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化学进展 2021, Vol. 33 Issue (6): 926-941 DOI: 10.7536/PC200728 前一篇   后一篇

• 综述 •

肿瘤微环境响应药物递送系统的设计

荆晓东1, 孙莹1, 于冰2, 申有青3, 胡浩1,*(), 丛海林1,*()   

  1. 1 青岛大学 材料科学与工程学院 生物医用材料与工程研究院 青岛 266071
    2 青岛大学 化学化工学院 生物多糖纤维成形与生态纺织国家重点实验室 青岛 266071
    3 浙江大学 化学工程与生物工程学院 生物质化工教育部重点实验室 杭州 310027
  • 收稿日期:2020-07-13 修回日期:2020-09-23 出版日期:2021-06-20 发布日期:2020-12-28
  • 通讯作者: 胡浩, 丛海林
  • 基金资助:
    国家自然科学(51703105); 国家自然科学(21675091); 国家自然科学(21874078); 山东省自然科学(ZR2017BEM012); 山东省泰山青年学者计划(TSQN20161027); 山东省重大科技创新项目(2018CXGC1407); 山东省重点研究开发项目(2016GGX102028); 山东省重点研究开发项目(2016GGX102039); 山东省重点研究开发项目(2017GGX20111); 中国博士后科学(2018M630752); 青岛市创新创业领军人才项目(168325zhc); 青岛市博士后科研基金; 山东省一流学科项目
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Rational Design of Tumor Microenvironment Responsive Drug Delivery Systems

Xiaodong Jing1, Ying Sun1, Bing Yu2, Youqing Shen3, Hao Hu1,*(), Hailin Cong1,*()   

  1. 1 Institute of Biomedical Materials and Engineering, College of Materials Science and Engineering, Qingdao University,Qingdao 266071, China
    2 State Key Laboratory of Bio-Fibers and Eco-Textiles, College of Chemistry and Chemical Engineering, Qingdao University,Qingdao 266071, China
    3 Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
  • Received:2020-07-13 Revised:2020-09-23 Online:2021-06-20 Published:2020-12-28
  • Contact: Hao Hu, Hailin Cong
  • About author:
    * Corresponding author e-mail: (Hao Hu);
    (Hailin Cong)
  • Supported by:
    National Natural Science Foundation of China(51703105); National Natural Science Foundation of China(21675091); National Natural Science Foundation of China(21874078); Natural Science Foundation of Shandong Province(ZR2017BEM012); Taishan Young Scholar Program of Shandong Province(TSQN20161027); Major Science and Technology Innovation Project of Shandong Province(2018CXGC1407); Key Research and Development Project of Shandong Province(2016GGX102028); Key Research and Development Project of Shandong Province(2016GGX102039); Key Research and Development Project of Shandong Province(2017GGX20111); China Postdoctoral Science Foundation(2018M630752); Innovation Leader Project of Qingdao(168325zhc); Postdoctoral Scientific Research Foundation of Qingdao; First Class Discipline Project of Shandong Province

化学药物治疗(化疗)是目前临床上治疗肿瘤最有效的方法之一,但传统的给药方式导致药物对肿瘤的靶向性差、药物利用率低。在杀伤肿瘤细胞的同时,化疗药物对人体正常细胞也有很大的损伤,因此在化疗过程中通常伴随着严重的副作用,例如恶心、呕吐以及脱发等。随着肿瘤学和纳米材料的迅速发展,多种纳米药物载体被应用于肿瘤的治疗。纳米药物载体具有提高药物利用率、降低药物的毒副作用等诸多优势,已成为药物递送领域的研究热点。其中,肿瘤微环境响应纳米药物载体在实现肿瘤部位药物的可控释放、载体保护壳的脱除以及肿瘤靶向等方面表现出优异的性能。本文讨论了基于肿瘤微环境的异常生化指标构建肿瘤微环境响应载体的常用策略,并总结了近年来肿瘤微环境响应纳米药物载体用于肿瘤治疗的研究进展,旨在为设计与制备高性能纳米药物载体提供参考。

关键词： 肿瘤微环境, 药物递送系统, 刺激响应, 载体设计, 癌症治疗

Chemotherapy is one of the most effective methods for cancer therapy in clinical practice, but the administration of chemotherapeutic drugs results in poor targeting of drugs to tumors and low utilization rates of drugs. While killing tumor cells, chemotherapeutic drugs also cause great damage to normal human cells, so chemotherapy is usually accompanied by serious side effects, such as nausea, vomiting, and hair loss. With the rapid development of oncology and nanomaterials, many nano-drug vectors have been used in the treatment of tumors. Nanometer drug vectors can improve the utilization rate of drugs and reduce side effects, which has become a research hotspot in the field of drug delivery. The tumor microenvironment responsive drug delivery systems have shown excellent performance in the controlled drug release, removal of the protective shell, and tumor targeting. In this paper, we discuss the common strategies for constructing tumor microenvironment responsive drug delivery systems based on abnormal biochemical indicators of tumor microenvironment or in tumor cells. The recent advances of tumor microenvironment responsive drug delivery systems are summarized. Finally, we outline the challenges and perspectives about the improvement of tumor microenvironment responsive drug delivery systems, aiming to provide a reference for the design and preparation of high-performance drug delivery systems.

