A Novel Brain-targeted Drug Delivery System Loaded With Curcumin For Alzheimer’s Disease Therapy

Objective:Alzheimer’s disease（AD）is the most common type of dementia in clinic.With the world’s aging population,the incidence of AD is rising steadily.Curcumin（Cur）,a natural compound,has shown great potential in the therapeutic field of AD from multiple perspectives,but its drawbacks such as low water solubility and low bioavailability limit the clinical translation.Besides,insurmountable blood-brain barrier（BBB）also limits the therapeutic effect of the drug.A new AD therapy based on brain-targeted nano-delivery system not only ensures the safety of drugs,but also significantly improves the therapeutic effect of drugs,which brings new hope for clinical AD treatment.Herein,we constructed a novel brain-targeted nano-delivery system（Ce/Zr-UiO@Cur-Lf）loaded with curcumin,and evaluated its safety,targeting and therapeutic effect in vitro and in vivo,in order to provide more options for the clinical treatment of AD.Methods:Firstly,a nanoscale bimetallic mixed metal-organic framework（Ce/Zr-UiO）was synthesized by solvothermal method,and Cur was loaded onto Ce/Zr-UiO by physical stirring to obtain Ce/Zr-UiO@Cur.Then through the principle of layer-by-layer self-assembly,the positive target ligand lactoferrin was wrapped onto the negative Ce/Zr-UiO@Cur to finally obtain Ce/Zr-UiO@Cur-Lf,during which physicochemical properties of prepared nanoparticles were characterized.In addition,in vitro drug release profile and reactive oxygen species（ROS）scavenging activity of nanoparticles were also investigated.Secondly,the safety of the nanoparticles at the cellular level,the effect on the intracellular ROS level,the uptake effect and uptake mechanism by PC12 and bEnd.3cells and the in vitro BBB permeation effect were investigated.Finally,the mouse AD model was established by intrahippocampal injection of Aβ_1-42,and the in vivo biodistribution,AD therapeutic effect and biosafety of the nanoparticles were researched at the animal level.Results:In this thesis,Ce/Zr-UiO@Cur-Lf nanoparticles with sustained drug release characteristic and ROS scavenging ability were prepared.The nanoparticles showed great safety on PC12 cells and could attenuate H₂O₂-induced oxidative damage in PC12 cells.Moreover,the nanocarrier could promote drug uptake by PC12 and bEnd.3 cells and facilitate drug transport across the BBB.In addition,the nanopreparation could selectively accumulate in the brain of mice after intravenous injection,which enhanced drug accumulation in the brain,After the treatment with Ce/Zr-UiO@Cur-Lf,multiple pathological features of AD model mice were improved,such as damaged neurons,excessive Aβdeposition,disordered central cholinergic system,oxidative stress and neuroinflammation.Furthermore,the nanoparticles had good biosafety,with no obvious toxic effects at the given doses.Conclusion:A novel brain-targeted delivery system（Ce/Zr-UiO@Cur-Lf）loaded with curcumin was successfully designed and constructed in this thesis,which has the characteristic of slowing drug release and the function of scavenging ROS.It shows enhanced brain targeting efficiency,significant improvement effect in AD pathology and great biosafety in in vitro and in vivo experiments,which demonstrates its potential clinical application value.