An oral delivery vehicle based on konjac glucomannan acetate targeting the colon for inflammatory bowel disease therapy

Abstract

Orally administered colon-targeted delivery vehicles are of major importance in the treatment of inflammatory bowel disease (IBD). However, it remains a challenge to maintain the integrity of such delivery vehicles during treatment, particularly in the gastric environment, which may cause untimely drug release before reaching the targeted colon. Herein, an oral colon-targeted drug delivery system (OCDDS) based on acetylated konjac glucomannan (AceKGM) has been developed in this work, which accomplishes colonic localization release and targets local inflammatory macrophages. The AceKGM nanoparticle-loading curcumin (Cur) was successfully fabricated by emulsion solvent evaporation techniques. DLS, AFM, and SEM were used in order to evaluate the nanoparticles' diameter as well as their in vitro drug release profile, and reactive oxygen species (ROS) scavenging results showed that the OCDDS considerably retained the activity of Cur treated with simulated gastric fluid (SGF) and controllably released in simulated intestinal fluid (SIF). In addition, the adhesion experiment results indicated that the nanoparticle could accumulate on the colonic macrophages. Evaluations in colitis mice showed that the treatment significantly alleviated the symptoms of colitis by decreasing the local level of myeloperoxidase (MPO) and the disease activity index (DAI) score in mice. In summary, the results of our research demonstrate that Cur-AceKGM nanoparticles exhibit significantly improved therapeutic efficacy compared to orally administered free Cur and can be developed as an effective drug delivery vehicle for IBD treatment.

Keywords: colonic macrophages; inflammatory bowel disease; konjac glucomannan; nanoparticle; targeting delivery.

FIGURE 1

Atomic force microscopy images of Cur–AceKGM NPs. (A) 2D image and (B) 3D image. Scanning electron microscopy image of Cur–AceKGM-NPs (C). Particle size distribution (D)and zeta potential (E) of Cur–AceKGM NPs. The dispersibility of Cur and Cur–AceKGM NPs in PBS (F).

FIGURE 2

FT-IR (A) and XRD (B) spectra of pure Cur, pure AceKGM nanoparticles, physical mixture of AceKGM and Cur, and Cur–AceKGM NPs.

FIGURE 3

Nanoparticles’ size variation and in vitro release of Cur from Cur–AceKGM NPs in SGF (A) and SIF (B); all the experiments were performed in triplicate.

FIGURE 4

(A) UV−vis spectra of blank DPPH, DPPH + Cur–AceKGM NPs in SGF, DPPH + Cur–AceKGM NPs in SIF, and Cur–AceKGM NPs. (B) DPPH scavenging effect of the Cur–AceKGM NPs. (C) Fluorescence intensity of DCFDA in RAW264.7 cells with different treatments. (D) Fluorescence microscopy images of RAW264.7 cells with different treatments, green: ROS. All the experiments were performed in triplicate, scale bar = 100 μm, and data are shown as the mean ± SD. ***p < 0.001.

FIGURE 5

Effects of Cur–AceKGM NP concentrations on the proliferation of RAW264.7 (A) and NIH3T3 (B) cells cultured at 24 and 48 h; all the experiments were performed in triplicate and **p < 0.01.

FIGURE 6

Adhesion of Cur–AceKGM NPs with NIH3T3 cell and RAW264.7 with different phenotypes; scale bar = 100 μm.

FIGURE 7

Therapeutic efficacy of Cur–AceKGM NPs in mice with DSS-induced colitis. (A) Body weight percentage variation during the treatment with physiological saline, physical mixture of curcumin and AceKGM nanoparticles (Cur&NPs), dexamethasone, and Cur–AceKGM NPs; **p < 0.01 and ***p < 0.001 versus the control group. (B) Disease activity index score. (C) MPO activity determination of the colon tissue. (D) Statistical analysis of colon length in different treatment groups, (E) colon tissue TNF-α amounts, measured by ELISA assays. (F) Gross view of the colon. All the experiments were performed in triplicate, and data are shown as mean ± SD. ***p < 0.001 and **p < 0.01.

FIGURE 8

Histological analyses of colon sections stained with H&E from the control group (A), physiological saline group (B), physical mixture Cur and NP group (C), dexamethasone group (D), and Cur–AceKGM NP group (E), respectively. (F) Corresponding histological scores. All the experiments were performed in triplicate; data are shown as mean ± SD. **p < 0.01.