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X射线刺激依赖NQO1的级联反应,以诱导用于MRI引导的癌症放射化学动力免疫治疗的强免疫原性。

X-ray stimulates NQO1-dependent cascade reactions to induce strong immunogenicity for MRI-guided cancer radio-chemodynamic-immunotherapy.

作者信息

He Li, Ma Jiao-Jiao, Wu Yi-Qun, Wang Chen-Guang, Lan Tong, Su Lu, Zhu Lin, Huang Shi-Wen, Deng Kai, Wei Yong-Chang

机构信息

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.

Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.

出版信息

Theranostics. 2025 Jun 9;15(14):6768-6788. doi: 10.7150/thno.110573. eCollection 2025.


DOI:10.7150/thno.110573
PMID:40585976
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12203676/
Abstract

Immunogenicity activation is vital for radioimmunotherapy, but the short-term oxidative damage caused by precise radiation planning limits this effect. Chemodynamic therapy (CDT) with prolonged generation of hydroxyl radical (•OH) can initiate immunogenicity in combination with X-rays, however, its performance is constrained by tumor insufficient H2O2. Here, we propose to construct β-lapachone-based nanoparticles (β-Lap/Fe NPs) which initiate cascade reactions to generate high levels •OH for an extended period in tumor following X-ray irradiation. β-Lap/Fe NPs, constructed by co-encapsulation of β-Lap and Fe3O4 nanoparticles in reactive oxygen species (ROS) responsive C16-S-mPEG2000 micelles, remain stable under normal conditions but rapid decompose and release β-Lap and Fe2+ when exposed to high level ROS. Upon X-ray irradiation, the upregulation of ROS and NAD (P) H: quinone oxidoreductase-1 (NQO1) in tumor cells accurately triggers β-Lap/Fe NPs to persistently generate high levels H2O2 and •OH for 12 hours, ultimately causing strong immunogenic cell death effects. Moreover, β-Lap/Fe NPs with excellent T2-weighted magnetic resonance imaging provide imaging reference for guiding precise X-ray radiation and predicting •OH generation. β-Lap/Fe NPs mediated radio-chemodynamic-immunotherapy remarkably against primary tumor growth, and further shows effective suppression on untreated distant tumors via the abscopal effect. In a word, this work proposed the simple but powerful strategy for cancer radio-chemodynamic-immunotherapy that combines X-ray and CDT to remote locally and visually actuated long-time production of H2O2 and subsequently persistent generation of •OH for initiating strong antitumor immune responses.

摘要

免疫原性激活对放射免疫治疗至关重要,但精确放疗计划引起的短期氧化损伤限制了这种效果。能够长时间生成羟基自由基(•OH)的化学动力疗法(CDT)可与X射线联合引发免疫原性,然而,其性能受到肿瘤内过氧化氢(H2O2)不足的限制。在此,我们提出构建基于β-拉帕醌的纳米颗粒(β-Lap/Fe NPs),其在X射线照射后能在肿瘤中引发级联反应,长时间产生高水平的•OH。β-Lap/Fe NPs是通过将β-拉帕醌和四氧化三铁纳米颗粒共包裹于活性氧(ROS)响应性的C16-S-甲氧基聚乙二醇2000(mPEG2000)胶束中构建而成,在正常条件下保持稳定,但在暴露于高水平ROS时会迅速分解并释放β-拉帕醌和Fe2+。在X射线照射后,肿瘤细胞内ROS和烟酰胺腺嘌呤二核苷酸(磷酸):醌氧化还原酶-1(NQO1)的上调精确触发β-Lap/Fe NPs持续产生高水平的H2O2和•OH达12小时,最终导致强烈的免疫原性细胞死亡效应。此外,具有优异T2加权磁共振成像的β-Lap/Fe NPs为引导精确的X射线放疗和预测•OH生成提供成像参考。β-Lap/Fe NPs介导的放射化学动力免疫疗法显著抑制原发性肿瘤生长,并通过远隔效应进一步有效抑制未治疗的远处肿瘤。总之,这项工作提出了一种简单而有效的癌症放射化学动力免疫治疗策略,即将X射线和CDT相结合,以远程、局部和可视化方式驱动长时间产生H2O2,随后持续生成•OH以引发强烈的抗肿瘤免疫反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/45e435686045/thnov15p6768g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/fcd54771bfcc/thnov15p6768g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/644a7ed4acbb/thnov15p6768g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/133d37fd0fec/thnov15p6768g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/043e50a40b03/thnov15p6768g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/dade735ec946/thnov15p6768g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/d58ddad59df3/thnov15p6768g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/45e435686045/thnov15p6768g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/fcd54771bfcc/thnov15p6768g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/644a7ed4acbb/thnov15p6768g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/133d37fd0fec/thnov15p6768g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/043e50a40b03/thnov15p6768g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/dade735ec946/thnov15p6768g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/d58ddad59df3/thnov15p6768g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/877b/12203676/45e435686045/thnov15p6768g007.jpg

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本文引用的文献

[1]
A multifunctional nanosystem catalyzed by cascading natural glucose oxidase and FeO nanozymes for synergistic chemodynamic and photodynamic cancer therapy.

Acta Biomater. 2024-12

[2]
Engineering Magnetic Extracellular Vesicles Mimetics for Enhanced Targeting Chemodynamic Therapy to Overcome Ovary Cancer.

ACS Appl Mater Interfaces. 2024-7-31

[3]
Metal-polyphenol self-assembled nanodots for NIR-II fluorescence imaging-guided chemodynamic/photodynamic therapy-amplified ferroptosis.

Acta Biomater. 2024-9-1

[4]
Theragnostic Gadolinium-Based Nanoparticles Safely Augment X-ray Radiation Effects in Patients with Cervical Cancer.

ACS Nano. 2024-7-2

[5]
Multifunctional Fe-based coordination polymer nano-bomb modified with β-lapachone and CaO for targeted tumor dual chemodynamic therapy with enhanced ferroptosis and HO self-supply.

J Nanobiotechnology. 2024-1-3

[6]
Amphiphilic polymeric nanodrug integrated with superparamagnetic iron oxide nanoparticles for synergistic antibacterial and antitumor therapy of colorectal cancer.

Acta Biomater. 2024-1-1

[7]
Prospects of nanoparticle-based radioenhancement for radiotherapy.

Mater Horiz. 2023-10-2

[8]
Strategies for enhancing cancer chemodynamic therapy performance.

Exploration (Beijing). 2022-3-7

[9]
In Situ STING-Activating Nanovaccination with TIGIT Blockade for Enhanced Immunotherapy of Anti-PD-1-Resistant Tumors.

Adv Mater. 2023-6

[10]
Tailored Beta-Lapachone Nanomedicines for Cancer-Specific Therapy.

Adv Healthc Mater. 2023-8

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