Dextran-drug Linkage Micellar Alzheimer's Disease Multi-drug Combination Treatment System

Alzheimer's disease currently presents an enormous global burden,including an increasing number of patients and expensive therapeutic costs.The non-specific nano-drug delivery system prevents the accumulation of drugs in diseased sites and limits the effective role of drugs in AD treatment.Therefore,there is an urgent need to develop new and effective responsive drug delivery systems.In view of this,based on the symptoms of abnormal glucose metabolism and oxidative stress in AD brain,two innovative microenvironment responsive polymer-drug conjugate nanocarriers capable of convenient preparation and controlled release of therapeutic agents were designed and synthesized for on-demand delivery of drugs,and their structures and properties were studied.The research contents as follows:?1?Phenylboronic acid-modified nateglinide?NA-APBA?and vitamin E succinate?VES-APBA?monomers were first synthesized by amidation reaction.Then,Dex-APBA-NA and Dex-APBA-VES with glucose and ROS dual sensitive behaviors were successfully synthesized through the formation of boron ester bonds between the dihydroxy group of phenylboronic acid and the o-diol of dextran,and insulin was encapsulated to form NA/INS and VES/INS,respectively.The structures of monomers and polymers were detenmined by ¹H-NMR and FT-IR.In vitro drug release test showed that the NA/INS and VES/INS PDC micelles can quickly break under glucose and H₂O₂ conditions,and the simultaneous release of the bonded drug and the encapsulated insulin obtained.?2?The NA,VES,NA/INS and VES/INS micelles performed protection capacity on insulin resistance and oxidative stress SH-SY5Y cell model.The Morris water maze test and pathology studies showed that PDC micelles significantly improved the spatial memory and recognition in SAMP8 mice and had certain protective effects on nerve cells in hippocampus and cortex.The NA/INS and VES/INS micelles significantly repaired mitochondrial dysfunction by improving abnormal glucose metabolism and alleviating oxidative stress.Our results also showed that NA/INS micelle exhibited most beneficial effect on the treatment of SAMP8 mice,suggesting that combination therapy of nateglinide and insulin exerted synergistic functions and reversed cognitive impairment in SAMP8 mice.