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Bubbles for Targeting and Treatment of Biofilm Infections

1st July 2022 to 30th June 2025

Antimicrobials, commonly known as antibiotics, are becoming less effective because of resistance. Antibiotic resistance is when bacteria or other microbes change so that antibiotics no longer work to treat infections. Antibiotic resistance is a global problem that is being made worse by antibiotic overuse. We can combat antibiotic resistance by developing better antibiotics as well as improving the way we use existing ones. Patients will continue to need antibiotics, particularly to treat serious infections, like sepsis, so we need to improve how they are used. Right now, 'broad-spectrum' antibiotics, that kill a wide range of bacteria, are often given in high doses to ensure that enough antibiotic reaches the microbes at the site of infection. Much higher doses than would be needed if we could deliver antibiotics just at the site of infection are used. These antibiotics kill many of the beneficial 'resident' bacteria living in our bodies, which drives resistance. It would be much better if we could use a 'personalised medicine' approach where antibiotics are delivered locally, at the site of infection, at doses necessary to treat the problem. By giving lower doses of targeted treatment and avoiding exposure of the normal colonising bacteria to antibiotics, our vision is to improve health outcomes and reduce the selection of resistant microbes.

Our project involves using tiny bubbles similar to those already used with ultrasound scanning to study the flow of blood through the heart and are currently being tested to treat cancers. These bubbles are given by injection into a vein. We propose to develop bubbles so that they can deliver antibiotics directly to a site of infection. The bubbles can also be burst using higher powered ultrasound, which is another possible way to kill bacteria. The bubbles are tiny, not much bigger than the bacteria, and will be coated with molecules that will allow the bubbles to stick to the surface of specific bacteria. This is known as 'molecular targeting'. By combining bubbles with ultrasound to trigger the release of antibiotics just at the site of infection, we aim to reduce the amount of antibiotics required to kill bacteria, without killing the helpful bacteria that live elsewhere in the body. Antibiotics often fail because the bacteria create their own local environment, the "biofilm", full of sticky chemicals, which also reduces the killing effects of antibiotics. Our approach will harness the energy released when an ultrasound pulse bursts bubbles to help drive drugs deep into this "biofilm" and hence help kill bacteria more effectively. In addition to getting more antibiotic into a biofilm, these drug-loaded bubbles will allow us to deliver new types of drugs, e.g. antimicrobial peptides (AMPs). AMPs are very effective at killing bacteria, but many cannot be given in the usual way, via a drip, into a vein to treat infections because they tend to be broken down in the blood before getting to the infection site. We can overcome this problem by loading the AMPs into tiny protective capsules attached to the bubbles and release them where/when they are required. Finally, we plan to investigate if bacteria can be released from their local biofilm environment using bubbles plus ultrasound. Here we will harness the mechanical energy released by bursting bubbles to break up the biofilm. The bacteria released from the biofilm are known as 'planktonic' and are more susceptible to conventional antibiotic treatments.
In summary, we propose to:
1. Develop new targeting agents to bind bubbles to bacteria and new drug-loaded cargoes to kill bacteria/ destroy biofilms.
2. See if bubbles and ultrasound can be used together to deliver drugs into bacterial biofilms and kill bacteria more effectively.
3. Use our approaches to deliver drugs that cannot currently be used to treat patients because they are broken down in the blood.

Microbubble Enhanced Imaging and Therapeutic Delivery

1st July 2017 to 30th June 2020

Our Programme of research addresses several key challenges that need to be resolved to allow the clinical development of MBs as combined therapy and diagnostic agents. In our recent EPSRC Programme we succeeded in building an instrument for the manufacture of MBs (that have a targeting agent and conjugated drug payload). This enabled us to test their ability to target cancer cells and to effectively treat tumours in pre-clinical models. In order to progress our MBs to the point where they could be used for first-in-man trials we need to satisfy regulatory agencies that our MBs are safe, and have clear clinical benefit. We will also need to demonstrate that they are cost effective, if providers are eventually to take- up this treatment modality.

We have developed a two-pronged approach to developing microbubbles for drug based delivery: 1) Many drugs fail to reach clinical trials because, whilst they are potent as drugs, they are difficult to deliver into cells, or tissue because of poor solubility or becasue they are too toxic to use. For this we propose to develop a new integrated screening platform, that will use the combination of MB+ultrasound, for aiding the delivery of such drugs into cells (and tumour models). This will not only allow re-assessment of many existing drugs but will also speed up the screening of new drugs. Through partnership with the Medicines Discovery Catapult we will promote uptake of this technology with pharmaceutical companies and thereby reduce cost for the identification of new drug candidates.

2) We will develop our, patented, MB production instrument to the point where it could be manufactured by an external company for the first-in-human trials. As part of this we need to optimise how we make the MBs, modify how the drugs and targeting agents are linked to each other and address issues such as ease of use, sterility etc. We also need to show that we can eliminate tumours completely using our MB+US approach. By using materials that have been manufactured according to specific standards (GMP), that are suitable for clinical trials, and processes that are in accord with Good Laboratory Practice we will undertake the necessary in-vitro and in-vivo testing required for moving this "Investigational Medicinal Product" to Phase 1 (First in Human) Clinical trials.

Hydrophobic Drug Delivery

1st April 2013 to 31st March 2016

This project is focused around the research of Microbubbles for Hydrophobic Drug Delivery and Enhanced Diagnostics. This will be used for personalised healthcare for the treatment of Colorectal Cancer, commonly referred to as Bowel Cancer. Professor Steve Evans, University of Leeds, School of Physics and Astronomy is leading the project.

Engineering Therapeutic Microbubbles

EPSRC funded - Sept 2010 - Feb 2014

Colorectal Cancer (CRC) is the third most common cancer in the UK, with approximately 32,300 new cases diagnosed and 14,000 deaths in England and Wales each year. Occurrence of colorectal cancer is strongly related to age, with 83% of cases arising in people older than 60 years. It is anticipated that as our elderly population increases, CRC will increase in prevalence (National Institute for Clinical Excellence, raises important questions relating to treatment in elderly patients balanced with quality-of-life and health economics considerations.

The challenge to nanotechnology and engineering is to deliver cost-effective, less invasive treatments with fewer side-effects and potential benefits for quality of life in patients. This is particularly important in CRC at the present time as the NHS bowel-screening programme is rolled out for all individuals aged 60 to 69. This raises important issues for rapid, accurate, and acceptable, safe and cost-effective investigation and treatment of older symptomatic patients.

Ultrasound has a clear and growing role in modern medicine and there is increasing demand for the introduction of ultrasound contrast agents such as microbubbles (MBs). These MBs are typically less than one hundredth of a millimetre in size, so that they can pass through the vasculature, and lead to imaging enhancements by scattering of the ultrasound signal. So-called "third generation" MBs will not only perform functional imaging with greatly enhanced sensitivity and specificity but will also carry therapeutic payloads for treatment or gene therapy. These will most likely be released by destroying the bubbles at the targeted site and their effect enhanced further by sonoporation (sound induced rupture of the cell walls to allow drugs in). Although the focus of our proposal is therapeutic delivery for cancer treatment, the basic technologies for MB development and ultrasound technology are equally applicable to other conditions e.g. cardiovascular and musculoskeletal disease where there is an unmet clinical need, particularly in ageing populations. As such this is a generic technology development relevant to different diseases.