CN111973746A - Application of iron death inducer in preparation of radiotherapy sensitizer - Google Patents
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Abstract
Description
技术领域technical field
本发明涉及医药技术领域,尤其是铁死亡诱导剂在制备放疗增敏剂中的应用,更具体地提供了铁死亡诱导剂在增敏放射治疗(或外照射治疗)和放射性核素治疗(或内照射治疗)中的应用。The invention relates to the technical field of medicine, in particular to the application of a ferroptosis inducer in the preparation of a radiotherapy sensitizer, and more specifically provides the application of a ferroptosis inducer in sensitizing radiation therapy (or external radiation therapy) and radionuclide therapy (or internal radiation therapy).
背景技术Background technique
放射治疗是利用放射线治疗肿瘤的一种治疗方法,放射线包括放射性同位素产生的α、β、γ射线和各类x射线治疗机或加速器产生的x射线、电子线、质子束及其他粒子束等。在作用机制上,放射治疗产生生物学效应的方式主要有两种,一是射线直接损伤DNA和脂质等生物分子,二是射线通过电离水分子产生大量以羟基为主的自由基,进一步损伤DNA等生物分子。放射治疗是仅次于手术的恶性肿瘤第二大治疗手段,但临床上常因正常组织耐受剂量的限制而不能给予肿瘤足够的照射剂量,而造成治疗失败,因此,如何提高肿瘤对射线的敏感性是临床肿瘤放疗面临的突出问题。放射增敏剂作为一种增强肿瘤放疗敏感性、提高放疗疗效的药物,通过增加辐射诱导的氧自由基及DNA损伤、调控放疗关键分子靶点以达到放射增敏目的。目前,放射增敏剂种类主要分为DNA前体碱基类似物、亲电子放射增敏剂(包括硝基咪唑类、硝基芳香烃及硝基杂环类化合物)、乏氧细胞放射增敏剂、生物还原化合物、放射损伤修复抑制剂、琉基抑制剂、氧利用抑制剂、类氧化合物、纲胞毒类增敏剂、靶向放射增敏剂、与基因有关的肿瘤放射增敏剂和中药等。尽管放疗增敏剂经过了数十年的发展,但相关研究仍无法满足放疗的临床需要。尤为关键的是,现有的放射增敏剂的临床应用并未完全得到肯定,尚需要明确其作用靶点和机制,进一步优化放射增敏剂,从而成为更有效的临床辅助手段。因此,开发靶点和作用机制明确的放疗增敏剂是下一代放疗增敏剂研发的重要方向之一。Radiation therapy is a treatment method that uses radiation to treat tumors. The radiation includes alpha, beta, and gamma rays produced by radioisotopes and x-rays, electron rays, proton beams, and other particle beams generated by various x-ray therapy machines or accelerators. In terms of mechanism of action, there are two main ways in which radiation therapy produces biological effects. One is that radiation directly damages biomolecules such as DNA and lipids. Biomolecules such as DNA. Radiation therapy is the second largest treatment for malignant tumors after surgery, but in clinical practice, due to the limitation of normal tissue tolerance dose, the tumor cannot be given enough radiation dose, resulting in treatment failure. Therefore, how to improve the tumor's radiation resistance? Sensitivity is a prominent problem faced by clinical tumor radiotherapy. Radiosensitizers are drugs that enhance the sensitivity of tumor radiotherapy and improve the efficacy of radiotherapy. They can achieve radiosensitization by increasing radiation-induced oxygen free radicals and DNA damage and regulating key molecular targets of radiotherapy. At present, the types of radiosensitizers are mainly divided into DNA precursor base analogs, electrophilic radiosensitizers (including nitroimidazoles, nitroaromatic hydrocarbons and nitroheterocyclic compounds), hypoxic cell radiosensitizers Agents, bioreductive compounds, radiation damage repair inhibitors, thiol inhibitors, oxygen utilization inhibitors, oxygen-like compounds, cytotoxic sensitizers, targeted radiosensitizers, gene-related tumor radiosensitizers and Chinese medicine, etc. Although radiosensitizers have been developed for decades, related research is still unable to meet the clinical needs of radiotherapy. More importantly, the clinical application of the existing radiosensitizers has not been fully confirmed, and it is still necessary to clarify the target and mechanism of its action, and to further optimize the radiosensitizer, so as to become a more effective clinical aid. Therefore, the development of radiosensitizers with clear targets and mechanisms of action is one of the important directions for the development of next-generation radiosensitizers.
