Application Of Mucus-permeable Nano Drug In The Treatment Of Ulcerative Colitis

Ulcerative colitis（UC）,an incurable and chronic inflammatory disease,mainly occurs in the mucosal layer of the colon and rectum,which is characterized by hematochezia,diarrhea,mucous injury and even the loss of body weight.Research have shown that the complex pathogenesis of UC was related to genetic inheritance,dietary habits,intestinal flora ecology,living environment and intestinal immune system of patients.Although the conventional treatment strategies（e.g.,anti-inflammatory drugs and immunosuppressive drugs）can alleviate UC symptoms to a certain extent,the long-term application of these therapeutics are restricted by their unsatisfactory treatment outcomes and unwanted side effects.Hematochezia caused by UC can lead to the accumulation of blood stasis,which may impede the healing of damaged mucosa.Due to the scavenging activity of the intestinal barrier,the ability of penetration in the intestinal mucus layer and macrophage-targeting play important roles in the therapeutic effect of UC.Therefore,advanced therapeutic strategies for UC treatment are urgently demanded.In the present study,Nano drug delivery system was established to solve this problem.1.The application of natural organic polymer nanoparticles in colitis treatmentIn the present study,fluorinated HA（FHA）was synthesized and characterized.Subsequently,it was used to functionalize the surface of the anti-inflammatory drug curcumin（CUR）-loaded regenerated silk fibroin（RSF）-based NPs（FHA-CUR-NPs）.Other NPs like HA-CUR-NPs and CUR-NPs were used as control.The generated FHA-CUR-NPs had hydrodynamic diameters of 172.9 nm and negatively charged surfaces（-17.5 m V）.It was found that the fluorination of NPs could improve their mucus-penetrating capacity and yield an obviously higher cell internalization percentage in macrophages than their counterparts（CUR-NPs and HA-CUR-NPs）,resulting in the strongest capacity to decrease the secreted amounts of pro-inflammatory cytokines（TNF-α,IL-6,and IL-12）.In vivo investigations suggested that oral administration of the hydrogel（chitosan/alginate）-encapsulating FHA-CUR-NPs preferentially accumulated in the colitis tissues and achieved much better therapeutic outcomes against UC,in comparison with hydrogel-embedding CUR-NPs or HA-CUR-NPs.2.The application of synthetic inorganic nano-enzyme in the treatment of UC.In this part of the study,calcium peroxide-cuprous oxide nanoparticles（CaO₂-Cu₂O-NPs）were prepared through chemical synthesis method,calcium peroxide nanoparticles（CaO₂-NPs）were treated as control group.The hydration particle size,surface potential and morphology of NPs were measured.It was found that the CaO₂-Cu₂O-NPs had the ability of reactive oxygen species scavenging and oxygen producing.The CaO₂-Cu₂O-NPs treated cells（macrophages and L929 mouse fibroblast cells）showed high cell viabilities after 24 or 48 h of co-incubation.The pro-inflammatory factors（TNF-αand IL-6）of CaO₂-Cu₂O-NPs treated cells were decreased,as well as the increase of anti-inflammatory cytokine（IL-10）.In vitro experiments suggested that the levels of reactive oxygen species（ROS）and reactive nitrogen species（RNS）effectively reduced.In vivo experiment suggested that CaO₂-Cu₂O-NPs significantly alleviated inflammatory response,regulated intestinal flora,inhibited the bleeding of tissues and participated in regulating the signal pathway.In conclusion,research focuse on the ability of nanoparticles to penetrate the colon mucus barrie.Respectively,we further construct natural polymer drug delivery system and synthetic inorganic drug delivery system.The hydrophobic and oleophobic properties of fluorinated polymers endow nanoparticles with mucus infiltration function,and the nanomolecular motor enhance the mechanical energy of NPs and propel the NPs through the mucus layer,which can reduce inflammatory response,restrict oxidative stress and rebuild gut microbes against UC.