Construction Of Novel Protein Delivery System For The Treatment Of Inflammation

Protein drugs has been among the most intensively studied of the new drug research,which so far have aroused great interest in researchers.However,there are many problems in the application of protein,such as high molecular weight,poor stability,short biological half-life and so on,which make the clinical application of protein drugs face great challenges.Therefore,It's had profound implications to explore a safe and effective drug delivery system to solve this problem.In this paper,there are focus on transcription factors,antioxidant enzymes,insulin and other therapeutic proteins to design a new carrier for protein delivery,so as to achieve the treatment of inflammation,diabetes and other related diseases.The main contents are as follows:(1)Highly efficient intranucleus delivery of transcriptional factor for effective protection of organ system from extensive damageBased on this,using cyclodextrin as the backbone structure,developing a transcription factor delivery platform WOA,introducing lysine hydrophobic chains,and transporting nuclear transcription factor 2(Nrf2)into the nucleus,WOA can effectively deliver Nrf2 into the nucleus of widely cell types and significantly up-regulation the gene transcription of Nrf2 on antioxidant responsive element(ARE)-driven cellular defense system against oxidative stress.Nrf2 loaded WOA nanocomposites(N/WOA)can significantly up-regulate classic ARE driven genes to protect organs from a variety of inflammatory injury in mouse modes.such as acute liver injury and colitis.These results collectively demonstrated that our work proposed a convenient and powerful scheme for intra-nucleus transcription factors delivery to treated disease in biology.(2)Oral Delivery of Antioxidant Enzymes for Efficient Treatment of Inflammatory DiseaseDeveloped an approach to encapsulate native anti-inflammatory proteins in wind chimes like cyclodextrin(WCC)for efficient oral protein delivery.The amphiphilic WCC can self-assemble into nanoparticles in aqueous solution and achieve superior encapsulation of two antioxidant enzymes such as superoxide dismutase(SOD)and catalase(CAT)by simply mixing with protein solution.WCC nanovehicles can effectively protect enzyme activity and enhance their intracellular delivery.SOD and CAT co-loaded WCC nanoparticles(SC/WCC)can integrate the synergistic effect of SOD and CAT for enhancing the removal of reactive oxygen species(ROS),effectively inhibit the inflammatory response and ROS-induced oxidative damage.In the mouse colitis model,SC/WCC administered orally was able to efficiently treated with the inflamed colon,significantly inhibited the expression of inflammatory response and notably alleviated the colonic epithelium restoration Therefore,the strategies e may provide a convenient and powerful platform for the treatment of other inflammatory diseases.(3)Stimuli-responsive self-assembled dendrimers for oral protein deliverySynthesized benzoboroxole-containing multi-armed poly(ethylene glycol)amphiphilic dendrimerssensitive to both p H and glucose.The multi-branched structure of dendrimer facilitated its self-assembly into micelles in aqueous solution and exhibited good encapsulation of insulin.The insulin loaded micelles were stable under strong acidic condition and showed glucose-responsive insulin release at physiological p H.The reversible binding between benzoboroxole and glucose can effectively regulate the disassembly of micelles and insulin release rate,which in turn stabilizes blood sugar fluctuations.Utilizing a mouse model of type 1 diabetes,it was demonstrated that these insulin loaded micelles could successfully control the blood glucose levels under a normoglycemic state and avoid the risk of hypoglycemia.Therefore,this smart delivery system shows great potential to significantly improve the effect of oral protein therap.