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Progress in Chemistry 2021, Vol. 33 Issue (6): 926-941 DOI: 10.7536/PC200728 Previous Articles   Next Articles

• Review •

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: Revised: Online: Published:
  • 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
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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
Fig.1 Schematic diagram of several abnormal biochemical indexes in the tumor tissue and tumor cells
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
Table 2 Examples of GSH-responsive structures
Name Structure
Disulfide bond
Diselenide bond
Table 3 Examples of ROS-responsive structures
structure Response mode
H2O2
[O]
H2O2
H2O2/H2O
H2O2
[O]
1O2/RNH2/H2O
[O]
H2O2
Fig.2 Design strategies of tumor microenvironment responsive drug delivery systems
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
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
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
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
Fig.7 GSH triggered Cu-CysNPs to produce ROS for tumor therapy[117]. Adopted with permission from ref. 117 Copyright 2019 American Chemical Society
Fig.8 ROS-activated breakdown of the vector to release siRNA[122]. Adopted with permission from ref. 122 Copyright 2020 John Wiley & Sons
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
Fig.10 Controlled release of hypoxic-responsive drug delivery system[124]. Adopted with permission from ref. 124 Copyright 2015 Royal Society of Chemistry
Fig.11 Schematic diagram of facultative anaerobes VNP2009 for targeted tumor therapy[126]. Adopted with permission from ref. 126 Copyright 2018 American Chemical Society
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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