Effect Of Physicochemical Properties Of Polymer Micro/Nanoparticles On Oral Treatment For Ulcerative Colitis

Ulcerative colitis(UC)is an idiopathic,chronic inflammatory bowel disease of the colonic mucosa.Its incidence has been increasing year by year worldwide,especially in North America and Western Europe,with the highest incidence and prevalence.Ulcerative colitis begins in the rectum and usually extends proximally in a continuous manner through part of or the entire colon.The clinical course is unpredictable and is characterized by alternating periods of deterioration and remission.Typical clinical symptoms are bloody diarrhea,abdominal pain,urgency,and post-emergency.Few patients experience weight loss or other systemic symptoms,such as low fever.The current treatment of UC includes surgical treatment and drug treatment,of which drug treatment is divided into traditional drug treatment(such as aminosalicylic acid,glucocorticoids)and non-traditional drug treatment(such as biological agents,immunosuppressants).Long-term medication will produce many side effects and seriously affect the quality of life of UC patients.Therefore,there is an urgent need for researchers to design a safe and effective drug delivery system that can deliver the maximum dose of drugs to specific parts of the body at the appropriate time to improve the efficacy and reduce toxic and side effects.Among the many routes of administration,the oral route of administration has attracted much attention due to its unique advantages(convenient and controlled way of administration,can increase patient compliance and reduce toxic and side effects,etc.).Particle system is the most common oral delivery system and has been widely used in the treatment of various diseases,among which micelles,liposomes,micro /nanoparticles are the most common oral delivery systems.Nowadays,the physical and chemical properties of micro / nanoparticles(particle size,surface charge,surface chemical composition,porosity,etc.)have been fully recognized in the key role of micro / nanoparticles and cells.Therefore,this paper constructs a drug-loaded micro /nano system based on polymer poly(lactic-co-glycolic acid)(PLGA)to investigate the effect of the physicochemical properties of polymer materials on the oal therapeutic effect of UC.The research content of this thesis is divided into the following three parts:(1)We adopt traditional emulsifying solvent volatilization method to prepare drug-loaded porous MPs and non-porous MPs based on PLGA in the presence or absence of ammonium bicarbonate,respectively.In the preparation process,curcumin(CUR)was encapsulated into microparticles(MPs).We characterized the hydrated particle size,surface charge,surface morphology,encapsulation efficiency,and drug release of these two types of microparticles.The obtained porous MPs have an average hydrodynamic diameter(about 1.23 ?m)and a negatively charged Surface charge(approximately-28.4 mV).Moreover,we simulated the drug release of porous MPs and non-porous MPs under different pH conditions.The results showed that the drug release rate of porous MPs was significantly higher than that of non-porous MPs.In addition,porous MPs were significantly better than non-porous MPs in the treatment of dextran sodium sulfate(DSS)-induced ulcerative colitis in a mouse model.These results confirm that porous MPs can be a promising oral route for treating UC.(2)We prepared curcumin(CUR)-loaded PLGA nanoparticles(NPs)containing Pluronic F127(PF127)functionalized surfaces with different contents.The obtained NPs(NPs-I,NPs-II,NPs-III,and NPs-IV)with a hydrodynamic particle size is about250 nm,a highly monodispersed particle size distribution and the surface charge is negative.The results show that PF127 functionalization can significantly improve the mucus permeability of NPs.Further cellular experiments showed that they showed good compatibility,and that PF127-functionalized NPs(NPs-II,NPs-III,and NPs-IV)were compared with NPs(NPs-I)not modified by PF127 in the phagocytic efficiency of CUR in macrophages is significantly higher.Interestingly,compared with other NPs,NPs-III significantly reduced the amount of TNF-? secreted in macrophages.Finally,mouse experiments have proven that NPs-III has the best therapeutic effect.Our results clearly show that PF127 functionalized polymeric NPs are a promising and highly effective UC nanotherapeutic drug.(3)We prepared curcumin(CUR)-loaded PLGA nanoparticles(NPs)with different particle sizes.The obtained nanoparticles have a particle size of 185~884nm and a zeta potential of about-25 mV.They all have ideal drug loading(5.1~6.1%)and high encapsulation efficiency(73.2~89.6%).In vitro cell phagocytosis experiments showed that the internalization efficiency of NPs increased with the increase of their particle size,and NPs(900)had the highest phagocytic efficiency of macrophages among all NPs.Importantly,compared with NPs(200)and NPs(500),NPs(900)significantly down-regulated the levels of proinflammatory cytokines secreted by macrophages.Further animal studies have shown that compared to NPs(200)and NPs(500),oral hydrogels(chitosan and alginate)embedding NPs(900)are more effective in accumulating in colitis tissues and are more effective against ulcers.Colitis(UC)is best treated.In summary,these findings can provide effective scientific support for the development of therapeutic drugs that have ideal cumulative efficiency in colitis tissues,maximize cell uptake efficiency of macrophages,and have good therapeutic effects on UC.The research work proves that during the oral treatment of UC,changing the physical and chemical properties of the micro/nano drug delivery system,such as increasing pores,introducing surface chemical components,and increasing the particle size of the nanoparticles,etc.,can help to improve the drug delivery system's effect on UC.This conclusion will provide a certain reference value for future research work.