高效X射线激发光动力治疗纳米系统构筑及低剂量下治疗策略研究

田倚; 付之光; 朱笑生; 展春景; 胡锦伟; 范黎; 宋朝君; 杨倩; 王宇; 石梅

doi:10.1007/s12613-023-2717-3

Volume 31 Issue 3

Mar. 2024

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文章导航 > 矿物冶金与材料学报（英文） > 2024 > 31(3): 599-610

Yi Tian, Zhiguang Fu, Xiaosheng Zhu, Chunjing Zhan, Jinwei Hu, Li Fan, Chaojun Song, Qian Yang, Yu Wang, and Mei Shi, Establishment of NaLuF₄:15%Tb-based low dose X-PDT agent and its application on efficient antitumor therapy, Int. J. Miner. Metall. Mater., 31(2024), No. 3, pp. 599-610. https://doi.org/10.1007/s12613-023-2717-3

Cite this article as:

Yi Tian, Zhiguang Fu, Xiaosheng Zhu, Chunjing Zhan, Jinwei Hu, Li Fan, Chaojun Song, Qian Yang, Yu Wang, and Mei Shi, Establishment of NaLuF4:15%Tb-based low dose X-PDT agent and its application on efficient antitumor therapy, Int. J. Miner. Metall. Mater., 31(2024), No. 3, pp. 599-610. https://doi.org/10.1007/s12613-023-2717-3

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研究论文

高效X射线激发光动力治疗纳米系统构筑及低剂量下治疗策略研究

1)
中国人民解放军空军军医大学西京医院放射治疗科, 西安 710032, 中国
2)
中国人民解放军空军军医大学空军特色医学中心肿瘤科, 北京 100142, 中国
3)
中国人民解放军空军军医大学空军特色医学中心放射治疗科, 北京 100142, 中国
4)
中国人民解放军南部战区空军医院消化内科, 广州 510062, 中国
5)
中国人民解放军空军军医大学药学系药物化学与药物分析学教研室, 西安 710032, 中国
6)
西北工业大学生命学院, 西安 710072, 中国
7)
中国人民解放军空军军医大学药学系天然药物学教研室, 西安 710032, 中国

通讯作者:
杨倩    E-mail: 12154521@qq.com

王宇    E-mail: wangyufmmu@163.com

石梅    E-mail: mshi82@fmmu.edu.cn

文章亮点

(1) 成功合成了具有高光转换效率的纳米粒子，并构建新型X射线激发光动力学治疗系统

(2) 该系统实现了低剂量X射线照射下高效的抗肿瘤治疗效果

(3) 该系统治疗可以激活小鼠的抗肿瘤免疫并抑制远处肿瘤的生长

中文摘要

X射线激发光动力学治疗（X-ray excited PDT，X-PDT）采用可被X射线激发的纳米发光材料（XLNPs）产生的可见光作为内部光源，激发与之耦合的光敏剂产生单态氧进行光动力治疗，得到了极大关注。X-PDT通过X射线激发被负载光敏剂的纳米颗粒发光，将能量传递给光敏剂产生肿瘤的光动力效应，产生ROS，促使肿瘤细胞凋亡。同时，一定X射线剂量下的X-PDT被视作放疗与光动力治疗的联用，可发挥二者的协同效果，实现高效深部肿瘤无创治疗。本文中采用共沉淀法合成NaLuF₄:15%Tb³⁺（NLF）作为X射线激发的发光纳米粒子并与光敏剂MC540通过表面吸附耦合，成功构建NLF-MC540的X-PDT系统。对该体系的X-PDT治疗效果进行体内外评价后，进一步探索了NLF-MC540的X-PDT系统对肿瘤免疫的激活能力。最终成功制备纳米发光颗粒NLF，可将X射线高效地转换为波长545 nm的可见光。以10:1质量比构建NLF-MC540治疗系统；该系统的体外实验中，在较低的剂量0.1Gy–0.3Gy下NLF-MC540可抑制CT26细胞存活率最低达24%，体内实验中，0.1 Gy射线激发的X-PDT治疗组抑瘤率89.5% ± 5.7% ，治疗效果明显低于X-PDT 文献报道的最低剂量，远低于临床常用的常规放疗剂量。各组别荷瘤小鼠实施X-PDT后，小鼠瘤体切片染色发现该组内瘤体中有大量Ly6G⁺、CD8⁺、CD11c⁺细胞浸润；治疗组小鼠体内分泌IFN-γ、TNF-α细胞因子的免疫细胞的水平升高，血清内两种细胞因子的水平同样发生了升高，且单侧的X-PDT照射能抑制远处肿瘤的生长，我们得知NLF-MC540系统在0.1 Gy低剂量X-PDT过程中发生了肿瘤局部的急性炎症反应。且低剂量X-PDT成功激活了小鼠的肿瘤免疫能力，提高了对肿瘤细胞杀伤能力。最终本研究成功构建新型 X-PDT 系统，该系统实现了低剂量X射线照射与光动力治疗的协同作用，能降低辐射产生的正常组织损伤；该系统的X-PDT治疗可以激活小鼠的抗肿瘤免疫并抑制远处肿瘤的生长。

