靶向叶酸受体和线粒体的载雷公藤红素PAMAM纳米递药系统构建及体外抗炎作用  

Construction of folate receptors and mitochondria targeting celastrol-loaded PAMAM nano-drug delivery system and its in vitro anti-inflammatory effect

作　　者：荆紫琪 王雪 闫天月 张玉杰[1] 马鹏凯[1] JING Zi-qi;WANG Xue;YAN Tian-yue;ZHANG Yu-jie;MA Peng-kai(School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 102488,China)

机构地区：[1]北京中医药大学中药学院,北京102488

出　　处：《药学学报》2023年第3期550-559,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82104404)。

摘　　要：促炎巨噬细胞在类风湿性关节炎的发生和发展中发挥关键调控作用。本研究构建了一种可靶向叶酸受体和线粒体的载雷公藤红素(celastrol,Cel)聚酰胺-胺树枝状聚合物(polyamide-amine dendrimer,PAMAM)纳米递药系统,实现可靶向炎症巨噬细胞的集化疗和光热于一体的协同治疗。以PAMAM为纳米载体,通过酰胺反应偶联叶酸受体靶向基团叶酸(folic acid,FA)和线粒体靶向基团IR808(同时作为光热剂),通过静电吸附作用负载抗炎药Cel,制备了FA-PAMAM-IR808/Cel纳米复合物。体外表征结果表明,该纳米复合物中Cel载药量为50.90%,粒径为130~160 nm,平均电位在1.0~3.5 mV,释药呈现pH敏感性,经近红外光照射10 min温度可达42.5℃;体外摄取实验表明,纳米复合物有明显的叶酸靶向性和线粒体靶向性;纳米复合物在近红外光照后可显著增强细胞毒性和诱导细胞凋亡能力,并浓度依赖性降低促炎因子肿瘤坏死因子α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、一氧化氮(NO)分泌量。本研究为开发新型的抗类风湿性关节炎纳米药物提供了思路。Pro-inflammatory macrophages play key regulatory role in the occurrence and development of rheumatoid arthritis(RA).In this study,we constructed a celastrol(Cel)-loaded polyamide-amine dendrimer(PAMAM)drug delivery system,which could target folate receptor and mitochondria.It could target inflammatory macrophages and realize chemo-photothermal synergistic therapy.Using PAMAM as the nano-carrier,folate receptortargeting group folic acid(FA)and mitochondria-targeting group IR808(also known as the photothermal agent)were conjugated with PAMAM through amide reaction,and then complexed with anti-inflammatory drug Cel to prepare the FA-PAMAM-IR808/Cel nanocomplex.In vitro characterization results showed that the drug loading efficiency of the nanocomplex was 50.90%,particle size was between 130 and 160 nm,average potential was between 1.0 and 3.5 mV,the drug release showed pH sensitivity,temperature reached to 42.5℃ after near-infrared(NIR)light irradiation for 10 min.In vitro cellular uptake experiments showed that the nanocomplex had obvious folate receptor-targeting and mitochondria-targeting ability.Following irradiation with NIR light,the cytotoxicity and cellular apoptosis enhanced.The secretion of pro-inflammatory factors tumor necrosis factorα(TNF-α),interleukin(IL)-1β,IL-6 and nitric oxide(NO)decreased in a concentration-dependent manner.This study provided insights for the development of novel anti-RA nanomedicines.

关 键 词：类风湿性关节炎 雷公藤红素 聚酰胺-胺树枝状聚合物 叶酸 线粒体 

分 类 号：R945[医药卫生—微生物与生化药学]