铁蛋白装载“铁-阿霉素”新策略  

A new strategy of loading ferritin with “iron-Dox” complex

作　　者：向建全 周彩玉 张若飞 曾凡才 范克龙[2] XIANG JianQuan;ZHOU CaiYu;ZHANG RuoFei;ZENG FanCai;FAN KeLong(Laboratory of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Southwest Medical University,Luzhou 646000,China;CAS Engineering Laboratory for Nanozyme,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China)

机构地区：[1]西南医科大学基础医学院,生物化学与分子生物学教研室,泸州646000 [2]中国科学院生物物理研究所,中国科学院纳米酶工程实验室,北京100101

出　　处：《中国科学：生命科学》2021年第7期871-878,共8页Scientia Sinica(Vitae)

基　　金：国家自然科学基金(批准号:31900981);中国科学院创新交叉团队(批准号:JCTD-2020-08)和中国科学院青年创新促进会(批准号:2019093)资助。

摘　　要：铁蛋白具备独特的笼状结构、自组装特性、内在的肿瘤靶向性、良好的生物相容性以及易于规模化生产等优势,是一种具有良好转化前景的纳米药物载体.目前,关于铁蛋白装载抗肿瘤药物阿霉素(doxorubicin,Dox)的研究较多,装载策略包括被动装载和主动内化两类,其中,预先螯合金属离子形成"金属-阿霉素"复合物以促进其主动进入铁蛋白内腔的装载方法具有装载量高、杀伤效应强等特点,然而,此类方法仍存在铁蛋白回收率低、蛋白完整性受损等缺陷.为此,本文结合温度孵育法,利用人重组重链铁蛋白(human heavy chain ferritin,human HFn)发展了一种基于铁离子的"金属-阿霉素"装载新策略,成功构建了"铁蛋白-铁-阿霉素"(HFn(Fe-Dox),HFeD)药物递送系统,该系统具有高装载量(80-100个/HFn)、高包封率(50%-63%)和高蛋白回收率(80%-90%)的特点.同时,该策略很好地保留了铁蛋白的结构完整性、肿瘤靶向性和药物释放可控性,因而保证了HFeD对肿瘤细胞的特异靶向和杀伤.该方法的报道有望增加HFeD成药的可能性,推动铁蛋白药物载体的发展与应用.Ferritin, owing to its unique nanocage architecture, self-assembling ability, inherent tumor-targeting, excellent biocompatibility and capability to be produced on a large scale, has emerged as a promising nano-drug carrier for clinical translation. Currently, loading of anti-tumor drug, especially doxorubicin(Dox), in ferritin has been widely investigated via either passive encapsulation or active internalization. Among these methods, strategies that pre-complex metal ions with Dox to form "metal-Dox" complexes that promote entry of Dox into the cavity of ferritin actively enable higher loading capacity and enhanced killing effect. However, these ways currently used still suffer from low recovery rate and impaired integrity. In order to overcome these shortcomings, we here report a new loading strategy, a temperature-related and iron ion-depended method, in which we utilized human heavy chain ferritin(human HFn) and successfully constructed the HFn(Fe-Dox) drug delivery system(HFe D), which achieved a high loading capacity(80–100 Dox per HFn), high encapsulation rate(50%–63%) and considerable recovery rate of HFn(80%–90%). Meanwhile, the strategy reported here preserves the structural integrity, tumor-targeting and controlled drug release of HFn, and thus HFe D is able to specifically target and kill tumor cells, which will inform the druggability of HFe D and application of ferritin-based nano-drug carriers.

关 键 词：铁蛋白 铁-阿霉素 药物递送 肿瘤 

分 类 号：R943[医药卫生—药剂学]