News Express: UM develops advanced nano-radiosensitizer to improve radiotherapeutic outcome of breast cancer

新聞快訊:澳大成功研發提升乳癌療效藥物

放療增敏納米藥物(PWAI NPs)的合成示意圖及治療策略
A schematic illustration of PWAI-relevant preparation and therapeutic mechanism

 

 

澳大成功研發提升乳癌療效藥物

澳門大學健康科學學院副教授代雲路的研究團隊成功研發出一種新型放療增敏納米藥物,能夠顯著提升放療對乳腺癌的治療效果。這種納米藥物不僅增強了放療的功效,還能逆轉放療所引發的MYC上調和免疫抑制,從而激發出強力的抗腫瘤免疫反應,有效抑制乳腺癌生長、復發及轉移。該研究成果已獲全球著名學術期刊《先進材料》刊登。

放療在臨床上對於腫瘤抑制雖然有效,但患者常常會遭受嚴重的免疫耐受和免疫抑制,主要是因為癌細胞在接受放射線治療後,會增加MYC蛋白的表達。這種蛋白質可以修復輻照引發的脱氧核醣核酸(DNA)損傷,從而促進癌細胞的增殖並抑制 IFN-I 型干擾素信號通路。受損的IFN-I 信號進一步阻礙抗原呈遞,干擾細胞毒性 T 淋巴細胞的激活,並觸發腫瘤相關調節性 T 細胞的擴增。MYC蛋白過度表達所帶來的這些連鎖效應極大地抑制了放療效果。因此,降低腫瘤細胞中MYC水平可克服關鍵的免疫抑制障礙,並引發強大的免疫放療效果。

研究團隊設計了一種新型納米放射增敏劑(PWAI),目的是引發放療中的雙表觀遺傳學重編程。在PWAI合成過程中,兩親性PEG-多酚聚合物能與放療增敏劑(鎢離子,W6+)通過金屬-多酚配位的方法自組裝成核殼結構,並將5-Aza(DNA甲基轉移酶抑制劑)和ITF-2357(組蛋白去乙酰化酶抑制劑)負載到疏水核中。

在外來輻射的刺激下,X射線增敏劑 W6+ 通過產生豐富的活性氧有效地破壞了腫瘤細胞的DNA鏈;同時,釋放的表觀遺傳抑制劑用於抑制MYC蛋白。在雙重表觀遺傳學治療過程中,5-Aza雖然下調了MYC蛋白,但並未明顯觸發IFN-α/IFN-β等免疫因子的產生。當其與 ITF-2357 聯合使用時,可顯著促進對 MYC 的抑制作用;更重要的是,IFN-α和IFN-β 等IFN-I 信號相關蛋白水平和主要組織相容性復合物 I水平也得以明顯提高。研究小組進一步利用PWAI納米放射增敏劑治療乳腺癌荷瘤小鼠,觀察到小鼠接受放療後產生有效的抗腫瘤免疫響應,包括樹突狀細胞的成熟、細胞毒性T細胞的募集及其記憶表型的形成,以及腫瘤相關巨噬細胞從免疫抑制狀態到免疫支持狀態的免疫極化。因此,該種聯合放療和雙表觀遺傳學治療的治療策略為免疫放療提供一種更可行的選擇。

是次研究的通訊作者為代雲路和澳大健康科學學院研究助理教授李蓓,博士畢業生王國浩、顏潔和田浩為共同第一作者,博士後李文曦,博士生余馨穎、豐與朝和周松濤亦對該研究作出重要貢獻。此項研究由澳門特別行政區科學技術發展基金(檔案編號:0103/2021/A, 0002/2021/AKP, 0133/2022/A3, 0009/2022/AKP 和 0006/2023/ITP1)和澳門大學(檔案編號:MYRG2022-00011-FHS 和 MYRG-GRG2023-00013-FHS-UMDF)資助。研究文章的完整版本可瀏覽:https://onlinelibrary.wiley.com/doi/full/10.1002/adma.202312588

