Inhalable nanomedicines for treatment of tuberculosis

Abstract: Date: 16/03/2022

The rapid spread of multi drug-resistant tuberculosis (TB) is a major threat to global public health. According to WHO ~1.8 million people die every year of TB, with an estimated 9.8 million new infections per year, which is exacerbated due to the number of patients infected with HIV/AIDs. Treatment of TB is lengthy (6-months for the short course), with the development of drug resistant organisms (Mycobacterium tuberculosis (M.tb)) due to incomplete or inappropriate treatment. The aim of the PhD is to develop an aerosolised, inhalable nanomedicine that delivers first line anti-tuberculous drugs embedded within antibacterial silver (Ag) nanoparticles (NPs) locally to the M.tb inside the host, infected macrophages in the peripheral respiratory zone. The antibacterial Ag NPs can permeabilise the M.tb cell envelope barrier to increase drug efficacy - with clinical potential to reduce the drug doses needed for treatment, avoid systemic side effects and increase patient compliance and reduce development of multidrug resistance. The engineered drug system will consist of a poly(lactic-co-glycolic acid) (PLGA) microparticle-encapsulation platform into AgNPs and first-line antibiotics (alone and in combination) will be loaded. The early focus will be given to first-line antibiotics, however the platform will be tailored for later inclusion of emerging drugs that treat drug resistant TB. The student will test the nanodrug in unique in vitro human co-culture of models of the human alveolar unit infected with M.tb, to assess its efficacy and safety and how it interacts with the host's immune system to facilitate successful microbial killing. The student will develop aerosol exposure systems to deliver the microparticle-drug formulations in vitro; medical drug delivery devices - either nebulisers or dry-powder inhalers - will be tested as potential delivery systems for use in the clinic to achieve therapeutically inhaled drug doses.

Relevant EPSRC research areas: Analytical science, Particle technology, Sensors and instrumentation, Clinical technologies (excluding imaging)

Aerosol science has a significant impact on a broad range of disciplines, extending from inhaled drug delivery, to combustion science and its health impacts, aerosol assisted routes to materials, climate change, and the delivery of agricultural and consumer products. Estimates of the global aerosol market size suggest it will reach $84 billion/year by 2024 with products in the personal care, household, automotive, food, paints and medical sectors. Air pollution leads to an estimated 30-40,000 premature deaths each year in the UK, and aerosols transmit human and animal infections. More than 12 million people in the UK live with lung disease such as asthma, and the NHS spends ~£5 billion/year on respiratory therapies. Many of the technological, societal and health challenges central to these areas rely on core skills and knowledge of aerosol science. Despite this, an Industrial Workshop and online survey (held in preparation for this bid) highlighted the current doctoral skills gap in aerosol science in the UK. Participating industries reported that only 15% of their employees working with aerosol science at doctoral-level having received any formal training. A CDT in aerosol science, CAS, will fill this skills gap, impacting on all areas of science where core training in aerosol science is crucial.

Impact on the UK aerosol community: Aerosol scientists work across governmental policy, industrial research and innovation, and in academia. Despite the considerable overlap in training needs for researchers working in these diverse sectors, current doctoral training in aerosol science is fragmentary and ad hoc (e.g. the annual Fundamentals of Aerosol Science course delivered by the Aerosol Society). In addition, training occurs within the context of individual disciplines, reinforcing artificial subject boundaries. CAS will bring coherence to training in the core physical and engineering science of aerosols, catalysing new synergies in research, and providing a focal point for training a multidisciplinary community of researchers. Working with the Aerosol Society, we will establish a legacy by providing training resources for future researchers through an online training portal.

Impact on industry and public-sector partners: 45 organisations have indicated they will act as CAS partners with interests in respiratory therapies, public health, materials manufacturing, consumer and agricultural products, instrumentation, emissions and environment. Establishing CAS will deliver researchers with the necessary skills to ensure the UK establishes and sustains a scientific and technical lead in their sectors. Further, it will provide an ideal mechanism for delivering Continuing Professional Development for the existing workforce practitioners. The activity of CAS is aligned to the Industrial Strategy Challenge Fund (e.g. through developing new healthcare technologies and new materials) and the EPSRC Prosperity Outcomes of a productive, healthy (e.g. novel treatments for respiratory disease) and resilient (e.g. adaptations to climate change, air quality) nation, with both the skilled researchers and their science naturally translating to long-lasting impact. Additionally, rigorous training in responsible innovation and ethical standards will lead to aerosol researchers able to contribute to developing: regulatory standards for medicines; policy on air quality and climate geoengineering; and regulations on manufactured nano-materials.

Public engagement: CAS will provide a focal point for engaging the public on topics in aerosol science that affect our daily lives (consumer products, materials) through to our health (inhalation therapeutics, disease transmission and impacts of pollution) and the future of our planet (geoengineering). Supported by a rigorous doctoral level training in aerosol science, this next generation of researchers will be ideally positioned to lead debates on all of these societal and technological challenges.