transport of therapeutic payloads, thus representing a highly promising candidate system for targeted oral delivery of biologics. Moreover, by varying the characteristics of the ultrasound field (e.g., amplitude and frequency), the intensity and mode of particle response could be modulated to meet patient- or disease-specific needs.

In this project we will first re-engineer current ultrasound-sensitive particle formulation and manufacturing strategies to enable effective loading of biologics. We will then assess their performance in vitro and ex vivo under patient-/disease-specific gastrointestinal exposure conditions, to customise the developed formulations.

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.