RONS-Scavenging Nanomedicines For The Treatment Of Ulcerative Colitis In Mice

Ulcerative colitis(UC)is a kind of inflammatory chronic disease characterized by unknown etiology,a high recurrence rate,and a high risk of developing into intestinal cancer.Diffuse mucosal inflammation in the colorectal mucosa is the most common clinical manifestation,accompanied by rectal hemorrhage,diarrhea,abdominal pain,and body weight loss,which greatly threat to human health.A large amount of reactive oxygen species and nitrogen species(RONS(·OH),(O2-·),(NO),(OONO-))is often found in the colon microenvironment of UC.Excessive accumulation of RONS could result in unstable redox homeostasis.Clinically,5-aminosalicylic acid,glucocorticoids,and immunosuppressive drugs are the main treatments for UC,but they have poor targeting,severe side effects,and poor prognoses.Due to their ability to improve drug water solubility,enhance drug targeting,and clear RONS,nanodrugs have become a favored topic in recent years.Specifically,this thesis focused on the development of nanodrug systems for improved anti-colitis therapy through clearing RONS.There are two parts of this thesis:1.A natural product may be defined as an extract or metabolite extracted from flora and fauna.They have been widely used in inflammation-related fields because of their unique characteristics,including a low incidence of adverse reactions,a stable curative effect,a broad range of targets and strong antioxidant properties.Procyanidin(PC),as a natural drug,has exhibited great potential in suppressing inflammation and oxidation.However,its clinical applications are highly limited,because of its low water solubility and poor permeability.Ruthenium(Ru)is a transition metal element characterized by a high level of redox activity.The coordination of ruthenium with natural products has rarely been reported.To solve the above problems,we constructed Ru-PC nanoparticles with the coordination of Ru-procyanidin.In this section,we explored the use of ruthenium-procyanidin coordination nanostructures for treating UC.We investigated the characterization of Ru-PC nanoparticles,investigated their mechanism of removing reactive oxygen species and reactive nitrogen at the cellular level,and investigated their therapeutic potential for UC by constructing a Dextran sulfate sodium(DSS)mouse model.We found that Ru-PC was successfully synthesized and eliminated RONS such as O2-·,NO and H2O2 at an in vitro level.These RONS are also eliminated at the cellular level and can also be involved in the transformation of macrophages from M1 to M2.Animal studies have shown that Ru-PC nanoparticles effectively alleviate RONS symptoms,regulate macrophage progression from M1 to M2,and increase expression of the tight junction proteins ZO-1 and Claudin-1 in a mouse model of prevention and delayed posttherapy.In this study,coordination of ruthenium with proanthocyanidin was demonstrated,showing an enhanced ability to scavenge RONS and achieve UC treatment.2.The elimination of RONS in the inflammatory colon has been proven effective in alleviating UC.The regulation of intestinal flora also has a good therapeutic effect on UC.Although many nano-antioxidants have been developed,preparing robust and efficient nano-antioxidants and regulating the gut flora remain challenging.Herein,by modifying bismuth selenide(Bi2Se3)nanodiscs with polyvinylpyrrolidone(PVP),a multifunctional nanozyme based on 2D nanomaterials was developed for the treatment of UC.In this study,we investigated the ability of Bi2Se3 nanodiscs to remove RONS at both the material and cellular levels.To verify the therapeutic effectiveness of DSS for inflammatory bowel disease,we established a mouse model.By eliminating multiple RONS,such as ·OH,O2-·,NO,H2O2,and Bi2Se3 nanodiscs,enhanced cellular survival after H2O2 stimulation.By repairing colonic injury,reducing body weight,and lowering the spleen index and proinflammatory cytokine levels in mice,RONS clearance alleviated intestinal inflammation in a prevention and delayed model of acute colitis.16S rDNA amplicon sequencing revealed that Bi2Se3 nanodiscs had the potential to regulate intestinal flora,increase the rate of Firmicutes to Bacteroidetes,inhibit Proteobacteria bacteria,and restore intestinal homeostasis.In this study,it was demonstrated that Bi2Se3 nanodiscs can be used as therapeutic agents for UC due to their good biocompatibility,their ability to neutralize RONS and their ability to regulate the intestinal flora.In summary,we investigated the properties of nanodrug systems that eliminate RONS in this doctoral dissertation.On the one hand,the coordination of ruthenium with the natural product proanthocyanidins was demonstrated in this study as a means of treating UC by removing RONS and regulating macrophage polarization.On the other hand,UC can be treated through the introduction of powerful and efficient nanoantioxidants that help to clear RONS from the body and help to regulate the intestinal flora.Our research provides guidance for better application of natural products and a novel approach to nanodrugs in the treatment of UC.