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A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization

Tingting Yang,  Yuzhu Hu,  Junming Miao,  Jing Chen,  Jiagang Liu,  Yongzhong Cheng,  Xiang Gao

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Tingting Yang, Yuzhu Hu, Junming Miao, Jing Chen, Jiagang Liu, Yongzhong Cheng, Xiang Gao. A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization[J]. 机械工程学报. doi: 10.1016/j.apsb.2022.02.009
引用本文: Tingting Yang, Yuzhu Hu, Junming Miao, Jing Chen, Jiagang Liu, Yongzhong Cheng, Xiang Gao. A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization[J]. 机械工程学报. doi: 10.1016/j.apsb.2022.02.009
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Tingting Yang, Yuzhu Hu, Junming Miao, Jing Chen, Jiagang Liu, Yongzhong Cheng, Xiang Gao. A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.009
Citation: Tingting Yang, Yuzhu Hu, Junming Miao, Jing Chen, Jiagang Liu, Yongzhong Cheng, Xiang Gao. A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.009
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A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization

doi: 10.1016/j.apsb.2022.02.009

  • a. Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China;

  • b. Department of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China

基金项目: 

This work was supported by the National Natural Science Foundation of China (No. 82172630, 81972347 and 82003493), the Key R&

D Projects of the Science and Technology Department of Sichuan Province (No. 2020YFS0213, China) and the 1·

3·

5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC21022, No. ZYYC21001 and 2019HXFH017, China).

详细信息
    通讯作者:

    Xiang Gao,E-mail:xianggao@scu.edu.cn

  • 中图分类号: https://www.sciencedirect.com/science/article/pii/S2211383522000594/pdf?md5=1c724b19bb49ae70a1c6c19e6e96bacb&pid=1-s2.0-S2211383522000594-main.pdf

A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization

  • a. Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China;

  • b. Department of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China

Funds: 

This work was supported by the National Natural Science Foundation of China (No. 82172630, 81972347 and 82003493), the Key R&

D Projects of the Science and Technology Department of Sichuan Province (No. 2020YFS0213, China) and the 1·

3·

5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC21022, No. ZYYC21001 and 2019HXFH017, China).

    摘要
  • 摘要: Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood-brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d,l-lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d,l-lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.

     

    Abstract: Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood-brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d,l-lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d,l-lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.

     

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  • 收稿日期:  2021-12-04
  • 修回日期:  2022-01-18
  • 录用日期:  2022-01-29
  • 网络出版日期:  2023-03-17

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