PhD: Design and evaluation of oral targeted nanoformulations of cyclosporine for the treatment of IBD
The aim of this project is to formulate cyclosporine nanoparticles and characterise their drug release kinetics and examine their uptake and efficacy in an in-vitro inflamed epithelial cell model.
- Principle investigator(s) Dr Zeibun Ramtoola, Prof. Brian Kirby
- Research theme Chemistry and Pharmaceutical Sciences, Immunity Infection and Inflammation
Inflammatory bowel disease (IBD) is a chronic inflammatory condition that affects the gastrointestinal tract (GIT) of the patient and comprises of Crohn’s disease (CD) and ulcerative colitis (UC). In CD, inflammation can occur in any part of the GIT, whereas in UC, ulceration is usually limited to the lower part of the GIT, namely small intestine, colon and rectum.
IBD patients suffer a wide variety of symptoms, including abdominal pain, diarrheoa, rectal bleeding, and anaemia, thus negatively impacting their quality of life. Current treatment comprises the administration of small molecule therapeutics such as 5‐aminosalicylic acid, corticosteroids, immunosuppressants including cyclosporine and sirolimus and the anti‐TNFα monoclonal antibodies (mAbs) such as infliximab and adalimumab. While conventional small molecules provide relief from IBD symptoms and maintain symptomatic remission, disease progression ultimately results in colectomy. The biological therapeutics, anti-TNFα mAbs, have been recognized to promote GI mucosal healing, limiting disease progression and reducing the need for surgery. Unfortunately 30% of the patients do not respond to mAbs and responders can develop resistance to treatment after time.
The immunosuppressant cyclosporine, originally developed for prevention of organ rejection following transplant, is used as a ’salvage therapy’ to reduce the incidence of colectomy. Cyclosporine is a BCS class-II drug and commercially available formulations are designed to increase its solubility, dissolution and absorption in the upper small intestine where the drug is absorbed. This is therefore not desirable in targeting and treating the inflamed lower GIT sites in UC. We previously designed cyclosporine micro and nanoparticulate formulations that showed modulated cyclosporine release. In addition, nanoparticulate formulations have been shown to accumulate in the inflamed tissues in IBD. This extended residence of the nanoparticulates in the inflamed tissues, coupled with modulated release of cyclosporine offers a novel approach to target the delivery of cyclosporine orally to the inflamed IBD tissues. We recently designed nanoparticles of the anti-TNFα mAb, infliximab and shown these to have enhanced cell uptake and transport in an in‐vitro intestinal inflamed epithelial cell model, reducing the inflammation and resulting in recovery of the epithelial barrier function.
Nanoparticles showing enhanced uptake and efficacy will be optimised for cyclosporine loading, drug release and stability. The optimised nanoparticles will be subsequently investigated in a colitis mouse model for their ability to target the inflamed intestinal tissues, reduce and treat the inflammation. Such a targeted strategy may allow oral delivery of cyclosporine with increased efficacy, safety and enhanced benefit to risk ratio of cyclosporine.
Tenure: This project is designed to support a 1.5-2 years MSc and a four-year PhD.
- PhD - upper second class (2.1) honours degree (or equivalent) in pharmacy, pharmacology or other biological, biomedical or heath sciences
- MSc - lower second class (2.2) honours degree (or equivalent) in pharmacy, pharmacology or other biological, biomedical or heath sciences
Desirable candidate specifications include:
- In-vitro cell culture techniques desirable, but not essential
There is an open rolling registration for this position.
Please apply with an up-to-date CV, a 500-word statement outlining your interest in and suitability for the position, and contact details of two referees to email@example.com.
Successful candidates will be able to attend a virtual interview if they wish.
The position will begin on 1 October 2020.