病理血脑屏障穿越BSc3094纳米制剂的制备表征及其靶向性评价  

Characterization of pathological blood-brain barrier crossing BSc3094 nanopreparations and evaluation of their targeting properties

作　　者：罗航 吕月 高会乐[2] 熊静远 LUO Hang;LÜYue;GAO Hui-le;XIONG Jing-yuan(West China School of Public Health/the Fourth Hospital of West China,Sichuan University,Chengdu 610041,China;West China College of Pharmacy,Sichuan University,Chengdu 610041,China)

机构地区：[1]四川大学华西公共卫生学院/华西第四医院,四川成都610041 [2]四川大学华西药学院,四川成都610041

出　　处：《药学学报》2024年第12期3388-3393,共6页Acta Pharmaceutica Sinica

基　　金：四川省科技厅资助项目(2021YJ0156)

摘　　要：异常过度磷酸化Tau蛋白引起的细胞内神经纤维缠结是阿尔茨海默病主要的病理标志之一。现有研究表明,BSc3094是一种有效的Tau蛋白聚集抑制剂,其可以与Tau蛋白结合,抑制Tau蛋白磷酸化,同时增强细胞活力,在治疗阿尔茨海默病方面具有极大潜力。然而,由于血脑屏障的存在,药物难以入脑发挥作用,同时,BSc3094是否可以通过抑制Tau蛋白聚集来治疗阿尔茨海默病尚未深入研究。因此,本研究通过搅拌法制得小粒径聚乳酸-羟基乙酸[poly (lactic-co-glycolic acid),PLGA]纳米颗粒,以其为载体,搭载BSc3094 (PLGA@BSc),为了进一步增加其入脑效率,在其表面修饰了病理血脑屏障靶向肽得到PLGA@BSc@K。本研究对该纳米体系的稳定性、细胞毒性及病理靶向性进行了表征,该纳米体系的粒径约90 nm,呈负电性;实验表明,纳米粒颗粒粒径在168 h内未见明显波动,稳定性较好;PLGA及BSc3094游离药物对细胞活力无显著影响,细胞毒性较低;在1及4 h都可以明显观察到病理状态下细胞对靶向修饰的纳米颗粒的摄取增加,表明PLGA@BSc@K具有较好的病理靶向效果。本研究为BSc3094纳米颗粒靶向入脑及阿尔茨海默病的治疗提供了新思路。Intracellular neurofibrillary tangles resulting from abnormal hyperphosphorylation of Tau protein constitute one of the principal pathological markers of Alzheimer′s disease.Existing studies have indicated that BSc3094 is an efficacious inhibitor of Tau protein aggregation,capable of binding to Tau protein,inhibiting Tau protein phosphorylation,and enhancing cell viability concurrently,holding significant potential in treating Alzheimer′s disease.Nevertheless,due to the presence of the blood-brain barrier,it is challenging for drugs to penetrate the brain and exert their effects,and whether BSc3094 can treat Alzheimer′s disease by inhibiting Tau protein aggregation has not been profoundly investigated.Hence,in this study,small-sized(PLGA) nanoparticles were fabricated through the stirring method.BSc3094 was loaded into the nanoparticles(PLGA@BSc).To further enhance the brain entry efficiency of PLGA nanoparticles,a pathological BBB-targeting peptide was modified on the surface to obtain PLGA@[e-mail] this study,the stability,cytotoxicity,and pathological targeting of the nanosystem were characterized.The particle size of the nanosystem was about 90 nm,which was negatively charged.The results demonstrated that the particle size of the nanoparticles did not fluctuate conspicuously within 168 h,and the stability was favorable.PLGA and BSc3094 had no notable impact on cell viability and displayed low cytotoxicity.At 1 and 4 h,it was observed that the uptake of targeted modified nanoparticles by cells in pathological states augmented,suggesting that PLGA@BSc@K had an excellent pathological blood-brain barrier targeting effect.This study provides a novel concept for the targeting of BSc3094 nanoparticles in the brain and the treatment of Alzheimer′s disease.

关 键 词：阿尔茨海默病 TAU蛋白 纳米颗粒 BSc3094 血脑屏障 

分 类 号：R943[医药卫生—药剂学]