Contents

1 Introduction

2 Design of microenvironment response vectors for tumor

2.1 Abnormal physiological indicators of tumor microenvironment

2.2 Design strategies of tumor microenvironment response vectors

3 Advances of microenvironment response vectors for tumor

3.1 pH responsive vectors

3.2 Redox responsive vectors

3.3 ROS responsive vectors

3.4 Anoxic response vectors

3.5 Enzyme responsive vectors

3.6 Other responsive vectors

4 Conclusion

Key words: tumor microenvironment, drug delivery system, stimuli response, vector design, cancer therapy
()
图1 肿瘤组织微环境以及肿瘤细胞中的几种异常的生化指标示意图
Fig.1 Schematic diagram of several abnormal biochemical indexes in the tumor tissue and tumor cells
表1 常用的酸敏感断裂结构
Table 1 Commonly used pH-responsive structures
Name Structure
Hydrazone bone
Imine linkage
Dimethyl maleate bond
Acylhydrazone bond
Oxime bond
Orthoester bond
Acetal/ketone bond
表2 GSH响应断裂化学键举例
Table 2 Examples of GSH-responsive structures
Name Structure
Disulfide bond
Diselenide bond
表3 ROS响应裂解的结构举例
Table 3 Examples of ROS-responsive structures
structure Response mode
H2O2
[O]
H2O2
H2O2/H2O
H2O2
[O]
1O2/RNH2/H2O
[O]
H2O2
图2 常用肿瘤微环境响应递药系统的设计策略示意图
Fig.2 Design strategies of tumor microenvironment responsive drug delivery systems
图3 (a)PBEAGA-CPT在肿瘤组织中的主动渗透机理图;(b)具有GGT响应的PBEAGA-CPT、无GGT响应的PEAGA-CPT以及GGT催化γ-谷氨酰胺水解为伯胺的结构图;(c)37 ℃下,在10、0.5、0.05 U·mL-1 GGT的存在下,Zeta电位随PBEAGA-CPT、PEAGA-CPT在HEPES(pH=7.4, 2 mg·mL-1)中时间的变化图[103]
Fig.3 (a) Active osmotic mapping of PBEAGA-CPT in tumor tissue;(b) The structures of the GGT-responsive cationizing drug-conjugate PBEAGA-CPT and the non-GGT-responsive conjugate PEAGA-CPT, and their GGT-catalysed γ-glutamylamide hydrolysis to the primary amine;(c) The zeta potentials as a function of incubation time of PEAGACPT and PBEAGA-CPT in HEPES(pH=7.4, 2 mg·mL -1) at 37 ℃ in the presence of 10, 0.5 or 0.05 U·mL-1 GGT[103]. Adopted with permission from ref. 103 Copyright 2019 Springer Nature
图4 微酸环境响应暴露细胞穿膜肽(CPPs)的示意图[108]
Fig.4 Schematic diagram of exposed cell-penetrating peptides(CPPs) in response to the acidic environment[108]. Adopted with permission from ref. 108 Copyright 2017 Dovepress
图5 利用肿瘤微环境活性氧响应实现载体尺寸收缩示意图[112]
Fig.5 A schematic diagram of vector size shrinkage via ROS response in the tumor microenvironment[112]. Adopted with permission from ref.112 Copyright 2019 Elsevier
图6 M1型巨噬细胞来源外泌体载体通过响应肿瘤微酸环境实现抗体的特异性释放[114]
Fig.6 Schematic diagram of the specific release of antibodies by M1 macrophage-derived exocrine vector in response to acid environment in tumor site[114]. Adopted with permission from ref. 114 Copyright 2020 John Wiley & Sons
图7 GSH触发铜-氨基酸自组装的纳米颗粒产生ROS用于肿瘤治疗[117]
Fig.7 GSH triggered Cu-CysNPs to produce ROS for tumor therapy[117]. Adopted with permission from ref. 117 Copyright 2019 American Chemical Society
图8 ROS触发响应型载体实现siRNA的可控释放[122]
Fig.8 ROS-activated breakdown of the vector to release siRNA[122]. Adopted with permission from ref. 122 Copyright 2020 John Wiley & Sons
图9 pH/ROS双重响应递药系统的级联反应抗肿瘤作用示意图[123]
Fig.9 Schematic diagram of the pH/ROS dual responsive drug delivery system for cancer therapy[123]. Adopted with permission from ref. 123 Copyright 2019 John Wiley & Sons
图10 肿瘤乏氧响应型纳米药物载体的响应释放[124]
Fig.10 Controlled release of hypoxic-responsive drug delivery system[124]. Adopted with permission from ref. 124 Copyright 2015 Royal Society of Chemistry
图11 兼性厌氧菌株VNP2009用于肿瘤靶向治疗示意图[126]
Fig.11 Schematic diagram of facultative anaerobes VNP2009 for targeted tumor therapy[126]. Adopted with permission from ref. 126 Copyright 2018 American Chemical Society
图12 组织蛋白酶B响应触发BIM药物释放[130]
Fig.12 BIM drug release triggered by enzyme cathepsin B[130]. Adopted with permission from ref. 130 Copyright 2017 American Chemical Society
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