Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer

Chenghua Liang; Xiangyang Bai; Cuiling Qi; Qingxue Sun; Xiaoyan Han; Tianyun Lan; Haibo Zhang; Xiaoming Zheng; Rongpu Liang; Ju Jiao; Zongheng Zheng; Jiafeng Fang; Purun Lei; Yan Wang; Diana Möckel; Josbert M. Metselaar; Gert Storm; Wim E. Hennink; Fabian Kiessling; Hongbo Wei; Twan Lammers; Yang Shi; Bo Wei

doi:10.1016/j.biomaterials.2020.120432

Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer

Chenghua Liang
, Xiangyang Bai
, Cuiling Qi
, Qingxue Sun
, Xiaoyan Han
, Tianyun Lan
, Haibo Zhang
, Xiaoming Zheng
, Rongpu Liang
, Ju Jiao
, Zongheng Zheng
, Jiafeng Fang
, Purun Lei
, Yan Wang
, Diana Möckel
, Josbert M. Metselaar
, Gert Storm
, Wim E. Hennink
, Fabian Kiessling
, Hongbo Wei^*

Twan Lammers, Yang Shi, Bo Wei

^*Corresponding author for this work

Sun Yat-Sen University
RWTH Aachen University
Guangdong Pharmaceutical University
Fraunhofer Institute for Digital Medicine

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Gastrointestinal (GI) cancers are among the most lethal malignancies. The treatment of advanced-stage GI cancer involves standard chemotherapeutic drugs, such as docetaxel, as well as targeted therapeutics and immunomodulatory agents, all of which are only moderately effective. We here show that Π electron-stabilized polymeric micelles based on PEG-b-p(HPMAm-Bz) can be loaded highly efficiently with docetaxel (loading capacity up to 23 wt%) and potentiate chemotherapy responses in multiple advanced-stage GI cancer mouse models. Complete cures and full tumor regression were achieved upon intravenously administering micellar docetaxel in subcutaneous gastric cancer cell line-derived xenografts (CDX), as well as in CDX models with intraperitoneal and lung metastases. Nanoformulated docetaxel also outperformed conventional docetaxel in a patient-derived xenograft (PDX) model, doubling the extent of tumor growth inhibition. Furthermore, micellar docetaxel modulated the tumor immune microenvironment in CDX and PDX tumors, increasing the ratio between M1-and M2-like macrophages, and toxicologically, it was found to be very well-tolerated. These findings demonstrate that Π electron-stabilized polymeric micelles loaded with docetaxel hold significant potential for the treatment of advanced-stage GI cancers.

Original language	English
Article number	120432
Number of pages	10
Journal	Biomaterials
Volume	266
DOIs	https://doi.org/10.1016/j.biomaterials.2020.120432
Publication status	Published - Jan 2021

Bibliographical note

Funding Information:
This work was supported by grants from Science and Technology Planning Project of Guangdong Province ( 2017B020227009 and 2017A010103009 ), by Fundamental Research Funds for the Central Universities ( 16ykjc23 ), by the National Natural Science Foundation of China ( 81472825 and 81773095 ), by the Outstanding Young Talents Support Program of the Third Affiliated Hospital of Sun Yat-sen University , by the China Scholarship Council ( CSC ), by the European Research Council (ERC: Consolidator Grant Meta-Targeting ( 864121 ) and Proof-of-Concept Grant PIcelles ( 813086 )), by German Research Foundation ( DFG : GRK/RTG 2375: Tumor-targeted Drug Delivery (project number 331065168 )), and by the Aachen Interdisciplinary Center for Clinical Research (IZKF; Project O3-2).

Publisher Copyright:
© 2020 Elsevier Ltd

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Funding

This work was supported by grants from Science and Technology Planning Project of Guangdong Province ( 2017B020227009 and 2017A010103009 ), by Fundamental Research Funds for the Central Universities ( 16ykjc23 ), by the National Natural Science Foundation of China ( 81472825 and 81773095 ), by the Outstanding Young Talents Support Program of the Third Affiliated Hospital of Sun Yat-sen University , by the China Scholarship Council ( CSC ), by the European Research Council (ERC: Consolidator Grant Meta-Targeting ( 864121 ) and Proof-of-Concept Grant PIcelles ( 813086 )), by German Research Foundation ( DFG : GRK/RTG 2375: Tumor-targeted Drug Delivery (project number 331065168 )), and by the Aachen Interdisciplinary Center for Clinical Research (IZKF; Project O3-2).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Gastrointestinal cancer
Nanomedicine
Polymeric micelles
Taxane therapy
Tumor microenvironment
Tumor targeting

Access to Document

10.1016/j.biomaterials.2020.120432

1-s2.0-S0142961220306785-mainFinal published version, 8.73 MBLicence: Taverne

Cite this

Liang, C., Bai, X., Qi, C., Sun, Q., Han, X., Lan, T., Zhang, H., Zheng, X., Liang, R., Jiao, J., Zheng, Z., Fang, J., Lei, P., Wang, Y., Möckel, D., Metselaar, J. M., Storm, G., Hennink, W. E., Kiessling, F., ... Wei, B. (2021). Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer. Biomaterials, 266, Article 120432. https://doi.org/10.1016/j.biomaterials.2020.120432

@article{ee3b7b10a7df40ab9523edab0b21ef48,

title = "Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer",

abstract = "Gastrointestinal (GI) cancers are among the most lethal malignancies. The treatment of advanced-stage GI cancer involves standard chemotherapeutic drugs, such as docetaxel, as well as targeted therapeutics and immunomodulatory agents, all of which are only moderately effective. We here show that Π electron-stabilized polymeric micelles based on PEG-b-p(HPMAm-Bz) can be loaded highly efficiently with docetaxel (loading capacity up to 23 wt\%) and potentiate chemotherapy responses in multiple advanced-stage GI cancer mouse models. Complete cures and full tumor regression were achieved upon intravenously administering micellar docetaxel in subcutaneous gastric cancer cell line-derived xenografts (CDX), as well as in CDX models with intraperitoneal and lung metastases. Nanoformulated docetaxel also outperformed conventional docetaxel in a patient-derived xenograft (PDX) model, doubling the extent of tumor growth inhibition. Furthermore, micellar docetaxel modulated the tumor immune microenvironment in CDX and PDX tumors, increasing the ratio between M1-and M2-like macrophages, and toxicologically, it was found to be very well-tolerated. These findings demonstrate that Π electron-stabilized polymeric micelles loaded with docetaxel hold significant potential for the treatment of advanced-stage GI cancers.",

keywords = "Gastrointestinal cancer, Nanomedicine, Polymeric micelles, Taxane therapy, Tumor microenvironment, Tumor targeting",

author = "Chenghua Liang and Xiangyang Bai and Cuiling Qi and Qingxue Sun and Xiaoyan Han and Tianyun Lan and Haibo Zhang and Xiaoming Zheng and Rongpu Liang and Ju Jiao and Zongheng Zheng and Jiafeng Fang and Purun Lei and Yan Wang and Diana M{\"o}ckel and Metselaar, \{Josbert M.\} and Gert Storm and Hennink, \{Wim E.\} and Fabian Kiessling and Hongbo Wei and Twan Lammers and Yang Shi and Bo Wei",

note = "Funding Information: This work was supported by grants from Science and Technology Planning Project of Guangdong Province ( 2017B020227009 and 2017A010103009 ), by Fundamental Research Funds for the Central Universities ( 16ykjc23 ), by the National Natural Science Foundation of China ( 81472825 and 81773095 ), by the Outstanding Young Talents Support Program of the Third Affiliated Hospital of Sun Yat-sen University , by the China Scholarship Council ( CSC ), by the European Research Council (ERC: Consolidator Grant Meta-Targeting ( 864121 ) and Proof-of-Concept Grant PIcelles ( 813086 )), by German Research Foundation ( DFG : GRK/RTG 2375: Tumor-targeted Drug Delivery (project number 331065168 )), and by the Aachen Interdisciplinary Center for Clinical Research (IZKF; Project O3-2). Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2021",

month = jan,

doi = "10.1016/j.biomaterials.2020.120432",

language = "English",

volume = "266",

journal = "Biomaterials",

issn = "0142-9612",

publisher = "Elsevier Ltd",

}

Liang, C, Bai, X, Qi, C, Sun, Q, Han, X, Lan, T, Zhang, H, Zheng, X, Liang, R, Jiao, J, Zheng, Z, Fang, J, Lei, P, Wang, Y, Möckel, D, Metselaar, JM, Storm, G , Hennink, WE, Kiessling, F, Wei, H, Lammers, T, Shi, Y & Wei, B 2021, 'Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer', Biomaterials, vol. 266, 120432. https://doi.org/10.1016/j.biomaterials.2020.120432

TY - JOUR

T1 - Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer

AU - Liang, Chenghua

AU - Bai, Xiangyang

AU - Qi, Cuiling

AU - Sun, Qingxue

AU - Han, Xiaoyan

AU - Lan, Tianyun

AU - Zhang, Haibo

AU - Zheng, Xiaoming

AU - Liang, Rongpu

AU - Jiao, Ju

AU - Zheng, Zongheng

AU - Fang, Jiafeng

AU - Lei, Purun

AU - Wang, Yan

AU - Möckel, Diana

AU - Metselaar, Josbert M.

AU - Storm, Gert

AU - Hennink, Wim E.

AU - Kiessling, Fabian

AU - Wei, Hongbo

AU - Lammers, Twan

AU - Shi, Yang

AU - Wei, Bo

N1 - Funding Information: This work was supported by grants from Science and Technology Planning Project of Guangdong Province ( 2017B020227009 and 2017A010103009 ), by Fundamental Research Funds for the Central Universities ( 16ykjc23 ), by the National Natural Science Foundation of China ( 81472825 and 81773095 ), by the Outstanding Young Talents Support Program of the Third Affiliated Hospital of Sun Yat-sen University , by the China Scholarship Council ( CSC ), by the European Research Council (ERC: Consolidator Grant Meta-Targeting ( 864121 ) and Proof-of-Concept Grant PIcelles ( 813086 )), by German Research Foundation ( DFG : GRK/RTG 2375: Tumor-targeted Drug Delivery (project number 331065168 )), and by the Aachen Interdisciplinary Center for Clinical Research (IZKF; Project O3-2). Publisher Copyright: © 2020 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2021/1

Y1 - 2021/1

N2 - Gastrointestinal (GI) cancers are among the most lethal malignancies. The treatment of advanced-stage GI cancer involves standard chemotherapeutic drugs, such as docetaxel, as well as targeted therapeutics and immunomodulatory agents, all of which are only moderately effective. We here show that Π electron-stabilized polymeric micelles based on PEG-b-p(HPMAm-Bz) can be loaded highly efficiently with docetaxel (loading capacity up to 23 wt%) and potentiate chemotherapy responses in multiple advanced-stage GI cancer mouse models. Complete cures and full tumor regression were achieved upon intravenously administering micellar docetaxel in subcutaneous gastric cancer cell line-derived xenografts (CDX), as well as in CDX models with intraperitoneal and lung metastases. Nanoformulated docetaxel also outperformed conventional docetaxel in a patient-derived xenograft (PDX) model, doubling the extent of tumor growth inhibition. Furthermore, micellar docetaxel modulated the tumor immune microenvironment in CDX and PDX tumors, increasing the ratio between M1-and M2-like macrophages, and toxicologically, it was found to be very well-tolerated. These findings demonstrate that Π electron-stabilized polymeric micelles loaded with docetaxel hold significant potential for the treatment of advanced-stage GI cancers.

AB - Gastrointestinal (GI) cancers are among the most lethal malignancies. The treatment of advanced-stage GI cancer involves standard chemotherapeutic drugs, such as docetaxel, as well as targeted therapeutics and immunomodulatory agents, all of which are only moderately effective. We here show that Π electron-stabilized polymeric micelles based on PEG-b-p(HPMAm-Bz) can be loaded highly efficiently with docetaxel (loading capacity up to 23 wt%) and potentiate chemotherapy responses in multiple advanced-stage GI cancer mouse models. Complete cures and full tumor regression were achieved upon intravenously administering micellar docetaxel in subcutaneous gastric cancer cell line-derived xenografts (CDX), as well as in CDX models with intraperitoneal and lung metastases. Nanoformulated docetaxel also outperformed conventional docetaxel in a patient-derived xenograft (PDX) model, doubling the extent of tumor growth inhibition. Furthermore, micellar docetaxel modulated the tumor immune microenvironment in CDX and PDX tumors, increasing the ratio between M1-and M2-like macrophages, and toxicologically, it was found to be very well-tolerated. These findings demonstrate that Π electron-stabilized polymeric micelles loaded with docetaxel hold significant potential for the treatment of advanced-stage GI cancers.

KW - Gastrointestinal cancer

KW - Nanomedicine

KW - Polymeric micelles

KW - Taxane therapy

KW - Tumor microenvironment

KW - Tumor targeting

UR - https://www.scopus.com/pages/publications/85092508585

U2 - 10.1016/j.biomaterials.2020.120432

DO - 10.1016/j.biomaterials.2020.120432

M3 - Article

C2 - 33069116

AN - SCOPUS:85092508585

SN - 0142-9612

VL - 266

JO - Biomaterials

JF - Biomaterials

M1 - 120432

ER -

Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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