Promoting Blood-Brain Barrier Transcytosis Nanoparticle For Multistage Targeted Treatment Alzheimer Diseases

Alzheimer’s disease(AD)is a degenerative disease of the central nervous system,which has caused great harm to families and society.At present,there is no ideal therapeutic drugs for AD in the clinic due to following reasons: the pathological mechanism of AD is complex;the blood-brain barrier(BBB)is difficult to penetrate;the non-selective distribution of drugs in the brain hinders the treatment of AD.Therefore,the focus of our research is to accurately delivery the therapeutic drugs to the lesion site of AD for enhancing the therapeutic effect and reducing the side effectsβ-amyloid(Aβ)deposition and tau protein phosphorylation(p-tau)are two major pathological changes in AD.They promote each other and together cause neuropathy.To inhibit the two pathological targets at the same time,this study used si RNA which could inhibit the production of Aβ plaque and D-peptide(Dp)which could inhibit p-tau to improve neuropathy outcome.However,these two macromolecular drugs are hard to penetrate into the brain,so we designed a programatically targeting nanoparticlebased on dendrigraft poly-L-lysine(DGL)to carry the two macromolecular drugs into the brain.Firstly,to improve the transmembrane transport efficiency in BBB,we modified the DGL with BBB targeting peptide T7 through acid-cleavable long-chain polyethylene glycol(PEG).It can not only promote the uptake of nanoparticles by BBB endothelial cells due to the high affinity between T7 peptide and BBB,but also enable the nanoparticles to quickly escape from lysosomes after entering cells so that to promote transcellular transport.Secondly,to promote the specific distribution of nanoparticles at AD lesions after they enter the brain,we modified the neuron targeting peptide Tet1 to DGL through short-chain PEG,which could be exposed only after the outer long-chain PEG was disconnected,thus enabling the nanoparticles to target brain neurons specifically.In the experimental of this paper,the cellular uptake proved that the nanoparticles had good targeting to b End.3 cells and nerve PC12 cells.In addition,lysosome co-localization,transmembrane efficiency of BBB model,in vivo and ex vivo imaging of mice proved that acid-cleavable T7 could promote transmembrane efficiency and increase the amount of m RNA expression in cells and tissues The behavioral tests of mice and immunostaining of brain tissues demonstrated that the nanoparticles could improve memory loss and neuropathy caused by AD.Besides,the nanoparticles have good stability and safety.In summary,this study designed a si RNA and Dp combined delivery system for AD,which effectively improved drug delivery efficiency and AD treatment effect in mouse,and provided innovative theoretical and experimental basis for the clinical treatment of AD.