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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (2/3): 15-25    DOI: 10.13523/j.cb.2207068
新型药物递送系统研发与应用专题     
疏水蛋白载药系统研究进展*
张文慧**,严健元**,陈渝萍***()
南华大学药学院 肿瘤微环境响应与药物研究湖南省重点实验室 衡阳 421001
The Progress of Hydrophobin-based Drug Delivery System
ZHANG Wen-hui**,YAN Jian-yuan**,CHEN Yu-ping***()
Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmacy, University of South China, Hengyang 421001, China
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摘要：

药物的临床使用常常因为其强疏水性、低稳定性和高毒副作用等问题受到限制。日新月异的药物递送体系(DDS)可以有效地包载与保护药物,提高其生物相容性、作用特异性和治疗效果。疏水蛋白是真菌在如子实体发育等特殊时期分泌的小分子蛋白质。其独特的两亲性不仅有助于它们自组装成胶束和载送疏水性药物,还便于它们修饰和改造其它载药体系。其超低的免疫原性和细胞毒性则进一步支撑了它们在药物递送中的应用。对近几年基于疏水蛋白所发展的载药系统的研究进展进行了综述。
关键词： 载药体系;  蛋白胶束;  疏水蛋白;  真菌    
Abstract:

The strong hydrophobicity, low stability and high side effects of drugs largely limit their clinical use. Drug delivery system (DDS) has undergone fast growth. It can effectively carry and protect drugs, thus increasing their biocompatibility, action specificity and effectiveness. Hydrophobins are small molecular proteins secreted during the special period of fungi, such as the development of fungal fruiting bodies. They possess unique amphiphilicity to aid their self-assembly into micellar structure and modification for other DDSs progress, while their extremely low immunogenicity and cytotoxicity further support their application in drug delivery. This paper reviews the research progress of hydrophobin-based DDS in recent years.
Key words: Drug delivery system    Protein micelles    Hydrophobin    Fungus
收稿日期: 2022-07-31 出版日期: 2023-03-31
ZTFLH:  Q819  
基金资助: *湖南省教育厅大学生研究性和创新性实验计划(s202110555236)
通讯作者: ***陈渝萍     E-mail: yuingc@usc.edu.cn
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引用本文:

张文慧, 严健元, 陈渝萍. 疏水蛋白载药系统研究进展*[J]. 中国生物工程杂志, 2023, 43(2/3): 15-25.

ZHANG Wen-hui, YAN Jian-yuan, CHEN Yu-ping. The Progress of Hydrophobin-based Drug Delivery System. China Biotechnology, 2023, 43(2/3): 15-25.

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https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2207068    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I2/3/15

