Oral colon-targeted responsive chitosan/pectin-based nanoparticles propels the application of tofacitinib in colitis therapy

Tofacitinib (Tof), a commercially available pan-Janus kinases inhibitor, is approved for the treatment of moderate to severe ulcerative colitis. However, its clinical application is limited due to dose-dependent systemic side effects. The present study aims to develop an efficient oral colon-targeted drug delivery systems using prebiotic pectin (Pcn) and chitosan (Csn) polysaccharides as a shell, with Tof loaded into a Bovine Serum Albumin (BSA) core, and improving it with chondroitin sulfate (Chs), thus constructing Tof@BSA-Chs-CP nanoparticles (NPs). Our results suggest that the pH-sensitive characteristics of the Pcn/Csn shell contribute to its capacity for attenuating absorption and systemic diffusion in the gastrointestinal tract, and exhibiting targeted localization at inflamed colonic sites in mice. Additionally, the gut microbiota-secreted polysaccharide-degrading enzyme acts as the triggering agent for Pcn/Csn shell degradation. In mice colitis models, we demonstrated that oral administration of Tof@BSA-Chs-CP NPs effectively ameliorated colitis and expedited its resolution by modulating the expression of pro-inflammatory cytokines and immune regulatory factors. Collectively, our synthetic NPs demonstrate the promising potential of Tof for the therapy of UC.

Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by recurrent diarrhea and abdominal pain1. The etiology and pathogenesis of UC are complex, characterized by dysregulation of immune response, alterations in colonic barrier function, and substantial dysbiosis of gut microbiota2. Conventional therapies such as 5-aminosalicylic acid (5-ASA), thiopurines, and corticosteroids are frequently employed for the management of mild to moderate UC by reducing inflammation, alleviating symptoms, and maintaining remission3,4. Although 5-ASA is considered the first-line therapy for UC, a subset of patients may experience intolerable adverse effects, resulting in treatment discontinuation and an elevated risk of undergoing colectomy5.

Recently, with the deepening of research into the pathogenesis of UC, molecular targeted therapies have gradually emerged. The excessive production of proinflammatory cytokines resulting from extensive infiltration of immune cells represents a pivotal pathological factor in UC, thereby rendering Janus kinases (JAKs) crucial therapeutic targets. Tofacitinib (Tof), an oral pan-JAK inhibitor primarily targeting JAK1 and JAK3, has demonstrated efficacy in inducing remission in active cases of UC6. However, concerns arise due to its extensive systemic distribution, which often leads to suboptimal drug concentrations within the colon, resulting in inadequate anti-inflammatory effects. Additionally, this distribution may have potential off-target consequences such as infections, cancers, and lymphoma7,8.

To address these challenges, oral colon-targeted drug delivery systems (OCDDSs) have been developed with the aim of specifically releasing medication in the colon. This ensures that therapeutic agents are concentrated at the site of disease while minimizing systemic exposure and reducing potential side effects. It is imperative to develop OCDDSs for Tof to enhance its therapeutic efficacy and minimize potential adverse effects, thereby effectively addressing the intricate challenges associated with the treatment of UC9. In our previous study, the valuable polysaccharides, such as chondroitin sulfate (Chs)10, chitosan (Csn)11, and pectin (Pcn)12, have been employed in OCDDSs due to their biodegradability, biocompatibility, and specific targeting capabilities.

In this study, we developed an innovative OCDDSs by desolvating Tofacitinib and encapsulating it within a bovine serum albumin (BSA) core. Chs was then introduced for surface modification, and further cross-linking was achieved through layer-by-layer (LBL) technology using a prebiotic shell composed of Csn and Pcn. The synthesized OCDDSs exhibits excellent pH-dependent and colon-targeting properties, offering promising prospects for clinical applications in UC treatment (Fig. 1).

Download the full article as PDF here Oral colon-targeted responsive chitosan/pectin-based nanoparticles propels the application of tofacitinib in colitis therapy

or read it here

Wu, C., Bi, C., Kim, Gs. et al. Oral colon-targeted responsive chitosan/pectin-based nanoparticles propels the application of tofacitinib in colitis therapy. Sci Rep 15, 1569 (2025). https://doi.org/10.1038/s41598-024-84322-2

Read also our introduction article on Orally Disintegrating Tablets (ODTs) here: