Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer
Liang, Chenghua; Bai, Xiangyang; Qi, Cuiling; Sun, Qingxue; Han, Xiaoyan; Lan, Tianyun; Zhang, Haibo; Zheng, Xiaoming; Liang, Rongpu; Jiao, Ju; Zheng, Zongheng; Fang, Jiafeng; Lei, Purun; Wang, Yan; Möckel, Diana; Metselaar, Josbert M.; Storm, Gert; Hennink, Wim E.; Kiessling, Fabian; Wei, Hongbo; Lammers, Twan; Shi, Yang; Wei, Bo
(2021) Biomaterials, volume 266
(Article)
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
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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.
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Keywords: Gastrointestinal cancer, Nanomedicine, Polymeric micelles, Taxane therapy, Tumor microenvironment, Tumor targeting, Taverne, Bioengineering, Ceramics and Composites, Biophysics, Biomaterials, Mechanics of Materials
ISSN: 0142-9612
Publisher: Elsevier Ltd
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.
(Peer reviewed)