Study On Target Gene-chem Co-delivery System For Parkinson's Disease Synergistic Therapy

For the neurodegenerative disease such as Parkinson's disease,the bottleneck of current treatment is that it can't alleviate the dopaminergic neuronal degeneration.Considering the key pathological of Parkinson's disease,?-synuclein(?-Syn),we propose a strategy of synergistic treatment with gene drugs and chemical drugs.There are a series of problems in the drug delivery process,such as poor tissue permeability,low lesion concentration,difficulty of drug controlled release and difficulty to track.Existing nanomedicines currently used for brain disease research rely primarily on the simple penetration of the blood-brain barrier(BBB)or the development of targeted neurons delivery,such as using CPP and other peptides.However,brain physiological functions are complex and drug delivery disorders are continuous,these single delivery step solutions are often not efficient.Therefore,efficient drug enrichment of brain tissue through rational design is a difficult point in drug delivery for brain diseases.Based on this,we construct a CT visualized gold nanoparticle gene-chemical drug delivery system.The system can achieve efficient brain drug enrichment and synergistic therapy The specific contents are as follows:(1)The system achieves cascade targeting of drugs:through cell-penetrating peptide B6,the nanoparticles are permeable to the brain through the blood-brain barrier,and achieves neurons target via mazindol which significantly increasing drug accumulation in the lesion.(2)The system achieves drug controlled release:thioether bonds in the carrier release the drug in response to H2O2,to achieve drug controlled release in the neuron.(3)The system realizes the visualization of drug delivery process:under the action of the Fe3+ responsive gold nanoparticle contrast agent core,there is a CT signal enhancement in the the brain of diseased mice,suggesting that the nanoparticles are enriched in the brain.In terms of therapeutic effect,the combined delivery of gene and chemical drugs can play a synergistic effect and effectively improve the motor behavioral characteristics of Parkinson's disease mice,especially in decreasing the dopaminergic neuron ?-Syn protein in the brain's substantia nigra region and recovering the number of neurons in the substantia nigra area.Therefore,the visual targeting nanosystem can provide a carrier platform for relieving dopaminergic neuron degeneration.Aiming at the problems of the existing traditional synthetic delivery system,such as natural immune response and poor cell uptake,exosome has been applied to drug delivery for brain diseases due to their advantages such as immune inertia in blood circulation and membrane fusion into cells.However,it is difficult to achieve efficient and simultaneous delivery of gene drugs and chemical drugs to brain lesions in the existing research.Therefore,exploring the combined delivery of targeted natural carriers for efficient drug enrichment in brain tissue is a difficult point in drug delivery for brain diseases.We propose a strategy of exosome coating polymer hybrid nanoparticle as combined drug delivery system for the synergistic treatment in order to enhance drug delivery efficiency.The main method consists of the synthesis and assembly of a hydrogen peroxide-responsive gene-chemical drug polymer carrier,the isolation of exosomes,the modification of targeted polypeptides on exosome and the assembly of complexes.We confirm the efficient drug delivery:(1)The system achieves brain tissue penetration and lesion enrichment of the drug:the RVG modified exosome mediates nanoparticles across the blood-brain barrier,penetrate into brain tissue and target neurons,which significantly increase drug accumulation in the lesion.(2)The system achieves controlled release of the drug:exosome membrane fuses with cells to improve the dual-drug polymer endocytosis.The endosome pathway is changed to the membrane fusion pathway,and the polymer based drug core is released into the cytoplasm.The phenylboronic acid group in the carrier core release the drug in response to H2O2.In terms of therapeutic effects:(1)The above-mentioned efficient delivery advantages can enhance the synergistic therapeutic effect of siSNCA and curcumin.(2)The system results in the treatment of various animal Parkinson's disease models:MPTP-induced Parkinson's disease mice,unilateral striatum ?-Syn oligomers injected Parkinson's disease rats and monkeys.(3)This study has confirmed the immunosuppressive effect of this system on T cells,which can provide new ideas for the application of immature dendritic exosome systems.Therefore,based on the potential synergistic effect of siSNCA and curcumin on the clearance of ?-synuclein aggregates,we construct two gene-chemical drug delivery systems:CT visualization gold nanoparticle for gene-chemical drug delivery system and exosome coating polymer co-delivery hybrid system.The systems are combined drug delivery for brain diseases,and have high drug tissue penetration,high lesion enrichment,controlled drug release and track ability.They have solved the difficulty of efficient enrichment of genes and chemical drugs in the brain,have relieved neuron degeneration and provide a prospective solution for targeted treatment of Parkinson's disease.