摘要
本研究旨在制备共载地塞米松(dexamethasone,DXMS)和卡托普利(captopril,CAP)的脂质体包被的聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid),PLGA]纳米粒,并在纳米粒表面修饰聚乙二醇和integrinα8抗体以得到载双药的核壳型免疫脂质体复合纳米粒(DXMS/CAP@PLGA-ILs),然后研究该载药纳米粒的肾脏靶向性、抗炎效果及对巨噬细胞分化的影响。结果表明,该纳米粒粒径为115.9±2.89 nm,粒径均一,在电镜下能观察到壳核结构,DXMS载药量为5.72%±0.37%,CAP载药量为7.51%±0.07%。体外细胞实验结果表明,DXMS/CAP@PLGA-ILs可降低M2型巨噬细胞特异性细胞因子的分泌和标志物的RNA表达水平,并促使M2型巨噬细胞往未极化的巨噬细胞方向分化。体内实验表明,DXMS/CAP@PLGA-ILs具有显著的肾靶向性,可使系膜增生性肾小球肾炎小鼠的肾指数、血肌酐和尿素氮水平恢复正常,减少肾脏中炎症细胞因子的分泌,并降低肾脏中M1型和M2型巨噬细胞标志物的RNA表达量。动物福利及实验过程均遵循四川农业大学动物伦理委员会的规定。综上所述,肾靶向性DXMS/CAP@PLGA-ILs纳米粒可有效调控巨噬细胞的极化,起到“抗炎/抗纤维化”的治疗效果,为肾小球肾炎的靶向治疗提供新的策略和依据。
In this study,dexamethasone(DXMS)and captopril(CAP)were co-loaded into poly(lactic-coglycolic acid)(PLGA)nanoparticles with a surface coating of a phospholipid bilayer,and then the core-shell nanoparticles were modified with polyethylene glycol and integrinα8 antibody to obtain immunoliposome-nanoparticle hybrids(DXMS/CAP@PLGA-ILs).The role of nanoparticles on the renal targeting,anti-inflammatory effects,and macrophage differentiation were investigated.The results showed that the particle size of the nanoparticles was 115.9±2.89 nm,and the core-shell structure could be observed under an electron microscope.The drug loading capacity of DXMS and CAP was 5.72%±0.37%and 7.51%±0.07%,respectively.The results of in vitro experiments showed that DXMS/CAP@PLGA-ILs could reduce the secretion of specific cytokines and the mRNA expression of markers in M2-type macrophages,thus promoting the differentiation of M2-type macrophages in the direction of unpolarized macrophages.In vivo experiments in mice showed that DXMS/CAP@PLGA-ILs had a significant renal targeting effect,which could restore the renal index,serum creatinine,and urea nitrogen levels of mesangial proliferative glomerulonephritis in mice.Moreover,DXMS/CAP@PLGA-ILs could reduce both the secretion of inflammatory cytokines and the mRNA expression levels of M1 and M2 macrophage markers in the kidney.All the animal experiments were in accordance with the regulations of Animal Ethics Committee of Sichuan Agricultural University.In conclusion,renal-targeting DXMS/CAP@PLGA-ILs could effectively regulate the polarization of macrophages and had an"anti-inflammatory/anti-fibrosis"therapeutic effect,providing a new strategy and basis for the targeted therapy of glomerulonephritis.
作者
李贤哲
周柳廷
赵越
刘天庆
刘红梅
何黎黎
袁志翔
韩露
LI Xian-zhe;ZHOU Liu-ting;ZHAO Yue;LIU Tian-qing;LIU Hong-mei;HE Li-li;YUAN Zhi-xiang;HAN Lu(College of Pharmacy,Southwest Minzu University,Chengdu 610225,China;College of Veterinary Medicine,Sichuan Agricultural University,Chengdu 611134,China;Department of Pharmacy,Sichuan Tianfu New Area People's Hospital,Chengdu 610213,China;Queensland Institute of Medical Research,Herston 4006,Australia;Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province,Chengdu 610041,China)
出处
《药学学报》
CAS
CSCD
北大核心
2022年第8期2388-2398,共11页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81973265,82003683)
四川省中医药管理局科学技术研究专项(2021MS030)
西南民族大学研究生创新型科研项目(ZD2022408)
发育与妇儿疾病四川省重点实验室开放课题资助项目(2022001).
