A tumor microenvironment-responsive micelle co-delivered radiosensitizer Dbait and doxorubicin for the collaborative chemo-radiotherapy of glioblastoma

Shuyue Zhang; Xiuxiu Jiao; Michal Heger; Shen Gao; Mei He; Nan Xu; Jigang Zhang; Mingjian Zhang; Yuan Yu; Baoyue Ding; Xueying Ding

doi:10.1080/10717544.2022.2108937

A tumor microenvironment-responsive micelle co-delivered radiosensitizer Dbait and doxorubicin for the collaborative chemo-radiotherapy of glioblastoma

Shuyue Zhang, Xiuxiu Jiao, Michal Heger, Shen Gao, Mei He, Nan Xu, Jigang Zhang, Mingjian Zhang, Yuan Yu, Baoyue Ding, Xueying Ding^*

^*Corresponding author for this work

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

Abstract

Glioblastoma is rather recalcitrant to existing therapies and effective interventions are needed. Here we report a novel microenvironment-responsive micellar system (ch-K5(s-s)R8-An) for the co-delivery of the radiosensitizer Dbait and the chemotherapeutic doxorubicin (DOX) to glioblastoma. Accordingly, the ch-K5(s-s)R8-An/(Dbait-DOX) micelles plus radiotherapy (RT) treatment resulted in a high degree of apoptosis and DNA damage, which significantly reduced cell viability and proliferation capacity of U251 cells to 64.0% and 16.3%, respectively. The angiopep-2-modified micelles exhibited substantial accumulation in brain-localized U251 glioblastoma xenografts in mice compared to angiopep-2-lacking micelles. The ch-K5(s-s)R8-An/(Dbait-DOX) + RT treatment group exhibited the smallest tumor size and most profound tumor tissue injury in orthotopic U251 tumors, leading to an increase in median survival time of U251 tumor-bearing mice from 26 days to 56 days. The ch-K5(s-s)R8-An/(Dbait-DOX) micelles can be targeted to brain-localized U251 tumor xenografts and sensitize the tumor to chemotherapy and radiotherapy, thereby overcoming the inherent therapeutic challenges associated with malignant glioblastoma.

Original language	English
Pages (from-to)	2658-2670
Number of pages	13
Journal	Drug Delivery
Volume	29
Issue number	1
DOIs	https://doi.org/10.1080/10717544.2022.2108937
Publication status	Published - 16 Aug 2022

Bibliographical note

Funding Information:
This work was supported by the National Natural Science Foundation of China (No. 81472349, No. 81872220, China); Shanghai Pujiang Program (No. 18PJD063, China); Key Science and Technology Program of Songjiang District (No. 18sjkjgg33, China); Tumor nanotargeting and TCM technology innovation team (Key Science and Technology Innovation Team of Jiaxing 2018, China). Michal Heger was supported by grants from the Dutch Cancer Foundation (KWF project # 10666), a Zhejiang Provincial Foreign Expert Program Grant, Zhejiang Provincial Key Natural Science Foundation of China (#Z20H160031), and a grant for the establishment of the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics. The authors thank Tony G. Kleijn at the Department of Pathology and Medical Biology, University of Groningen for his assistance in the histological analysis.

Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81472349, No. 81872220, China); Shanghai Pujiang Program (No. 18PJD063, China); Key Science and Technology Program of Songjiang District (No. 18sjkjgg33, China); Tumor nanotargeting and TCM technology innovation team (Key Science and Technology Innovation Team of Jiaxing 2018, China). Michal Heger was supported by grants from the Dutch Cancer Foundation (KWF project # 10666), a Zhejiang Provincial Foreign Expert Program Grant, Zhejiang Provincial Key Natural Science Foundation of China (#Z20H160031), and a grant for the establishment of the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics. The authors thank Tony G. Kleijn at the Department of Pathology and Medical Biology, University of Groningen for his assistance in the histological analysis.

Keywords

chemo-radiotherapy
Glioblastoma
mic-roenvironment-responsive
radiosensitization
targeted nanotherapeutics

Access to Document

10.1080/10717544.2022.2108937Licence: CC BY

A tumor microenvironment responsive micelle co delivered radiosensitizer Dbait and doxorubicin for the collaborative chemo radiotherapy ofFinal published version, 4.17 MBLicence: CC BY

Cite this

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title = "A tumor microenvironment-responsive micelle co-delivered radiosensitizer Dbait and doxorubicin for the collaborative chemo-radiotherapy of glioblastoma",

abstract = "Glioblastoma is rather recalcitrant to existing therapies and effective interventions are needed. Here we report a novel microenvironment-responsive micellar system (ch-K5(s-s)R8-An) for the co-delivery of the radiosensitizer Dbait and the chemotherapeutic doxorubicin (DOX) to glioblastoma. Accordingly, the ch-K5(s-s)R8-An/(Dbait-DOX) micelles plus radiotherapy (RT) treatment resulted in a high degree of apoptosis and DNA damage, which significantly reduced cell viability and proliferation capacity of U251 cells to 64.0% and 16.3%, respectively. The angiopep-2-modified micelles exhibited substantial accumulation in brain-localized U251 glioblastoma xenografts in mice compared to angiopep-2-lacking micelles. The ch-K5(s-s)R8-An/(Dbait-DOX) + RT treatment group exhibited the smallest tumor size and most profound tumor tissue injury in orthotopic U251 tumors, leading to an increase in median survival time of U251 tumor-bearing mice from 26 days to 56 days. The ch-K5(s-s)R8-An/(Dbait-DOX) micelles can be targeted to brain-localized U251 tumor xenografts and sensitize the tumor to chemotherapy and radiotherapy, thereby overcoming the inherent therapeutic challenges associated with malignant glioblastoma.",

keywords = "chemo-radiotherapy, Glioblastoma, mic-roenvironment-responsive, radiosensitization, targeted nanotherapeutics",

author = "Shuyue Zhang and Xiuxiu Jiao and Michal Heger and Shen Gao and Mei He and Nan Xu and Jigang Zhang and Mingjian Zhang and Yuan Yu and Baoyue Ding and Xueying Ding",

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AU - Gao, Shen

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