2012年,哥伦比亚大学知名学者Stockwell教授发现了一种全新的铁依赖性细胞死亡方式,并将其命名为铁死亡(Ferroptosis)。铁死亡在本质上是细胞内脂质过氧化物的代谢障碍,即由于谷胱甘肽(GSH)耗竭,膜脂修复酶谷胱甘肽过氧化物酶(GlutathionePeroxidase 4, GPX4)活性下降,脂质过氧化物不能通过GPX4催化的GSH还原反应代谢,进而在铁离子的催化下异常代谢,造成脂质过氧化物积累,触发细胞死亡。例如,Erastin和SAS可通过抑制胱氨酸/谷氨酸转运体(System XC-),使GPX4活性下降,在氧化应激状态下触发铁死亡。放射治疗过程中也会产生大量氧自由基,通过调控铁死亡信号通路,是否可以实现放疗增敏,目前尚未有文献报道。因此,以铁死亡为靶点研发放疗增敏剂药物是本领域研究人员亟需解决的问题,也是本发明的核心创新点。In 2012, Professor Stockwell, a well-known scholar at Columbia University, discovered a new iron-dependent cell death method and named it Ferroptosis. Ferroptosis is essentially a metabolic disorder of intracellular lipid peroxides, that is, due to glutathione (GSH) depletion, the activity of the membrane lipid repair enzyme GlutathionePeroxidase 4 (GPX4) decreases, The lipid peroxides cannot be metabolized by the GSH reduction reaction catalyzed by GPX4, and then abnormally metabolized under the catalysis of iron ions, resulting in the accumulation of lipid peroxides and triggering cell death. For example, Erastin and SAS can reduce GPX4 activity by inhibiting the cystine/glutamate transporter (System XC-) and trigger ferroptosis under oxidative stress. A large number of oxygen free radicals are also generated during radiotherapy. Whether radiosensitization can be achieved by regulating the ferroptosis signaling pathway has not been reported in the literature. Therefore, the development of radiosensitizer drugs with ferroptosis as the target is an urgent problem for researchers in the field to solve, and is also the core innovation of the present invention.
发明内容SUMMARY OF THE INVENTION
针对上述情况,为克服现有技术之缺陷,本发明之目的就是提供一种铁死亡诱导剂在制备放疗增敏剂中的应用。In view of the above situation, in order to overcome the defects of the prior art, the purpose of the present invention is to provide an application of a ferroptosis inducer in the preparation of a radiosensitizer.
其解决方案是,铁死亡诱导剂在制备治疗放疗增敏剂中的应用。The solution is the application of a ferroptosis inducer in the preparation of a radiotherapy sensitizer for treatment.
优选地,铁死亡诱导剂是通过调控铁死亡信号通路达到放疗增敏效应的。Preferably, the ferroptosis-inducing agent achieves the radiosensitization effect by regulating the ferroptosis signaling pathway.
优选地,所述的铁死亡诱导剂优选自Erastin,RSL3,FIN56,谷氨酰胺,顺铂,柳氮磺胺吡啶,索拉菲尼,青蒿琥酯,双氢青蒿素,蒿甲醚和维生素E。Preferably, the ferroptosis inducer is preferably selected from Erastin, RSL3, FIN56, glutamine, cisplatin, sulfasalazine, sorafenib, artesunate, dihydroartemisinin, artemether and Vitamin E.
优选地,所述放疗增敏剂是含有有效剂量的铁死亡诱导剂以及任选的药学可接受的载体和/或辅料。Preferably, the radiosensitizer contains an effective dose of a ferroptosis inducer and optionally a pharmaceutically acceptable carrier and/or adjuvant.
优选地,所述放疗增敏剂的给药途径包括口服给药,静脉注射,肌肉注射,皮下注射,鼻腔给药,腹腔注射,舌下给药或经皮给药。Preferably, the route of administration of the radiosensitizer includes oral administration, intravenous injection, intramuscular injection, subcutaneous injection, intranasal administration, intraperitoneal injection, sublingual administration or transdermal administration.
