Study On Targeted Nano Delivery System For Alzheimer's Disease Therapy

Alzheimer's disease(AD)is the most common neurodegenerative disorder among the elderly,which causes the progressive cognitive and memory decline.The current drugs used in clinic can only meliorate the symptoms to some extent,which can not prevent the disease progression.This may be attributed to the short plasma half-time and the obstacle of the blood brain barrier(BBB),which result in poor drug accumulation in the brain.Furthermore,the pathogenesis of AD is very complex,and single drug may not achieve enough therapeutic result.Therefore,it is urgent to find a new and effective strategy for the AD therapy.To solve the problems of "poor enrichment of target sites" and "poor therapeutic effect of symptomatic treatment",we aim at the pathogenesis of AD and develop rational delivery systems.The therapeutic effect was investigated in in vitro and in vivo.The results demonstrated that the drugs could be delivered to diseased sites effectively,and the therapeutic effect of AD was improved remarkably.In detail,the works mainly included the following issues1)The vicious circle between dysfunctional microglia and amyloid-?(A?)is a crucial pathological event and accelerates the progression of AD.Therefore,we present the strategy of regulating the function of microglia and reducing A? burden simultaneously to break the negative feedback loop.To achieve this,a zwitterionic poly(carboxybetaine)(PCB)based nanoparticles(MCPZFS NPs)with normalizing the dysfunctional microglia and A? recruitment are established for the treatment of AD Compared with the neural polyethylene glycol(PEG)-based nanoparticles(MEPZFS NPs),the brain enrichment of MCPZFS NPs is more effectively.And it is demonstrated that the PCB based nanoparticles significantly alleviate the priming of microglia by decreasing the A? induced cytotoxicity and the level of pro-inflammatory mediators Most importantly,we discover MCPZFS NPs exhibited the behavior to recruit A? into microglia,which significantly enhanced the A? phagocytosis.Moreover,MCPZFS NPs can carry A? escape from lysosomes to cytoplasm rapidly and mediate A? degraded by proteasomes,which is quite different from the lysosomal/autophagy pathway of MEPZFS NPs.After the treatment with the nanopaticles,the A? burden,neuron damages,memory deficits,and neuroinflammation of AD mice are significantly attenuated in the brain.Therefore,the PCB-based nanoparticles have great potential to serve as an " A? cleaner" and provide a new insight into the therapeutic strategy for AD therapy.2)As research continues,it has been found that excessive metal ions in the brain can promote the aggregation of A? and increase the toxicity.Moreover,tau phosphorylation in the neurons can take place independently of A?,which lead to the damages of neuron,loss of synaptic function and generation of oxidative stress.Based on the above complex etiology,this chapter proposes a triple strategy for the treatment Firstly,Histidine was employed as metal ion chelating agent to inhibit the aggregation of A?.Secondly,Salsalate was introduced to reduce the expression of acetyltransferase p300 and phosphorylation of tau in neuron.Moreover,RNA interference was used to down-regulate the expression of NF-?B for oxidative stress modulation.In order to achieve enrichment and controlled release of the drug at the lesion site,a metal ion/enzyme dual-responsive delivery system is developed.It is demonstrated that the nanoparticles could permeate BBB and target to neuronal cells effectively.The cytotoxicity induced by A? aggregation,the expression of p300,phosphorylated tau and NF-?B in neuronal cells were reduced significantly.In animal experiment,the cognitive and memory damage of AD mice were significantly alleviated,the expression of A? and p-tau were reduced and the inflammation level decreased remarkably Therefore,the nanoparticles with the triple-synergistic mechanism provide a new horizon to the therapeutic strategy for AD therapyIn summary,this article proposes two treatment strategies based on the complex etiology of AD,which deliver drugs to the lesion site effectively and significantly alleviate the pathology of AD.The new strategies provide new perspective for the treatment of AD in the future.