Colon-Targeting Angelica sinensis Polysaccharide Nanoparticles with Dual Responsiveness for Alleviation of Ulcerative Colitis.

Abstract

Intestinal immune dysfunction and gut microbiota dysbiosis are critically causative factors in the pathogenesis of ulcerative colitis (UC); however, the current first-line drugs for UC treatment in clinics often remain great challenges due to their nontargeting therapeutic efficacy and severe side effects. In the current study, colon-targeting nanoparticles based on Angelica sinensis polysaccharide with pH- and redox-responsiveness were fabricated to specifically release the naturally active compound ginsenoside Rh2 in the colonic inflammatory site, which greatly alleviated the UC symptoms and improved the gut microbial homeostasis. These dual responsive Rh2-loaded nanoparticles (Rh2/LA-UASP NPs) with a particle size of 117.00 ± 4.80 nm were prepared using the polymer LA-UASP obtained by grafting A. sinensis polysaccharide with urocanic acid and α-lipoic acid (α-LA). As expected, these Rh2/LA-UASP NPs achieved dual pH- and redox-responsive drug release at pH 5.5 and 10 mM GSH. The stability, biocompatibility, and in vivo safety experiments exhibited these prepared nanoparticles had excellent colon-targeting ability and significant accumulation of Rh2 in the inflammatory colon. Meanwhile, these Rh2/LA-UASP NPs could escape from lysosomes and be efficiently internalized into intestinal mucosal cells, thereby effectively inhibiting the release of proinflammatory cytokines. The animal experiments indicated that Rh2/LA-UASP NPs significantly improved the integrity of intestinal mucosa and increased the colon length compared with UC mice. Additionally, the weight loss, histological damage, and inflammation level were greatly ameliorated. The homeostasis of intestinal flora and the level of short-chain fatty acids (SCFAs) were significantly improved after being treated with Rh2/LA-UASP NPs in UC mice. Our study proved that these Rh2/LA-UASP NPs with dual pH-and redox-responsiveness are promising candidates for UC treatment.