Dr Z Ramtoola
Dr B Kirby
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
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 and immunosuppressants and more recently, the anti‐TNFα monoclonal antibodies (mAbs) including infliximab, adalimumab and certolizumab pegol. While conventional small molecules provide relief from IBD symptoms and maintain symptomatic remission, disease progression ultimately leads to surgical resection of diseased tissues.
It is now recognised that anti-TNFα mAbs in addition to causing induction and maintenance of remission also promote GI mucosal healing, now recognized as a key goal of IBD treatment, as this reduces the need for surgery. A major disadvantage of the mAb therapy, however, is the resulting severe adverse effects such as leucopenia, serious infection and increased risk of malignancy due to their systemic administration at high doses. In addition, intravenous administration requires skilled personnel and mAb short shelf life after reconstitution, adds to the overall cost of IBD therapy. The development of novel drug delivery strategies of anti-TNFα therapeutics that can enhance their efficacy and reduce their side effects is a priority for treatment of IBD. Biodegradable PLGA nanoparticles of budesonide administered orally in a colitis mouse model, were shown to be preferentially taken up by the inflamed gastrointestinal cells, resulting in enhanced efficacy and reduced side effects. Nanoparticles of biological therapeutics have not been formulated and studied due to their known sensitivity to environmental and processing stressors. We recently studied the effect of various processing stressors and environmental factors on the stability of the anti-TNFα mAb, Infliximab, and designed novel nanoformulations of Infliximab, in non-digestible polymeric envelopes, to provide stability of the mAb. We demonstrated retention of biological activity of Infliximab from these nanoformulations and showed enhanced cell uptake and transport of the nanoformulations in an in‐vitro intestinal inflamed epithelial cell model. Treatment with these Infliximab nanoformulations resulted in reduced inflammation and recovery of the epithelial barrier function.
The aim of this project is to examine the potential of these novel Infliximab nanoformulations, administered orally, in targeting the inflamed intestinal mucosa of IBD, in a colitis mouse model. As part of this project the nanoformulations will be formulated and optimised for drug loading, drug release and stability. Optimised nanoformulations will be investigated in an in vivo colitis mouse model for their ability to target and interact with the inflamed intestinal tissues, to reduce inflammation and promote healing. Such a targeted strategy may provide increased efficacy and dose reduction, resulting in lower systemic side effects and improve the benefit to risk ratio of anti-TNFα mAbs).
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the anti‐TNF‐alpha monoclonal antibody, Infliximab. Current Pharmaceutical Biotechnology, Volume 17, Number 10, pp. 905‐914(10),2016.