Colon-specific delivery of methotrexate using hyaluronic acid modified pH-responsive nanocarrier for the therapy of colitis in mice.

Oral immunosuppressant methotrexate (MTX) is an effective method for the treatment of inflammatory bowel disease (IBD). To overcome the defects of clinical application of MTX, poly (lactic-co-glycolic acid) (PLGA), Eudragits® S100 (ES100), chitosan (CS) and hyaluronic acid (HA) were used to structure the MTX-loaded HA-CS/ES100/PLGA nanoparticles (MTX@hCEP). MTX@hCEP had a hydrodynamic particle size of approximately 202.5 nm, narrow size distribution, negative zeta potential (-18.7 mV), and smooth surface morphology. In vitro drug release experiments under simulated gastrointestinal conditions indicated that MTX@hCEP exhibited colonic pH-sensitive drug release properties. The cellular uptake capacity of hCEP nanoparticles was significantly enhanced in RAW 264.7 macrophages. Moreover, we further found that the MTX@hCEP also inhibited the proliferation and the secretion of pro-inflammatory cytokines in the LPS-stimulated macrophages. In vivo imaging results not only demonstrated that the accumulated in the colon of colitis mice, but also indicated the extended retention time of MTX in the colon. Additionally, MTX@hCEP alleviated inflammatory symptoms via decreasing the activities of myeloperoxidase and pro-inflammatory factors, promoting mucosal repair in vivo. Collectively, these results clearly demonstrated that MTX@hCEP with properties of colon-specific and macrophages targeting can be exploited as an efficient nanotherapeutic for IBD therapy.

XA pH-Responsive and Colitis-Targeted Nanoparticle Loaded with Shikonin for the Oral Treatment of Inflammatory Bowel Disease in Mice.

Epidemiology shows that more than 6.8 million people in the world are influenced by inflammatory bowel disease (IBD) each year. IBD is a refractory inflammatory disease, and the disease mainly affects the colon. Shikonin (SK) was originally extracted from traditional Chinese medicine "Zicao" (with an English name Lithospermum erythrorhizon) and found to inhibit inflammation, regulate immunity, and be involved in healing wounds. Herein, we used chitosan (CS), hyaluronic acid (HA), and pH-responsive polymer Eudragits S100 (ES100) to design SK-loaded ES100/HA/CS nanoparticles (SK@SAC) as an oral delivery system to treat the colitis mice. Particle size of SK@SAC was 190.3 nm and drug loading efficiency was 6.6%. SAC nanoparticles accumulated in RAW264.7 macrophages and exhibited colitis-targeted ability by increasing the local drug concentration as well as reducing nonspecific distribution after oral gavage. In TNBS-induced IBD mice, SK@SAC treatment had significant therapeutic effects, regulated of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) and anti-inflammatory cytokines (IL-10 and TGF-ß), and also inhibited COX-2 and iNOS activity. SK@SAC also increased tight junction protein ZO-1 and occludin to some extent. These promising results showed that this novel oral SK-loaded nanoparticle drug delivery system for targeted treatment provides a new strategy for the management of IBD.

A ROS-responsive fluorescent probe detecting experimental colitis by functional polymeric nanoparticles.

Current evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of inflammatory bowel disease (IBD). TotalROX (λabs/λem = 425/525 nm) is a ratiometric probe with high detection sensitivity and a superior capacity to monitor total cellular oxidative capacity. Herein, we investigated the potential of combining totalROX with an oral nanoparticle delivery system to detect the degree of colitis. This detection system also featured pH-responsive Eudragit S100, hyaluronic acid with high affinity to the CD44 receptor, and chitosan, and demonstrated improved loading efficiency and stability. An experimental mouse model of experimental colitis was induced by dextran sodium sulfate do that we could investigate the ability of our nanoparticles to target the colon and determine the degree of inflammation. We also determined and validated the positive correlation between the fluorescence intensity of the detection product (Ox670, λabs/λem = 650/675 nm) and myeloperoxidase activity (R2 = 0.97) and the histopathological score (R2 = 0.98). TotalROX had significant ability to measure reactive oxygen species (ROS) produced by cells under inflammatory conditions, as confirmed by in vitro experiments with Caco-2 cells. Collectively, the data generated demonstrate that when loaded with totalROX, these functional nanoparticles are promising tools for cellular imaging after oral administration. This is the first description of a ROS-responsive fluorescent probe to evaluate the degree of colitis in experimental animal models and provides a promising approach for the diagnosis of inflammation in IBD with fluorescence-guided colonoscopy.