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Engineered environment-responsive nanomedicines 

Principal Supervisor: Dr Sarah A Kuehne, School of Dentistry

Co-supervisor: Dr Marie C Jones, School of Pharmacy

PhD project title: Engineered environment-responsive nanomedicines

University of Registration: University of Birmingham

Project outline:

Background:

The human microbiome is normally in a state of homeostasis with the host, however disturbance can lead to dysbiosis which results in disease. The human gut is densely colonised with bacteria playing various roles. For example some gut bacteria have been shown to protect the epithelium from colonisation by pathogens [1]. The microbiome is closely interlinked with the host immune system. During dysbiosis the interactions between the bacteria and the host have changed. An increased inflammatory response can lead to the initiation or progression of irritable bowel disease (IBD). IBD has been characterised as an excessive activation of the immune response to intestinal the microbiota. While the development of IBD is a combination of genetic and non-genetic factors, research has clearly demonstrated the importance of the microbiota. A study has shown that more bacteria with pro- inflammatory properties are found in IBD, like Ruminococcus gnavus and Campylobacter concisus [2-4]. These pathogenic bacteria increase in abundance and change the intestinal permeability, influencing pro-inflammatory gene expression which then leads to colitis. This also leads to metabolic changes, like for example the increased abundance of sulphate reducing bacteria producing hydrogen sulphide which is toxic to intestinal epithelial cells [5]. One study showed that the IBD associated microbiota cannot metabolise tryptophan as well [6]. One characteristic of IBD is the formation of ulcers in the intestine. Infected ulcers can be found in many other serious conditions too, for example gastric ulcers.

Effective treatment of gastro-intestinal ulcers can be difficult and hindered by location access and ways to deliver drugs in a targeted manner. Here, we suggest the use of targeted nanomedicines, specifically designed to release their drug cargo upon encountering a trigger molecule. [7]

Objectives:

The overall aim of this project is to develop a specific drug release mechanism, based on sensing particular molecules indicative of pathogen presence to target wound (ulcer) healing.

· Firstly an established infected wound model will be used to develop and exemplify nanoparticles with a targeted drug-release mechanism.

· Secondly this will be applied to the more complex environment of ulcers in the intestinal tract.

Methods:

Microbiology:

The project will involve aerobic and anaerobic microbiology to create wound models as described previously [8]. These models will be used to test the designed and created nanoparticles.

Live/dead qPCR will used to determine efficacy of drug release. Additionally live/dead confocal imaging and quantitative image analysis will be employed.

Nanopharmacology:

In a first-instance, environment-responsive nanoparticles will be designed and tested for their ability to release a drug in response to inflammation. As a starting point, in vitro models of LPS-triggered inflammation will be used.

Once the final ulcer model has been established, alternative nanoparticles composition will be designed and tested. At this point, it is anticipated that more strain specific molecules will be used to trigger drug release from the nanoparticles.

References:

  • Frick JS, Autenrieth IB. The gut microflora and its variety of roles in health and disease. Curr Top Microbiol Immunol. 2013;358:273-89
  • Joossens M, Huys G, Cnockaert M,et al. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives. Gut. 2011 May;60(5):631-7
  • Man SM, Zhang L, Day AS, et al. Campylobacter concisus and other Campylobacter species in children with newly diagnosed Crohn's disease. Inflamm Bowel Dis. 2010 Jun;16(6):1008-16
  • Mukhopadhya I, Hansen R, El-Omar EM, Hold GL. IBD-what role do Proteobacteria play? Nat Rev Gastroenterol Hepatol. 2012 Feb 21;9(4):219-30.
  • Pitcher MC, Beatty ER, Cummings JH. The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis. Gut. 2000 Jan;46(1):64-72.
  • Lamas B, Richard ML, Leducq V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016 Jun;22(6):598-605.
  • Saravanakumar G, Kim J, Kim WJ. Reactive-oxygen-species-responsive drug delivery systems: promises and challenges. Adv Sci 2017: 4(1): 1600124.
  • Townsend EM, Sherry L, Rajendran R, Hansom D, et al. Development and characterisation of a novel three-dimensional inter-kingdom wound biofilm model. Biofouling. 2016 Nov;32(10):1259-1270.

BBSRC Strategic Research Priority: Molecules, Cells and Systems

Techniques that will be undertaken during the project:

  • Aerobic and anaerobic microbiology
  • Growth of bacteria in single and multispecies biofilms
  • Establishment of an in vitro wound model
  • qPCR, advanced microscopy
  • Image analysis
  • Nanoparticle synthesis and characterization
  • Analytical chemistry
  • In addition to wet skills the student will have the opportunity to gain experience in preparing and giving presentations, writing reports, be involved in the day-to-day running of the laboratory

Contact: Dr Sarah A Kuehne, School of Dentistry