Targeted delivery of ibrutinib to tumor-associated macrophages by sialic acid-stearic acid conjugate modified nanocomplexes for cancer immunotherapy

Qiu, Qiujun; Liu, Cong; Song, Yanzhi; Shi, Tao; Luo, Xiang; Zhang, Hongxia; Hu, Ling; Yan, Xinyang; Zheng, Huangliang; Li, Mengyang; Liu, Mingqi; Liu, Min; Yang, Shuaishuai; Liu, Xinrong; Chen, Guoliang; Deng, Yihui

doi:10.1016/j.actbio.2019.05.030

Cited by 75 publications

(52 citation statements)

References 61 publications

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“…Ibrutinib has shown antitumour effects on chronic lymphocytic leukaemia [20][21][22][23]. Ibrutinib also inhibited growth in solid cancers, but the results were limited [24][25][26][27]. Based on these findings, a series of derivatives were developed.…”

Section: Discussionmentioning

confidence: 99%

The Ibr-7 derivative of ibrutinib radiosensitizes pancreatic cancer cells by downregulating p-EGFR

et al. 2020

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Background Radiotherapy is one of the main treatments for pancreatic cancer, but radiation resistance limits its clinical application. As a result, novel therapeutic agents to improve radiosensitivity are urgently needed. This study aimed to investigate the effect of Ibr-7 (a derivative of ibrutinib) on the radiosensitivity of human pancreatic cancer cells. Methods The effect of Ibr-7 on pancreatic cancer cell proliferation was detected by CCK-8 assays. Radiosensitivity was assessed by clonogenic formation assays. Cell cycle and cell apoptosis were analysed by flow cytometry. DNA damage was evaluated by immunofluorescence analysis. The expression levels of PARP, Cleaved caspase 3, p-EGFR and EGFR were determined by western blot. Results Ibr-7 showed an anti-proliferative effect on PANC-1 and Capan2 cells in a dose- and time-dependent manner. Ibr-7 (2 μmol/L) enhanced the effect of radiation on PANC-1 and Capan2 cells. Further findings showed that this combination enhanced G2/M phase arrest and increased cell apoptosis. Additional molecular mechanism studies revealed that the expression of p-EGFR was decreased by Ibr-7 alone or in combination with radiation. Overexpression of p-EGFR reversed the cell apoptosis induced by Ibr-7 combined with radiation. Moreover, the expression of γ-H2AX was significantly decreased in the Ibr-7 plus radiation group. Conclusions Our study indicated the potential application of Ibr-7 as a highly effective radiosensitizer for the treatment of pancreatic cancer cells.

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Section: Discussionmentioning

confidence: 99%

The Ibr-7 derivative of ibrutinib radiosensitizes pancreatic cancer cells by downregulating p-EGFR

et al. 2020

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“…Ibrutinib has shown anti-tumor effects towards chronic lyphocytic leukemia [20][21][22][23]. It also shown growth inhibitory effect in solid cancers, but the results is limited [24][25][26][27]. Based on these, a series of derivatives are obtained.…”

Section: Discussionmentioning

confidence: 99%

The Ibr-7 Derivative of Ibrutinib Exhibits Radiosensitivity in Pancreatic Cancer Cells via Targeting EGFR

Tan¹,

Zhang²,

Yan

et al. 2020

Preprint

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Background: Radiotherapy is one of the main therapeutic methods for pancreatic cancer, but radiation resistance limits the clinical application. As a result, novel therapeutic agents to improve the radiosensitivity is urgent. This study aimed to investigate the effect of Ibr-7 (the derivative of ibrutinib) on radiosensitivity of human pancreatic cancer cells.Methods: The effect of Ibr-7 on pancreatic cancer cell’s proliferation were detected by CCK-8 assay. Radiosensitivity was assessed by clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage was detected by immunofluorescence analysis. The expression of p-EGFR, EGFR were determined by western blot.Results: Ibr-7 showed anti-proliferative effect in PANC-1 and Capan2 cells in a dose- and time-dependent manner. Ibr-7 (2 µmol/L) enhanced the effect of radiation in PANC-1 and Capan2 cells. Further findings showed that this combination enhanced G2/M phase arrest and increased cell apoptosis. Additional molecular mechanism studies revealed that the expression of p-EGFR was decreased by Ibr-7 alone or combined with radiation. Overexpression of EGFR reversed the cell apoptosis induced by Ibr-7 combined with radiation. Moreover, the expression of γ-H2AX was significantly decreased in Ibr-7 combined with radiation group.Conclusions: Our study indicated that the potential application of Ibr-7 as a highly effective radiosensitizer for the treatment of pancreatic cancer cells.

