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Abstract
Ulcerative colitis (UC) is a global, chronic, and refractory disease. Corticosteroids are first-line drugs for the treatment of UC but also cause adverse side effects. Budesonide (BUD), a corticosteroid with relatively low side effects, has been approved by the Food and Drug Administration for use as enteric capsules (Entocort EC) for the treatment of inflammatory bowel disease (IBD). However, this formulation lacks specific targeting ability to UC lesions. Herein, we describe the development of an advanced macrophage-targeted oral lentinan (LNT)–based nanoparticles (NPs) loaded BUD for treatment of UC. Briefly, LNT was used as a food source and natural carrier to load BUD by a simple solvent evaporation method to form LNT/BUD-NPs. LNT showed good loading capacity with high encapsulation and loading efficiencies to BUD of approximately 92.19 and 9.58%, respectively. Evaluation of the gastric stability of LNT/BUD-NPs indicated that LNT could effectively protect BUD from gastric acid and digestive enzymes. The release behavior and transmission electron microscopy image of LNT/BUD-NPs in the intestinal content of mice confirmed that intestinal flora can promote BUD release from LNT. Moreover, evaluation of cellular uptake showed that LNT/BUD-NPs could specifically target macrophages and enhance their uptake rate via the Dectin-1 receptor. In biodistribution studies, LNT/BUD-NPs were able to efficiently accumulate in the inflamed colon of mice. As expected, LNT/BUD-NPs could significantly alleviate inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Therefore, LNT/BUD-NPs have the advantages of good gastric stability, release mediated by mouse intestinal content, macrophage-targeting, and anti-UC effects. These advantages indicate LNT-based NPs are a promising oral drug delivery system for UC therapy.
Highlights
Ulcerative colitis (UC) is a common inflammatory bowel disease (IBD), which is defined by mucosal inflammation involving mainly the colon and the rectum (Luo et al, 2021)
LNT were purchased from DESITE Biological Technology Co., Ltd. (>98%, DST200405085, Sichuan, China), BUD were purchased from DESITE Biological Technology Co., Ltd. (>98%, DSTSB027201, Sichuan, China), and Dimethyl sulfoxide (DMSO) was purchased from Macklin Biochemical Co., Ltd. (Shanghai, China)
The characterization of LNT/BUD-NPs focused on size distribution, morphology, zeta potential, EE, LE, X-ray diffraction (XRD), and FT-IR, the results were as follows
Summary
Ulcerative colitis (UC) is a common inflammatory bowel disease (IBD), which is defined by mucosal inflammation involving mainly the colon and the rectum (Luo et al, 2021). BUD has fewer side effects by oral administration, which is due to 90% of BUD being inactivated in the liver before reaching the systemic circulation, with only 10% BUD entering the systemic circulation (Miehlke et al, 2018). Entocort EC, a BUD enteric capsule formulation, was approved by the Food and Drug Administration in 2001 for the treatment of Crohn’s disease leading to a positive outcome (McKeage and Goa, 2002). Enteric capsules are more suitable for Crohn’s disease which usually involves the entire intestine, rather than UC which is located at the distal part of the colon (Edsbacker and Andersson, 2004). Entocort EC was used to treat UC by retention enema instead of oral administration, leading to poor patient compliance. Based on the application of BUD in UC treatment, it is necessary to develop an effective and specific oral system for the delivery of BUD to UC lesions
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