PhD Studentship: Localised antibiotic delivery and release with luminescent mesoporous silica nanop

Bacterial infections are becoming harder to treat as antibiotic resistance becomes increasingly prevalent. There is also a lack of new drugs to take the place of those that can no longer be used due to resistance and novel therapeutic options are needed.

Many Gram-negative pathogens, such as Pseudomonas aeruginosa, are particularly difficult to treat because their membrane structure makes them relatively impermeable to many antibiotics. This project will develop a novel tool using silica nanoparticles to deliver antibiotic molecules across the membranes of these bacteria. This novel drug delivery system will increase efficacy of antibiotic treatment and provide new treatment options for hard to treat infections, particularly those that cause wound or surface infections.

Mesoporous silica nanoparticles (MSN) can act as efficient tools for drug delivery as they have a high surface area of more than 900 m2/g and pore volume over 0.9 cm3/g both of which ensure loading with high concentrations of drug. The sizes of the MSNs are usually 100-300 nm in diameter and pores can be designed to be hexagonal of about 4 nm to include drug molecules. However, approaches to include drug molecules in the MSNs have relied on the simple adsorption of the drug inside the pores which has a major disadvantage of fast drug release in solutions. In this project we will develop methodologies of producing MSNs with encapsulated drugs and control their release with a stimulus such as ultrasound or photoactivation. Our proposed methodology includes pre-inclusion of the drug in the silica structure together with a luminescent metal centre (such as ruthenium, iridium complexes) which will be a reporter of the release. This will allow the release of the drug to be controlled with ultrasound or photoactivation based on the properties of the drug, the size of the pores and the luminescent reporter chosen. This will allow localized delivery of the antibiotic containing MSN to the infected area and the antibiotic can be released once the MSNs have entered the bacterial cells.
This project has two main arms. The antibiotic containing MSNs will be developed in the School of Chemistry within the laboratory of Professor Zoe Pikramenou using expertise of the group in previously studying inclusion of luminescent reporters in silica nanoparticles (Lamgmuir 2013). The particles will be characterized by a suite of surface techniques for their porosity, size. Ultrasound experiments will be initially established in solution and monitored by spectroscopic techniques obtaining kinetic profiles of antibiotic release. Preliminary results of a project using ultrasound with silica nanoparticles have provided the proof of concept for using ultrasound as stimuli in antibacterial agents for dental applications (with Walmsley, Sammons, Kuhne in Dentistry).

The microbiological testing of the antibiotic containing MSNs will take place in the Institute of Microbiology and Infection within the laboratory of Dr Jessica Blair. We will develop models to test the efficacy of the antibiotic containing MSNs to kill various bacterial species. This will include measuring their efficacy against bacterial biofilms which are adherent multicellular communities of bacterial cells that have increased resistance to antibiotics making many wound infections even harder to treat. We will also determine the effect of this targeted delivery system of the development of resistance to different antibiotics and compare this to traditional drug delivery to see if resistance rates are altered.

This project aligns with the global challenges theme of Vaccines and Infectious Disease. The World Health Organisation recently ranked antibiotic resistant Pseudomonas aeruginosa as one of three priority one pathogens of critical importance for the development of new therapeutics. Therefore, this project is timely and its outcomes could provide a significant step forward in treating infections caused by globally important pathogens.

Funding Notes

Global Challenges Scholarship Scheme

References

Santos, A, Aw, M.S., Bariana, M., Kumeria, T., Wang, Y., Losic ,D. J Mater Chem B., 2014, 2, 6157–6182.
Lewis, D., Dore, V., Rogers, N., Mole, T., Nash, G., Angeli, P. and Pikramenou, Z. Langmuir, 2013, 29, 14701.