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“…Thus, BTK appears to serve as a key regulator of TAM crosstalk and anti-tumor immune responses [93]. Unfortunately, in some cases in vivo ibrutinib is rapidly cleared, and thus, the low accumulation of ibrutinib results in the tumor, rendering these targeted therapies ineffective [95]. Qiu et al have designed, synthesized, and investigated a sialic acid-stearic acid (SA) conjugate that encapsulates the BTK inhibitor ibrutinib within amphiphilic egg phosphatidylglycerol (EPG) as a novel immunotherapeutic approach to allow for prolonged exposure of TAM to ibrutinib [95].…”

Section: The Role Of Btk In Tumor-associated Macrophages (Tam)mentioning

confidence: 99%

“…Immunofluorescence staining demonstrated that the SA/IBR/EPG nanocomplex accumulated in TAM both in vitro and in vivo. This agent inhibited angiogenesis, Th2 tumorigenic cytokine secretion, and tumor progression and represents a promising targeted approach for targeting BTK in TAM [95].…”

Section: The Role Of Btk In Tumor-associated Macrophages (Tam)mentioning

confidence: 99%

Bruton’s tyrosine kinase: an emerging targeted therapy in myeloid cells within the tumor microenvironment

Good

Benner

Carson

2021

Cancer Immunol Immunother

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Bruton’s tyrosine kinase (BTK) is a non-receptor kinase belonging to the Tec family of kinases. The role of BTK in B cell receptor signaling is well defined and is known to play a key role in the proliferation and survival of malignant B cells. Moreover, BTK has been found to be expressed in cells of the myeloid lineage. BTK has been shown to contribute to a variety of cellular pathways in myeloid cells including signaling in the NLRP3 inflammasome, receptor activation of nuclear factor-κβ and inflammation, chemokine receptor activation affecting migration, and phagocytosis. Myeloid cells are crucial components of the tumor microenvironment and suppressive myeloid cells contribute to cancer progression, highlighting a potential role for BTK inhibition in the treatment of malignancy. The increased interest in BTK inhibition in cancer has resulted in many preclinical studies that are testing the efficacy of using single-agent BTK inhibitors. Moreover, the ability of tumor cells to develop resistance to single-agent checkpoint inhibitors has resulted in clinical studies utilizing BTK inhibitors in combination with these agents to improve clinical responses. Furthermore, BTK regulates the immune response in microbial and viral infections through B cells and myeloid cells such as monocytes and macrophages. In this review, we describe the role that BTK plays in supporting suppressive myeloid cells, including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), while also discussing the anticancer effects of BTK inhibition and briefly describe the role of BTK signaling and BTK inhibition in microbial and viral infections.

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Targeted delivery of ibrutinib to tumor-associated macrophages by sialic acid-stearic acid conjugate modified nanocomplexes for cancer immunotherapy

Cited by 75 publications

References 61 publications

The Ibr-7 derivative of ibrutinib radiosensitizes pancreatic cancer cells by downregulating p-EGFR

The Ibr-7 derivative of ibrutinib radiosensitizes pancreatic cancer cells by downregulating p-EGFR

The Ibr-7 Derivative of Ibrutinib Exhibits Radiosensitivity in Pancreatic Cancer Cells via Targeting EGFR

Bruton’s tyrosine kinase: an emerging targeted therapy in myeloid cells within the tumor microenvironment

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