Dextran-polycaprolactone Vesicles Alzheimer's Disease Multi-drug Combination Treatment System

Complex neuropathology has stalled the clinical treatment of Alzheimer’s disease（AD）.Until the source pathogenesis is discovered,symptom-based multi-drug treatment strategy is considered the most effective way to improve the patient’s condition.In view of this,this article elaborately designed nanocarriers for multi-drug combined delivery,and conducted systematic research from improving drug enrichment and exploring synergies between multiple drugs.The research contents are as follows:（1）Using Polycaprolactone-2-bromoisobutyric acid 2-hydroxyethyl（PCL-HEBIB）,dextran-acryloyl chloride（Dex-AC）and glycidyl methacrylate（GMA）as comonomers,Alanine-Alanine-Asparagine-Cysteine-Lysine（AK polypeptide）and2-cyano-6-aminobenzothiazole（CABT）as targets,PCL-Dex-PGMA-AK and PCL-Dex-PGMA-CABT polymers was carefully designed and successfully prepared.The structure of monomers and polymers was verified ¹H-NMR tests.Dynamic light scattering（DLS）and transmission electron microscope（TEM）tests showed that the two polymers self-assembled in water to form response vesicles(Vesicle _AK)and chaperone vesicles(Vesicle _CABT),and a cross-linking reaction occured under the action of endopeptidase to form micron-sized composite nanoparticles.Rhodamine B was used as a model drug,confocal laser scanning microscope（CLSM）and flow cytometry were used to observe that the intelligent vesicles could be carried into the cytoplasm through the endocytosis and remained in the cells.The Morris water maze experiment revealed that the combined therapy regimen mediated by smart vectors could effectively improve the memory ability of senescence accelerated mouse prone8（SAMP8）mice.Molecular biology testing verified that the combined therapy regimen could repair abnormal glucose metabolism,reduce active oxygen content,and improve synaptic function.Ex-vitro tissue imaging and liquid chromatography-mass spectrometry（LC-MS）validated that smart carriers could achieve brain enrichment of drugs.（2）PCL-g-Dex amphiphilic polymer was synthesized by ATRP polymerization using PCL-HEBIB and Dex-AC as polymerization monomers.¹H-NMR tests verified the structure of the monomers and polymers.DLS and TEM studies showed that PCL-g-Dex could form nanovesicle.Cell damage models were established by using insulin resistance inducers,and the therapeutic effect of different combination treatment plans was verified by CLSM and flow cytometry.The combination treatment plan consisting of insulin,rigaglinide and metformin hydrochloride drug-containing vesicles could reverse the memory ability of SAMP8 mice,the combination treatment plan basing on exogenous insulin as the main drug,DON and MEM as adjuvants has also been successful.There was a synergistic effect among the drugs in the above plans,and the synergistic effect could continuously stimulate related organisms signals,maintain the stability of glucose metabolism and energy circulation,improve synaptic plasticity and activate advanced physiological circuits in cells,ensuring smooth communication between neurons.