Sustained-release of SOD from multivesicular liposomes accelerated the colonic mucosal healing of colitis mice by inhibiting oxidative stress.

Oxidative stress has long been known as a pathogenic factor of ulcerative colitis. Superoxide dismutase (SOD) has been demonstrated to mitigate gut mucosal injury via combating oxidative stress. Herein, we developed SOD-loaded multivesicular liposomes (S-MVLs) as sustained-release depot for ulcerative colitis treatment. S-MVLs were spherical honeycomb-like particles with average particle size of 27.3 ± 5.4 µm and encapsulating efficiency of 78.7 ± 2.6 %. Moreover, the two-phase release profiles of SOD from S-MVLs were exhibited, that was, the burst release phase within 4 h and the sustained-release phase within 96 h. After intraperitoneally injecting S-MVLs, in situ retention time of SOD at bowel cavity extended by 4-fold in comparison with SOD solution. In vitro cells experiment showed that S-MVLs had the protective effect on LPS-treated RAW 264.7 cells via scavenging ROS and inhibiting pro-inflammatory cytokines production. S-MVLs ameliorated the body weight loss, DAI score and the colon shortening of colitis mice. Meanwhile, the colonic morphology and the epithelial barrier of colitis mice were effectively recovered after S-MVLs treatment. The therapeutic mechanism might be associated with polymerizing M1 macrophages to M2 phenotypes and alleviating oxidative stress. Collectively, multivesicular liposomes might be a promising sustained-release depot of SOD for ulcerative colitis treatments.

Hydrogel-forming viscous liquid in response to ROS restores the gut mucosal barrier of colitis mice via regulating oxidative redox homeostasis.

The disrupted oxidative redox homeostasis plays a critical role in the progress of ulcerative colitis (UC). Herein, hydrogel-forming viscous liquid (HSD) composed of cysteamine-grafted hyaluronic acid (HS) and superoxide dismutase (SOD) has been designed for UC. When the viscous HSD liquid was infused into colitis colon, SOD would convert the pathological superoxide (O2·-) to hydrogen peroxides (H2O2), which was subsequently scavenged by HS. Accordingly, the sol-gel transition of HSD was initiated by scavenging H2O2, enhancing its adhesion toward colitis colon. H2O2-treated HSD presented the higher storage modulus and stronger adhesion force toward porcine colon than the untreated HSD. Besides, H2O2-treated HSD presented the slower erosion profile in the colitis-mimicking medium (pH 3-5), while its rapid degradation was displayed in physiologic condition (pH7.4). The combination of pH-resistant erosion and ROS-responsive adhesion for HSD rendered it with the specifical retention on the inflamed colonic mucosa of DSS-induced colitis mice. Rectally administrating HSD could effectively hinder the body weight loss, reduce the disease activity index and improve the colonic shorting of DSS-induced colitis mice. Moreover, the pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) were substantially decreased, the colonic epitheliums were well rearranged and the tight junction proteins were greatly recovered after HSD treatment. Besides, HSD also modulated the gut flora, markedly augmenting the abundance of Firmicutes, Barnesiella and Lachnospiraceae. Moreover, HSD treatment could regulate oxidative redox homeostasis via activating Nrf2-HO-1 pathway to reduce ROS and malondialdehyde and upregulate antioxidant enzymes (SOD, GPx and GSH). Collectively, HSD might be a promising therapy for UC treatments. STATEMENT OF SIGNIFICANCE: Herein, a hydrogel-forming viscous liquid (HSD) was designed by cysteamine-grafted hyaluronic acid (HS) and superoxide dismutase (SOD) for UC treatments. When the viscous HSD liquid was infused into a colitis colon, SOD would convert the pathological superoxide to hydrogen peroxides (H2O2), which was subsequently scavenged by HS. Accordingly, the sol-gel transition of HSD was initiated by scavenging H2O2, enhancing its adhesion to the colitis colon. The colonic epitheliums of DSS-induced colitis mice were well rearranged and the tight junction proteins (Zonula-1 and Claudin-5) were greatly recovered after the HSD treatment. Moreover, the HSD treatment could regulate oxidative redox homeostasis via activating the Nrf2-HO-1 pathway to reduce ROS and malondialdehyde and upregulate antioxidant enzymes (SOD, GPx and GSH).

Growth Factors-Loaded Temperature-Sensitive Hydrogel as Biomimetic Mucus Attenuated Murine Ulcerative Colitis via Repairing the Mucosal Barriers.