欲瀏覽官網版可登入以下連結:
https://www.um.edu.mo/zh-hant/news-and-press-releases/campus-news/detail/58271/

 

UM develops advanced nano-radiosensitizer to improve radiotherapeutic outcome of breast cancer

A research team led by Dai Yunlu, associate professor in the Faculty of Health Sciences at the University of Macau (UM), has developed a novel nano-radiosensitizer capable of significantly improving the radiotherapeutic outcome of breast cancer. This nanomedicine not only improves the efficacy of radiotherapy but also relieves the MYC-correlated immunosuppression induced by radiation, thereby triggering a systemic anti-tumour immune response and effectively inhibiting the growth, recurrence, and metastasis of breast cancer. The research has been published in the internationally renowned journal Advanced Materials.

Although radiotherapy is clinically effective in inhibiting tumour growth, patients often suffer from severe immune tolerance and immunosuppression. One main reason is that cancer cells increase the expression of MYC protein after receiving the radiation. This protein possesses the capacity to repair DNA damage caused by radiotherapy, which promotes the proliferation of cancer cells and inhibits the type I interferon (IFN-I) signalling pathway. Impaired IFN-I signalling further impedes antigen presentation, disturbs the activation of cytotoxic T lymphocytes (CTLs), and triggers the expansion of tumour-associated regulatory T (Treg) cells. These cascade effects that MYC overexpression brings in highly inhibit the radiotherapeutic outcomes. Therefore, downregulating the MYC level of tumour cells may overcome the critical immunosuppressive barrier and elicit robust immuno-radiotherapy.

The research team designed an advanced nano-radiosensitizer (PWAI) to launch a dual-epigenetic reprogramming in radiotherapy. The PWAI can coordinate high-Z tungsten metal ions (W6+) with PEG-polyphenols by utilising a metal-phenolic network and load 5-Aza (a DNA methyltransferase inhibitor) and ITF-2357 (a histone deacetylase inhibitor) into the hydrophobic core.

Under the stimulation of exotic radiation, X-ray-sensitive W6+ efficiently destroyed the DNA strands of tumour cells by generating plentiful reactive oxygen species and meanwhile, two types of epigenetic inhibitors were released to modulate MYC dual-epigenetically. 5-Aza alone did not trigger IFN-α/IFN-β generation although it downregulated MYC protein. To combine 5-Aza and ITF-2357, apparent MYC inhibitory effect was still recognised in treated cancer cells; and more importantly, cellular levels of IFN-I signal-related proteins involving IFN-α, IFN-β, and the major histocompatibility complex I were significantly enhanced. To treat 4T1 tumour-bearing mice with PWAI nano-radiosensitizers, the research team identified the awakened anti-tumour immune response after radiotherapy, including the maturation of dendritic cells, cytotoxic T lymphocytes recruitment and their memory-phenotype formation, as well as the immune polarization of tumour-associated macrophages from immunosuppressive state to immunosupportive condition. Bringing dual-epigenetic reprogramming in radiotherapy may provide a potential strategy for advanced immuno-radiotherapy.

The corresponding authors of this paper are Dai Yunlu, and Li Bei, research assistant professor in the Faculty of Health Sciences at UM. PhD graduates Wang Guohao, Yan Jie, and Tian Hao are the co-first authors. Postdoctoral fellows Li Wenxi and PhD students Yu Xinying, Feng Yuzhao and Zhou Songtao also made important contributions to the study. The research project is funded by the Science and Technology Development Fund of the Macao SAR (File no: 0103/2021/A, 0002/2021/AKP, 0133/2022/A3, 0009/2022/AKP, and 0006/2023/ITP1), UM (File no: MYRG2022-00011-FHS and MYRG-GRG2023-00013-FHS-UMDF). The full text of the research paper is available at: https://onlinelibrary.wiley.com/doi/full/10.1002/adma.202312588

To read the news on UM’s official website, please visit the following link:
https://www.um.edu.mo/news-and-press-releases/campus-news/detail/58271/