Study On The Application Of Mp-based Nano-drug Delivery System In Spinal Cord Injury

Spinal cord injury(SCI)refers to the temporary or permanent neurological changes in the spinal cord tissue under the action of various factors,which are mainly manifested as sensory,motor and autonomic dysfunction below the injured segment.SCI is a common disabling and fatal injury in spinal diseases,which brings a serious burden to patients,families and society.At present,the clinical treatment of SCI is extremely limited,mainly through surgery to reduce compression,and high-dose methylprednisolone(MP)for shock therapy.However,due to the narrow treatment window of MP,large doses and serious side effects such as infection,gastrointestinal bleeding,pulmonary embolism,etc.,its recommended level in the clinical treatment guidelines for SCI is continuously decreasing.The unsatisfactory effect of treating SCI may be related to a series of secondary cascade reactions after acute SCI,including reactive oxygen species,inflammation,excitotoxicity,calcium ion overload,and mitochondrial dysfunction.Among them,reactive oxygen species and inflammatory response are the core pathological processes.If they are not intervened in time,the damage will be further aggravated and cause permanent neurological damage.In recent years,a variety of new therapies have been developed to treat spinal cord injuries,including nanomedicine therapy,cell transplantation,and tissue engineering.Among them,the application of nanoparticles to treat SCI has been considered an effective treatment strategy.Nanoparticles can combine small molecule drugs with carriers through physical packaging or chemical bonding to prepare nano drugs,which can overcome the disadvantages of poor targeting of small molecule drugs,short plasma half-life,and large toxic and side effects,and improve the therapeutic effect of drugs.Based on the characteristics of nanoparticles,this study intends to use nano-drugs loaded with MP to improve the bioavailability of MP,reduce side effects,and achieve combined treatment of SCI for the cascade reaction after SCI.For this purpose,the following Two parts of work:Part 1:Rutin-coated MP delivery system with ROS response characteristics(1)Designed and synthesized a prodrug TK-MP₂ with ROS response characteristics,and verified its ROS responsive release characteristics;(2)Application of amphiphilic polyphenol Rutin(RU)and TK-MP₂ co-assembled to form RU-TK-MP₂ nanoparticles,and the particle size,morphology and drug loading efficiency of the nanoparticles were characterized.The results showed that the Nanoparticles have a very high loading efficiency of 80.3%for MP;(3)The biocompatibility,antioxidant capacity and cytoprotective ability of RU-TK-MP₂nanoparticles were verified at the cellular level;in addition,the anti-inflammatory effects of MP2-TK-RU nanoparticles at the cellular level were verified;(4)The results of animal experiments show that RU-TK-MP₂ nanoparticles can effectively inhibit secondary SCI and protect damaged neurons,and promote the recovery of nerve function;Part 2:Minocycline-loaded Poly(?-lipoic acid)-methylprednisolone prodrug Nanoparticle for Combined Anti-inflammatory Treatment of Spinal Cord Injury(1)Designed and synthesized a poly(?-lipoic acid)-based MP prodrug(P?LA-MP),and encapsulated the positively charged anti-inflammatory drug minocycline(MC)to prepare p H and ester Enzyme dual-responsive nanoparticles(MC-P?LA-MP).The load efficiency of MC-P?LA-MP to MC can be as high as 64.5%.It can release MP and MC in the presence of acidic environment and esterase;(2)It has been verified at the cellular level that MC-P?LA-MP nanoparticles can be effectively endocytosed by microglia and a variety of cells in the spinal cord have good biocompatibility;in addition,it has also been verified that MC-P?LA-MP nanoparticles are in the cell Level of anti-inflammatory effect;(3)The results of animal experiments show that MC-P?LA-MP nanoparticles can quickly reach the injured spinal cord and release drugs,reduce the production of inflammatory reactions,thereby inhibit secondary SCI and promote the recovery of nerve function.