关键词:

Research Article

Establishment of NaLuF₄:15%Tb-based low dose X-PDT agent and its application on efficient antitumor therapy

+ Author Affiliations

1)
Department of Radiation Oncology, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, China
2)
Department of Oncology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing 100142, China
3)
Department of Tumor Radiotherapy, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing 100142, China
4)
Department of Gastroenterology, Air Force Hospital of Southern Theater Command, Guangzhou 510062, China
5)
Department of Pharmaceutical Chemistry and Analysis, School of Pharmacy, The Fourth Military Medical University, Xi’an 710032, China
6)
School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
7)
Institue of Materia Medica, School of Pharmacy, The Fourth Military Medical University, Xi’an 710032, China

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
*These authors contributed equally to this work and share first authorship.

Corresponding authors:
Qian Yang    E-mail: 12154521@qq.com

Yu Wang    E-mail: wangyufmmu@163.com

Mei Shi    E-mail: mshi82@fmmu.edu.cn
Received: 9 June 2023; Revised: 20 July 2023; Accepted: 7 August 2023; Available online: 10 August 2023

Abstract

Abstract

X-ray excited photodynamic therapy (X-PDT) is the bravo answer of photodynamic therapy (PDT) for deep-seated tumors, as it employs X-ray as the irradiation source to overcome the limitation of light penetration depth. However, high X-ray irradiation dose caused organ lesions and side effects became the major barrier to X-PDT application. To address this issue, this work employed a classical co-precipitation reaction to synthesize NaLuF₄:15%Tb³⁺ (NLF) with an average particle size of (23.48 ± 0.91) nm, which was then coupled with the photosensitizer merocyanine 540 (MC540) to form the X-PDT system NLF–MC540 with high production of singlet oxygen. The system could induce antitumor efficacy to about 24% in relative low dose X-ray irradiation range (0.1–0.3 Gy). In vivo, when NLF–MC540 irradiated by 0.1 Gy X-ray, the tumor inhibition percentage reached 89.5% ± 5.7%. The therapeutic mechanism of low dose X-PDT was found. A significant increase of neutrophils in serum was found on the third day after X-PDT. By immunohistochemical staining of tumor sections, the Ly6G⁺, CD8⁺, and CD11c⁺ cells infiltrated in the tumor microenvironment were studied. Utilizing the bilateral tumor model, the NLF–MC540 with 0.1 Gy X-ray irradiation could inhibit both the primary tumor and the distant tumor growth. Detected by enzyme linked immunosorbent assay (ELISA), two cytokines IFN-γ and TNF-α in serum were upregulated 7 and 6 times than negative control, respectively. Detected by enzyme linked immune spot assay (ELISPOT), the number of immune cells attributable to the IFN-γ and TNF-α levels in the group of low dose X-PDT were 14 and 6 times greater than that in the negative control group, respectively. Thus, it conclude that low dose X-PDT system could successfully upregulate the levels of immune cells, stimulate the secretion of cytokines (especially IFN-γ and TNF-α), activate antitumor immunity, and finally inhibit colon tumor growth.
- X-ray excited photodynamic therapy;
- singlet oxygen;
- low dose X-Ray irradiation;
- efficient antitumor therapy;
- anti-tumor immunity

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