The pathogenesis of ulcerative colitis (UC) is associated with the shedding of the gut mucus. Herein, inspired by the biological functions of mucus, growth factors-loaded in situ hydrogel (PHE-EK) was designed for UC treatment by integrating dihydrocaffeic acid-modified poloxamer as a thermosensitive material with hyaluronic acid (colitis-specific adhesive), epigallocatechin-3-gallate (antibacterial agent), and bioactive factors (KPV tripeptide and epidermal growth factor). PHE-EK presented good thermosensitive properties, as a flowable liquid at room temperature and gelled within 10 s when exposed to body temperature. PHE-EK hydrogel presented good mechanical strength with a strain of 77.8%. Moreover, PHE-EK hydrogel displayed antibacterial activity against Escherichia coli. Importantly, in vitro and in vivo adhesive tests showed that the PHE-EK hydrogel could specifically adhere to the inflamed colon via electrostatic interaction. When PHE-EK as a biomimetic mucus was rectally administrated to colitis rats, it effectively hindered the body weight loss, reduced the disease activity index and improved the colonic shorting. Moreover, the expression of pro-inflammatory cytokines (e.g., IL-1ß, IL-6, and TNF-α) at the laminae propria or epitheliums of the colon for colitis rats was substantially inhibited by PHE-EK. Besides, the colonic epitheliums were well rearranged, and the tight junction proteins (Zonula-1 and Claudin-5) between them were greatly upregulated after PHE-EK treatment. Collectively, PHE-EK might be a promising therapy for UC.

Polydopamine-cladded montmorillonite micro-sheets as therapeutic platform repair the gut mucosal barrier of murine colitis through inhibiting oxidative stress.

Montmorillonite (MMT), a layered aluminosilicate, has a mucosal nutrient effect and restores the gut barriers integrity. However, orally administrating MMT is not effective to combat the reactive oxygen species (ROS) and alleviate the acute inflammatory relapse for colitis patients. Herein, polydopamine-doped montmorillonite micro-sheets (PDA/MMT) have been developed as a therapeutic platform for colitis treatment. SEM and EDS analysis showed that dopamine monomer (DA) was easily polymerized in alkaline condition and polydopamine (PDA) was uniformly cladded on the surface of MMT micro-sheets. The depositing amount of PDA was reaching to 2.06 â€‹± â€‹0.08%. Moreover, in vitro fluorescence probes experiments showed that PDA/MMT presented the broad spectra of scavenging various ROS sources including •OH, •O2-, and H2O2. Meanwhile, the intracellular ROS of Rosup/H2O2 treated Caco-2 â€‹cell was also effectively scavenged by PDA/MMT, which resulted in the obvious improvement of the cell viability under oxidative stress. Moreover, most of orally administrated PDA/MMT was transited to the gut and form a protective film on the diseased colon. PDA/MMT exhibited the obvious therapeutic effect on DSS-induced ulcerative colitis mouse. Importantly, the gut mucosa of colitis mouse was well restored after PDA/MMT treatment. Moreover, the colonic inflammation was significantly alleviated and the goblet cells were obliviously recovered. The therapeutic mechanism of PDA/MMT was highly associated with inhibiting oxidative stress. Collectively, PDA/MMT micro-sheets as a therapeutic platform may provide a promising therapeutic strategy for UC treatment.

In situ polyphenol-adhesive hydrogel enhanced the noncarcinogenic repairing of KGF on the gut epithelial barrier on TNBS-induced colitis rats.

Ulcerative colitis (UC) is a chronic recurrent disease affecting the gastrointestinal tract especially colorectum. Keratinocyte growth factor (KGF) plays the vital roles in maintaining the colonic mucosal barrier. The poor stability and off-target of KGF were two hindering factors for its clinical application. Herein, in situ hydrogel (PE) with mucoadhesive ability was constructed by using temperature-sensitive poloxamer and EGCG as hydrogel-forming material and adhesive enhancer, respectively. Incorporation of EGCG led to the slight decrease of the gelled temperature and shortened the gelled time of PE hydrogel. When the concentration of EGCG is 0.1 %, PE hydrogel exhibits the suitable viscosity of 280 ± 20 Pa·s and the strong adhesive force of 725 ± 25 mN. KGF was soluble in cold PE solution to obtain KGF-loaded PE hydrogel (KGF@PE). PE hydrogel could improve the stability of KGF in vitro. KGF@PE not only could recover greatly the body weight of TNBS-induced rats but also repair their colonic morphology and goblet cell function. Moreover, the potential of repairing the epithelial barrier was indicated by upregulating tight junction proteins. Importantly, the safety of KGF@PE hydrogel for colitis was also confirmed on AOM/DSS-induced mice models. Conclusively, KGF@PE may be a promising therapeutic platform without obvious side effect for ulcerative colitis.