Colon-targeted delivery of cyclosporine A using dual-functional Eudragit^® FS30D/PLGA nanoparticles ameliorates murine experimental colitis

Abstract

BackgroundColon-targeted oral nanoparticles (NPs) have emerged as an ideal, safe, and effective therapy for ulcerative colitis (UC) owing to their ability to selectively accumulate in inflamed colonic mucosa. Cyclosporine A (CSA), an immunosuppressive agent, has long been used as rescue therapy in severe steroid-refractory UC. In this study, we developed CSA-loaded dual-functional polymeric NPs composed of Eudragit® FS30D as a pH-sensitive polymer for targeted delivery to the inflamed colon, and poly(lactic-co-glycolic acid) (PLGA) as a sustained-release polymer.MethodsCSA-loaded Eudragit FS30D nanoparticles (ENPs), PLGA nanoparticles (PNPs), and Eudragit FS30D/PLGA nanoparticles (E/PNPs) were prepared using the oil-in-water emulsion method. Scanning electron microscope images and zeta size data showed successful preparation of CSA-loaded NPs.ResultsPNPs exhibited a burst drug release of >60% at pH 1.2 (stomach pH) in 0.5 h, which can lead to unwanted systemic absorption and side effects. ENPs effectively inhibited the burst drug release at pH 1.2 and 6.8 (proximal small intestine pH); however, nearly 100% of the CSA in ENPs was released rapidly at pH 7.4 (ileum–colon pH) owing to complete NP dissolution. In contrast to single-functional PNPs and ENPs, the dual-functional E/PNPs minimized burst drug release (only 18%) at pH 1.2 and 6.8, and generated a sustained release at pH 7.4 thereafter. Importantly, in distribution studies in the gastrointestinal tracts of mice, E/PNPs significantly improved CSA distribution to the colon compared with PNPs or ENPs. In a mouse model of colitis, E/PNP treatment improved weight loss and colon length, and decreased rectal bleeding, spleen weight, histological scoring, myeloperoxidase activity, macrophage infiltration, and expression of proinflammatory cytokines compared with PNPs or ENPs.ConclusionOverall, this work confirms the benefits of CSA-loaded E/PNPs for efficiently delivering CSA to the colon, suggesting their potential for UC therapy.

Colon-Targeted Therapy of Tacrolimus (FK506) in the Treatment of Experimentally Induced Colitis

“…Tacrolimus (FK506) microparticles were shown to ameliorate the experimentally induced colitis with minimal potential for adverse renal effects [15,16], with successfully delivered cyclosporine to the colon using CTDS. Naeem et al [12] documented the utility of cyclosporine A-loaded biodegradable polymer (PLGA) nanoparticles, coated with pH-sensitive Eudragit FS30D for effective CSA targeting to the colon. The authors demonstrated the efficacy of this novel CSA delivery system in ameliorating experimentally induced colitis in mice [12].…”

“…Naeem et al [12] documented the utility of cyclosporine A-loaded biodegradable polymer (PLGA) nanoparticles, coated with pH-sensitive Eudragit FS30D for effective CSA targeting to the colon. The authors demonstrated the efficacy of this novel CSA delivery system in ameliorating experimentally induced colitis in mice [12].…”

“…However, its associated adverse effects may be of great concern, which may preclude some medical practitioners and gastroenterologists from using it. The principle of targeted therapy is to minimize the absorption of the drugs in the unaffected areas along the gastrointestinal tract (GIT) and to enable the drug to reach the affected sites unaltered and without the need for a higher dosage [12,13].…”

New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy

“…In fact, some studies showed that the absorption of drug could become important and that, in addition, the nanoparticles themselves can be absorbed in the colon and rectum of patients with IBD [41]. They reported the accumulation of microparticles (MPs) in active inflammation, but negligible amount of nanoparticles could be detected [23,42]. This meant that MPs, probably due to their bioadhesion, could be accumulated in the inflamed mucosal wall, but they could not be absorbed.…”

Significance of Ligand-Anchored Polymers for Drug Targeting in the Treatment of Colonic Disorders

“…As per a study contemplated by Naeem et al (2018) colontargeted delivery of cyclosporine A using the dual-functional Eudragit® FS30D/PLGA nanoparticles ameliorates murine experimental colitis was explored in the study. The study elucidated how colon-targeted oral nanoparticles have been perceived to emerge as an ideal, effective, and safe therapy for UC owing to their ability to accumulate in inflamed colonic mucosa selectively.…”