图1  疏水蛋白在亲疏水界面的自组装
类型 疏水蛋白 来源 递药体系 功能 参考文献
I型 HGFI 灰树花 Cur 增强药物抗肿瘤效果 [21]
I型 HGFI 灰树花 Cur 增加药物溶解性和稳定性 [22]
I型 HGFI 灰树花 menaquinone-7 增加药物溶解性 [23]
I型 MGF3、MGF6 灰树花 IND 增加药物的溶解性和稳定性,缓释药物 [24]
I型 MG24 灰树花 MWCNTS 提高纳米管的分散稳定性 [25]
I型 MGF6 灰树花 MGF6-HNTS-Dox 促进药物分散和延缓药物释放 [26]
I型 HPB 真菌 HPB-PLGA-Cur 增强药物抗肿瘤效果 [27]
II型 HFB-1 里氏木霉菌 HFB-1-Nio-DOX 改善药物分布、增加药物血液循环时间和免疫逃逸功能 [28]
II型 HFBIV 里氏木霉菌 Tf-HFBIV-Psi 靶向配体,提高纳米颗粒摄取 [29]
II型 HFBII 里氏木霉菌 HFBII-NP-PTX 谷胱甘肽响应性缓释药物,降低药物IC50 [30]
II型 HFBII 里氏木霉菌 HFBII-FNPs 降低纳米颗粒与血浆蛋白的吸附性 [31]
II型 HFBII 里氏木霉菌 HFBII-NFC-O-IBU 作为表面活性剂稳定乳液 [32]
II型 HFBI 里氏木霉菌 FA 结晶抑制剂 [33]
表1  应用于载药等生物医用的疏水蛋白
用途分类 融合疏水蛋白 表达体系 纯化方法 优点 应用 文献
抗原抗体的制备、检测和固定 rK39-HFBI 植物 ATPS 消除了通过额外步骤去除纯化标签的需要 用于内脏利什曼病免疫诊断 [35]
Hydrophobin-Protein A 植物 单一ATPS 纯化成本更低并且蛋白质回收率相当,增加蛋白A树脂的寿命,减少单克隆抗体的损失 提高西尼罗河病毒单克隆抗体(E16)产量 [36]
HFB-DomIII-1
HFB-DomIII-2		 昆虫幼虫杆状病毒系统 ATPS 快速、简便和成本效益高的方法用于生产与HFB融合的重组抗原,并且重组抗原的安全性较高 固定抗原DENV,检测抗体水平 [38]
医疗器械抗菌涂层 LL37-Vmh2 大肠杆菌表达系统 超滤回收
Vmh2		 提高抗菌肽抗表皮葡萄球菌生物膜活性并且对革兰氏阳性和革兰氏阴性菌都有效 用于医疗器械的涂层,抑制其表面微生物生长 [40]
生物传感器 ArsC-Vmh2 Vmh2-ArsC 大肠杆菌表达系统 包涵体变性复性 嵌合蛋白既具有vm2的黏附特性,又具有耐热砷酸还原酶的砷传感能力 电化学生物传感器用于检测As(III) [41]
Ccg2-EPSPS 大肠杆菌表达系统 镍柱亲和
纯化		 降低了传统传感器程序的复杂性,并允许实时检测 高度灵敏传感器用于检测草甘膦 [42]
Lac-Vmh2 毕赤酵母表达系统 上清液浓缩并透析 方法简单、环保且用途广泛,既可用作FLG的表面活性剂,也克服了在剥离石墨烯过程中的分散稳定性 用于修饰玻碳类化合物的电化学传感器 [43]
Vmh2-ScFvSTX
Vmh2-ScFvDA		 大肠杆菌表达系统 包涵体变性复性 方法简单智能,Vmh2允许ScFv将MBs直接功能化不需任何化学修饰,MBs可以使用磁场回收重复利用 固定抗体ScFvs,诊断抗原 [34]
表2  生物医用的新型融合疏水蛋白
融合标签 蛋白质 表达体系 纯化方法 优点 应用 文献
ramp DewA 大肠杆菌表达系统 异丙醇改进的双相水分离 避免耗时且低效的蛋白质复性和纯化步骤,且纯化过程只使用IPA一种试剂 提高疏水蛋白的表达和产量 [45]
CBD CBD-HGFI 大肠杆菌表达系统 镍柱亲和纯化 CBD特异性与BC结合,促进从粗提取物中快速分离和纯化疏水蛋白 提高疏水蛋白的表达和产量 [44]
Ffu312 EAS-Ffu312
HFBII-Ffu312		 大肠杆菌表达系统 镍柱亲和纯化 融合蛋白分泌到周质和培养基中简化了纯化,便于提供氧化环境和二硫异构酶,促进疏水蛋白二硫键的形成 提高疏水蛋白的表达和产量 [47]
表3  生物医用疏水蛋白制备新方法——融合标签
表达体系 疏水蛋白 纯化方法 优点 应用 文献
大肠杆菌无细胞表达系统 I型:EASΔ15、EAS、DewY - a DewA mutant、RodA、MPG1
II型:NC2		 Ni-NTA亲和层析 克服重组疏水蛋白的变性重折叠问题以允许正确折叠并提高蛋白质产量,反应环境可以直接控制 提高疏水蛋白的表达和产量 [49-50]
SHuffle T7大肠
杆菌表达系统		 I型:PC1、WL1、SL1、SC16 IMAC柱纯化 有效形成二硫键的还原环境,持续产生高水平、高纯度的疏水蛋白 提高疏水蛋白的表达和产量 [51]
表4  生物医用疏水蛋白制备新方法——表达体系
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