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Optimisation and Preclinical Evaluation of Targeted Nanoformulations of Anti‐TNF‐α Therapeutics for the Treatment of Inflammatory Bowel Disease (IBD)

  • Full or part time
    Dr Z Ramtoola
    Dr B Kirby
  • Application Deadline
    Monday, December 02, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

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[1]. IBD patients suffer a wide variety of symptoms including abdominal pain, diarrheoa, rectal bleeding, and anaemia, thus negatively impacting their quality of life[2]. 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[3]. 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[4]. 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[5]. 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).

References

1. Collnot, E.M., H. Ali, and C.M. Lehr, Nano and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. Journal of controlled
release, 2012, 20;161(2):235‐46 .
2. Van Deventer, S., Small therapeutic molecules for the treatment of inflammatory bowel disease. Gut, 2002. 50(suppl 3): p.iii47‐iii53.
3. Cote-•‐Diagenold, J, Bouin, M, Lahaei, R, Colombel JF and Poitras, P. Biologics in inflammatory bowel disease: what are the data? United
European Gastroenterol J. 2015 Oct; 3(5): 419–428.
4. Ali H, Weigmann B, Collnot EM, Khan SA, Windbergs M, Lehr CM. Budesonide Loaded PLGA Nanoparticles for Targeting the Inflamed Intestinal
Mucosa‐Pharmaceutical Characterization and Fluorescence Imaging. Pharm Res. 2016;33 (5):1085‐92
5. Alsaddique J, Pabari R, Ramtoola Z. Effect of thermal and shear stressors on the physical properties, structural integrity and biological activity of
the anti‐TNF‐alpha monoclonal antibody, Infliximab. Current Pharmaceutical Biotechnology, Volume 17, Number 10, pp. 905‐914(10),2016.

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