Pharmaceutical Nanotechnology Cyclosporine A-loaded lipid nanoparticles in inflammatory bowel disease Melissa Guada a,b , Ana Beloqui c , Mireille Alhouayek d , Giulio G. Muccioli d , Maria del Carmen Dios-Viéitez a , Véronique Préat c , Maria J. Blanco-Prieto a,b, * a Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, E-31008 Pamplona, Spain b Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, E-31008 Pamplona, Spain c Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium d Université catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Research Group, 1200 Brussels, Belgium A R T I C L E I N F O Article history: Received 26 January 2016 Received in revised form 8 March 2016 Accepted 9 March 2016 Available online 10 March 2016 Keywords: Cyclosporine A Immunosuppressant Nanoparticles Colitis Dextran sodium sulfate Inflammatory bowel diseases A B S T R A C T Cyclosporine A (CsA) is a well-known immunosuppressive agent used as rescue therapy in severe steroid- refractory ulcerative colitis (UC). However, toxicity issues associated with CsA when administered in its commercially available formulations have been reported in clinical practice. Since nanotechnology has been proposed as a promising strategy to improve safety and efficacy in the treatment of inflammatory bowel disease (IBD), the main purpose of this study was to evaluate the effect of oral administration of CsA-loaded lipid nanoparticles (LN) in the dextran sodium sulfate (DSS)-induced colitis mouse model using Sandimmune Neoral 1 as reference. The results showed that the formulations used did not decrease colon inflammation in terms of myeloperoxidase activity (MPO), tumor necrosis factor (TNF)-a expression, or histological scoring in the acute stage of the disease. However, further studies are needed in order to corroborate the efficacy of these formulations in the chronic phase of the disease. ã 2016 Elsevier B.V. All rights reserved. The term “inflammatory bowel disease” (IBD) covers various chronic, relapsing-remitting inflammatory disorders of the gas- trointestinal tract. Ulcerative colitis (UC) and Crohn’s disease (CD) are the two major forms of IBD (Alhouayek and Muccioli, 2012). The pharmacological strategy for IBD treatment depends on the severity of the illness and the patient’s progress (Talaei et al., 2013). Conventional therapies for UC and CD include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti-tumor necro- sis factor agents (Burger and Travis, 2011). Although corticoste- roids are used as first line therapy for the severe stage of the pathology, approximately 30–40% of the patients do not respond to intravenous steroid treatment, and may require hospitalization for intensive health care or even colectomy if clinical enhancement is not observed. Over the last few years, cyclosporine A (CsA) has been used as rescue therapy in clinical practice owing to its rapid onset of action in severe steroid-refractory UC. However, the potential adverse effects associated with this immunosuppressant, including nephrotoxicity, hypertension, seizures and neurotoxicity, along with the need for careful monitoring of the drug during the treatment to prevent toxicity, restrict its use (Eun and Han, 2015). Given the lack of a safe and effective curative therapy of IBD, medical care is focused on minimizing complica- tions by the induction and maintenance of IBD remission (Talaei et al., 2013). Nanotechnology has demonstrated promising outcomes in IBD therapy thanks to the ability of nanoparticles to selectively target the inflamed tissue when taken orally (Beloqui et al., 2013, 2014). In this regard, nanomedicine could achieve increased efficacy, specifically in intestinal inflammatory cells (Viscido et al., 2014). Among the nanocarriers described so far, lipid-based nanocarriers may provide a promising improvement in the safety and efficacy of anti-inflammatory drugs (Lim et al., 2012). Therefore, the aim of this work was to investigate the in vivo efficacy of orally administered CsA-loaded lipid nanoparticles (LN) in the dextran sodium sulfate (DSS)-induced colitis mouse model using Sandimmune Neoral 1 as reference, which is the most popular marketed formulation for CsA oral administration. For this purpose, three CsA LN formulations were produced differing in the stabilizer system used (Guada et al., 2015). The lipid phase consisted of Precirol 1 ATO 5 (Gattefossé, Lyon, France) and CsA (Roig Farma S.A., Barcelona, Spain) and the aqueous phase contained 2% (w/v) of: (i) Tween 1 80 (Tw, Roig Farma S.A., * Corresponding author at: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, E- 31008 Pamplona, Spain. E-mail addresses: mjblanco@unav.es, maria.blanco@nanomedicinas.es (M.J. Blanco-Prieto). http://dx.doi.org/10.1016/j.ijpharm.2016.03.012 0378-5173/ ã 2016 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 503 (2016) 196–198 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l home page : www.e lsevier.com/loca te/ijpharm