Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

doi:10.1016/j.cjche.2021.06.023

中国化学工程学报 ›› 2021, Vol. 39 ›› Issue (11): 219-227.DOI: 10.1016/j.cjche.2021.06.023

• Biotechnology and Bioengineering • 上一篇下一篇

Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

Dong Wan¹, Sunfan Li¹, Jianxin Zhang¹, Guilei Ma², Jie Pan¹

1 School of Chemistry and Chemical Engineering, Tiangong University, Tianjin 300387, China;
2 The Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China

收稿日期:2021-01-20 修回日期:2021-06-13 出版日期:2021-11-28 发布日期:2021-12-27
通讯作者: Guilei Ma, Jie Pan
基金资助:
The authors are grateful for financial support from the National Natural Science Foundation of China (22078246, 81673027), Tianjin Natural Science Fund for Distinguished Young Scholars (17JCJQJC46400), CAMS Innovation Fund for Medical Sciences (CAMS-I2M-3-026).

Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

Dong Wan¹, Sunfan Li¹, Jianxin Zhang¹, Guilei Ma², Jie Pan¹

1 School of Chemistry and Chemical Engineering, Tiangong University, Tianjin 300387, China;
2 The Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China

Received:2021-01-20 Revised:2021-06-13 Online:2021-11-28 Published:2021-12-27
Contact: Guilei Ma, Jie Pan
Supported by:
The authors are grateful for financial support from the National Natural Science Foundation of China (22078246, 81673027), Tianjin Natural Science Fund for Distinguished Young Scholars (17JCJQJC46400), CAMS Innovation Fund for Medical Sciences (CAMS-I2M-3-026).

摘要/Abstract

摘要： Compared with physical drug-loaded nanocarriers, polymeric prodrug micelles have many advantages such as high drug loading and enhanced stability in blood, so they have great potential in cancer therapy. However, these micelles have a big disadvantage, which cannot achieve long-term circulation in vivo and high absorption of tumor cells simultaneously, resulting in low administration efficiency and poor therapeutic effect on cancer. To solve problems of traditional polymeric prodrug micelles, novel polymeric micelles with tumor microenvironment response were designed in this work. The prodrug formed by covalently linking D-α-tocopherol polyethylene glycol succinate (TPGS₃₃₅₀), peptide (Pep), and doxorubicin (DOX) (TPGS₃₃₅₀-Pep-DOX) was self-assembled into micelles by encapsulating DOX physically. When the micelles entered the tumor tissue, the long-chain polyethylene glycol (PEG) was sensitively cut by the matrix metalloproteinase 2/9 (MMP2/9) enzyme, exposing the targeting molecule folate, then it entered the cell through the endocytic pathway mediated by the folate receptor. The drug loading content, encapsulation efficiency, critical micelle concentration, and invitro release of the micelles invented in this study were measured to characterize their properties. The particle size and zeta potential of micelles were characterized by dynamic light scattering. Images were scanned by transmission electron microscopes. In vitro cytotoxicity, cellular uptake, and in vivo antitumor effect evaluation experiments were measured to show that smart micelles have made much progress in material chemistry and drug delivery, making it possible to apply a stimulus-response carrier drug delivery system in clinical application.

关键词: Micelles, Drug delivery, Tumor, Enzyme, Polymers, Peptide

Abstract: Compared with physical drug-loaded nanocarriers, polymeric prodrug micelles have many advantages such as high drug loading and enhanced stability in blood, so they have great potential in cancer therapy. However, these micelles have a big disadvantage, which cannot achieve long-term circulation in vivo and high absorption of tumor cells simultaneously, resulting in low administration efficiency and poor therapeutic effect on cancer. To solve problems of traditional polymeric prodrug micelles, novel polymeric micelles with tumor microenvironment response were designed in this work. The prodrug formed by covalently linking D-α-tocopherol polyethylene glycol succinate (TPGS₃₃₅₀), peptide (Pep), and doxorubicin (DOX) (TPGS₃₃₅₀-Pep-DOX) was self-assembled into micelles by encapsulating DOX physically. When the micelles entered the tumor tissue, the long-chain polyethylene glycol (PEG) was sensitively cut by the matrix metalloproteinase 2/9 (MMP2/9) enzyme, exposing the targeting molecule folate, then it entered the cell through the endocytic pathway mediated by the folate receptor. The drug loading content, encapsulation efficiency, critical micelle concentration, and invitro release of the micelles invented in this study were measured to characterize their properties. The particle size and zeta potential of micelles were characterized by dynamic light scattering. Images were scanned by transmission electron microscopes. In vitro cytotoxicity, cellular uptake, and in vivo antitumor effect evaluation experiments were measured to show that smart micelles have made much progress in material chemistry and drug delivery, making it possible to apply a stimulus-response carrier drug delivery system in clinical application.

Key words: Micelles, Drug delivery, Tumor, Enzyme, Polymers, Peptide

Dong Wan, Sunfan Li, Jianxin Zhang, Guilei Ma, Jie Pan. Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy[J]. 中国化学工程学报, 2021, 39(11): 219-227.

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Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

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