Study Of Targeted Nano Delivery Systems For Treatments Of Brain’s Diseases

Brain disease is heterogeneous neurological and mental disorder that occurs in the brain.Among various brain diseases,brain tumors represented by glioblastoma multiforme(GBM)and neurodegenerative diseases represented by Alzheimer’s disease(AD)and Parkinson’s disease(PD)are particularly concerned due to the facts that the number of patients worldwide is relatively high and the consequences of the disease are severe.However,the current drug treatments are not effective yet.The reason is mainly due to the low concentration of the free drugs at the lesion/target site.Specifically,the drug half-life of blood circulation is relatively short,the drug enrichment at the lesion site is relatively low,the targeting properties of drug is poor toward the target site,the controlled-release properties of drug is not ideal at the target site.To solve the problems above,the nano drug delivery systems were designed and constructed for targeted delivery of drugs and antigens for GBM,AD and PD respectively.The delivery efficiency and therapeutic effects of the system were investigated through in vitro and in vivo experiments.The detail research work is as follows:(1)A microenvironmentally responsive nano delivery system was designed,which was constructed of poly(amino acids)to contain the anti-tumor drug doxorubicin(DOX)for GBM treatment(DOX@PLSPL).The nano system can prolong the drug half-life of blood circulation,increase the drug enrichment in the tumor site,and enable the controlled release of drug at the target site.DOX@PLSPL was a spherical micelle with a hydraulic particle size of about 127 nm with uniform morphology.It had a higher drug loading efficiency(32.5%),a ROS responsiveness and a controlled release ability.Compared with free DOX,it significantly improved cell endocytosis efficiency(increased by about 1.8 times),illustrated good anti-tumor cell ability which was similar to free DOX,and showed higher biocompatibility of system materials.Compared with free DOX,the blood circulation half-life of DOX@PLSPL was extended by 2.3 times.It increased the drug enrichment at tumor lesions by about 3.1 times,and improved the anti-tumor ability by about 1.75 times.In addition,DOX@PLSPL also showed high biological safety.(2)A targeting-modified nanoparticle was designed to encapsulate the antigen of Tau polypeptide for AD immunotherapy(MPEG-Chol-MPLA-P).The nano system can efficiently target the antigen presenting cells,effectively induce the cell maturation,and activate the immune response.MPEG-Chol-MPLA-P was a nanoparticle with a hydraulic particle size of about 117 nm.It had a high antigen encapsulation rate(70.8%)with good antigen protection.Through membrane fusion,it significantly improved the efficiency of antigen entry into cells(3.2 times than that of free antigen).Afterwards,MPEG-Chol-MPLA-P efficiently initiated the antigen presentation process of bone marrow dendritic cells as well as induced the cell maturation(increased the CD40 positive expression by 3.7 times and the MHC Ⅱexpression by 1.4 times),and activated the immune response.Compared with free antigen,MPEG-Chol-MPLA-P efficiently induced the migration of antigen-presenting cells into the lymph nodes,effectively increased the antigen enrichment in lymph nodes(2.7 times than that of free antigen).At the same time,it significantly improved the behavior of AD mice:the number of water maze crossings increased to 4 times,and the proportion of staying time in the target quadrant increased to 2 times).Meanwhile,MPEG-Chol-MPLA-P obviously repaired the neuron damages of AD mice.(3)A traceable nano-hybrid system was designed with ROS-esterase dual-responsiveness to load gene-chemical drug combination for PD synergistic treatment(GC-TRIO).The nanoparticle can significantly improve the drug enrichment at the brain lesions,and enable the controlled release of drug at the lesions.GC-TRIO was a spherical nanoparticle with a hydraulic particle size of about 32 nm with uniform morphology.It had good stability,higher siRNA loading capacity and MRI sensitivity(2.1 times higher of relaxation rate).Meanwhile,it showed better blood-brain barrier crossing ability(neuron targeting efficiency increased by 1.6 times)and significantly improved the drug’s ability of endosome escaping as well as of controlled release,which effectively promoted the treatment of cells at lesions(the ROS level reduced by 15 times,the mitochondrial function restored by 8.6 times,and the content of α-syn reduced by 8.7 times).In addition,GC-TRIO illustrated in PD mice the obvious drug enrichment at brain lesions and magnetic resonance tracing.In summary,according to the treatment bottlenecks of GBM,AD and PD,the treatment strategies were proposed respectively to effectively deliver the drugs/antigens to the target sites through the nano drug delivery systems,which significantly improved the drug/antigen concentration at the target cells,and therefore significantly improved the efficacy of disease treatment.Hence,the research work provides new possibilities for the treatment of brain diseases in the future.