The use of drug “capped” silver nano-particles and drug-silver complexes for the sight-saving, treatment of eye infections

Supervisors: Andy Porter, Douglas Fraser-Pitt

Project description:

This PhD will take place at the exciting interface between organic and inorganic chemistry to further refine, control and characterise the production of silver-drug Nanoparticles and complexes and importantly then determine how these drug formulations are predicted to separate in a biological environment impacting dosing levels, dosing frequency and efficacy.  The student will determine in vitro the potency of these new drug formulations and their ability to kill a range of fungal (and bacterial/viral) pathogens before completing topical studies in infection models.

The student will have the opportunity to work and/or collaborate with our industry partner (NovaBiotics Ltd), Public Health England, University of Aberdeen, AFGrica Unit in South Africa as well as within University labs.  The PhD student will be actively encouraged to embrace the social and commercial impact of their research.

Eye infections, particularly in the developing world, remain one of the most significant causes of sight loss (incidence 500 times that of the UK).  Infections are mainly caused following accidental eye traumas and are the result of colonisation by fungi such as Aspergillus and Fusarium species (mycotic fungal keratitis, keratomycosis) and several, difficult to diagnose, opportunistic bacterial pathogens.

For many individuals, eye loss results from a combination of delayed diagnosis, misdiagnosis and poor access to anti-fungal drugs, with antibiotic given in error or as the only available treatment.   Even where anti-fungal therapies are available these drugs have been tailored for systemic fungal infections with poor or very limited topical efficacy.  What is urgently required is a broad spectrum anti-microbial that would be available cheaply and easily, could be administered immediately as drops or gel; and where an established regulatory path exists that would facilitate rapid and cost effective adoption. 

Silver has been used as a broad spectrum anti-microbial for over 2000 years without AMR issues.  It is used extensively today as a topical dressing to facilitate wound healing through a mechanism of microbial killing (in combination with its known anti-inflammatory activity) and in many geographies silver-nitrate solution is still approved for use in the “under-fives” as an eye drop for bacterial/viral conjunctivitis.  More recently, the potency of silver therapy has been given a boost with the development of silver nanoparticles (Ag-NP), which afford greater efficacy through improved silver bio-availability, delivered because of increased surface to volume ratios.

Whilst Ag-NPs have been shown to be effective in vitro at killing clinical isolates of both Aspergillus and Fusarium species there still remains the problem of delivery into the eye at effective concentrations as compound can be lost quickly via a combination of blinking/tears and the eyes’ extensive blood supply.  Using a multi-disciplinary approach, we have successfully established methods for the capping/complexing of Ag (-NPs) with a current eye drop/gel treatment drug.  This drug has a long history of clinical use/efficacy and has known anti-microbial and anti-biofilm properties.  It is hoped that by optimising the combination of silver and drug we will deliver: rapid/safe uptake into the eye, potent anti-microbial killing, inexpensive manufacture and a straightforward regulatory path for approvals. 

References:

  1. Marina Kovaleva, Katherine Johnson, John Steven, Mischa Muller, Caroline J. Barelle, Andrew Porter (2017) The therapeutic potential of shark anti-ICOSL VNAR domains is exemplified in a murine model of autoimmune non-infectious uveitis.  Frontiers of Immunology. (in Press)

 

  1. Palliyil, S., Downham, C., Broadbent, I., Charlton, K. and Porter, A.J. (2014). High-sensitivity monoclonal antibodies specific for homoserine lactones protect mice from lethal Pseudomonas aeruginosa infections. Applied and Environmental Microbiology 80(2):462-469. (PMCID: PMC3911118)

 

  1. Fraser-Pitt D, Mercer D, Lovie E, Robertson J, O’Neil D. (2016). Activity of cysteamine against the cystic fibrosis pathogen Burkholderia cepacia Complex. Antimicrob Agents Chemother. 60(10):6200-6206

 

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