Periodic Reporting for period 1 - ColoFILM (Multifunctional polymeric film-based drug delivery system for oral anti-TNF-alpha-based inflammatory bowel disease therapy)
Okres sprawozdawczy: 2017-05-01 do 2019-04-30
Inflammatory bowel disease (IBD) is an umbrella term to define relapsing chronic inflammation of the gastrointestinal (GI) tract. Ulcerative colitis and Crohn’s disease are its two variants. IBD is one of the most prevalent GI diseases, especially in Western countries with ca. 2.5–3.0 million cases in Europe and an estimated direct annual health-care cost of €4.6–5.6 billion. Conventional IBD therapies include drugs such as aminosalicylates, corticosteroids, thiopurines, which mainly provide symptomatic relief. Currently, antibodies against TNF-α (anti-TNF-α) are considered as second line of treatment. However, the use of anti-TNF-α is limited to systemic administration, which in turn has serious adverse effects such as opportunistic infections, infusion reactions, and autoimmune diseases. IBD can. In addition to major adverse effect, IBD has a colossal socio-economic impact by greatly deterring patient’s quality of life by impeding their daily (personal and professional) lives, instilling social stigma and afflicting substantial healthcare costs. Therefore, the aim of the project has been to develop an advanced drug delivery system that could target and localize the anti-TNF-α antibody at the site of action with minimal exposure to systemic circulation and other healthy tissues, which would overcome the critical limitations of the current therapeutic approach to provide safer and efficacious anti-TNF-α therapy for IBD patients. During the project period, we successfully developed nanoparticles-in-film formulation, which encapsulated anti-TNF-α antibody. We demonstrated that after oral administration of antibody-loaded nanoparticles, the inflammatory markers were greatly reduced in murine colitis model.
We developed an advanced drug delivery system comprising of nanoparticles in film for orally delivering anti-TNF-α for IBD therapy. Based on previous studies and preliminary experiments, we selected polymeric nanoparticles with polyethylene glycol (PEG) modification (PEGylation) to impart mucus-inert properties. After screening, we selected two polymers with different PEG chain lengths to encapsulate the antibody. We focused mainly on studying the influence of these PEG chains on how the antibody will be encapsulated and released, and how they interacted with mucin and intestinal cells/tissues. Antibody were successfully loaded in the nanoparticles, and was shown to have TNF-α neutralizing effect from both stimulated intestinal cell lines and macrophages.
We demonstrated that both PEG chain lengths did not have any influence on in vitro studies, both showed significant influence on the level of interaction with the intestinal cells and tissues. To study this, we set up and validated an ex vivo model in the laboratory, which I was trained on during a research visit to University College Dublin as a secondment.
To further evaluate our formulations, we performed in vivo studies on acute and chronic colitis model in mice. As expected from the in vitro and ex vivo studies, the in vivo study also demonstrated the differences between two different PEG lengths in different inflammatory parameters and histology.
The results from this project has been disseminated at several national and international meetings and conferences. The results from this project will be disseminated as publications, one original research article and a review paper.
Besides the main project, several other collaborative projects were also performed during the period, which also resulted in several research articles and a book chapter.
We demonstrated that both PEG chain lengths did not have any influence on in vitro studies, both showed significant influence on the level of interaction with the intestinal cells and tissues. To study this, we set up and validated an ex vivo model in the laboratory, which I was trained on during a research visit to University College Dublin as a secondment.
To further evaluate our formulations, we performed in vivo studies on acute and chronic colitis model in mice. As expected from the in vitro and ex vivo studies, the in vivo study also demonstrated the differences between two different PEG lengths in different inflammatory parameters and histology.
The results from this project has been disseminated at several national and international meetings and conferences. The results from this project will be disseminated as publications, one original research article and a review paper.
Besides the main project, several other collaborative projects were also performed during the period, which also resulted in several research articles and a book chapter.
The results from the project enabled us to understand the role of density of PEG on surface of nanoparticles on the interaction with intestinal tissues and cells. Overall, the project allowed establishing of several new techniques and models in the host university that could be exploited furthermore in future. In addition, the methods developed as a part of this project can be utilized as great tools for selecting optimal formulations for oral delivery systems. Furthermore, the work would not only have an impact on IBD therapy, but also on oral delivery of other fragile macromolecules, such as insulin. The knowledge garnered from this work will provide a good groundwork and learning opportunities to further develop and optimize the oral and local delivery of such fragile molecules.