优选地,所述放疗增敏剂在放射治疗(或外照射治疗)和放射性核素治疗(或内照射治疗)中的应用。Preferably, the radiosensitizer is used in radiotherapy (or external beam therapy) and radionuclide therapy (or internal beam therapy).
本发明的有益效果:本发明公开了一种铁死亡诱导剂在制备放疗增敏剂中的应用。本发明首次揭示了铁死亡诱导剂在放射治疗(外照射治疗)和放射性核素治疗(内照射治疗)中的增敏作用和分子机制,为以铁死亡为靶点的放疗增敏剂药物的研发提供了新思路。Beneficial effects of the invention: The invention discloses the application of a ferroptosis inducer in the preparation of a radiosensitizer. The present invention discloses for the first time the sensitizing effect and molecular mechanism of ferroptosis inducing agent in radiotherapy (external radiation therapy) and radionuclide therapy (internal radiation therapy), and is the first development of radiotherapy sensitizer drugs targeting ferroptosis. R&D provides new ideas.
附图说明Description of drawings
图1为铁死亡诱导剂增敏放射治疗的分子机制图;Figure 1 is a diagram of the molecular mechanism of ferroptosis-inducing agent-sensitized radiotherapy;
图2为(A)A549、(B)MCF-7和(C)HepG2细胞分别接受不同剂量放射治疗(2、4和6 Gy)、铁死亡诱导剂Erastin预处理12 h + 不同剂量放射治疗(2、4和6 Gy)和铁死亡抑制剂Fer-1预处理12 h + 不同剂量放射治疗(2、4和6 Gy)后的细胞活性图;Figure 2 shows (A) A549, (B) MCF-7 and (C) HepG2 cells receiving different doses of radiation therapy (2, 4 and 6 Gy), ferroptosis inducer Erastin pretreatment for 12 h + different doses of radiation therapy ( 2, 4 and 6 Gy) and ferroptosis inhibitor Fer-1 pretreatment for 12 h + different doses of radiotherapy (2, 4 and 6 Gy) after cell viability;
图3为(A)A549、(B)MCF-7和(C)HepG2细胞分别接受生理盐水、6 Gy放射治疗、细胞凋亡抑制剂Z-VAD预处理12 h + 6 Gy放射治疗、铁死亡抑制剂Fer-1预处理12 h + 6 Gy放射治疗后的细胞活性图;Figure 3: (A) A549, (B) MCF-7 and (C) HepG2 cells were treated with saline, 6 Gy radiotherapy, apoptosis inhibitor Z-VAD pretreatment for 12 h + 6 Gy radiotherapy, ferroptosis, respectively Figures of cell viability after pretreatment with inhibitor Fer-1 for 12 h + 6 Gy radiotherapy;
图4为A549、MCF-7和HepG2细胞分别接受生理盐水、6 Gy放射治疗、铁死亡诱导剂Erastin预处理12 h + 6 Gy放射治疗、铁死亡抑制剂Fer-1预处理12 h + 6 Gy放射治疗后的细胞中还原型谷胱甘肽(GSH)含量变化(A)、谷胱甘肽过氧化物酶-4(GPX-4)表达变化(B)和脂质过氧化物(LPO)含量变化(C)图;Figure 4 shows that A549, MCF-7 and HepG2 cells received normal saline, 6 Gy radiotherapy, ferroptosis inducer Erastin pretreatment for 12 h + 6 Gy radiotherapy, and ferroptosis inhibitor Fer-1 pretreatment for 12 h + 6 Gy Changes in reduced glutathione (GSH) content (A), glutathione peroxidase-4 (GPX-4) expression (B) and lipid peroxide (LPO) in cells after radiotherapy Content change (C) diagram;
图5为铁死亡诱导剂增敏A549移植瘤放射治疗的实验研究示意图;Figure 5 is a schematic diagram of an experimental study of ferroptosis-inducing agent-sensitized A549 xenograft radiotherapy;
图6为(A)不同治疗组荷瘤裸鼠在12d时,离体肿瘤组织示意图;荷瘤裸鼠治疗过程中肿瘤体积(B)和体重变化图(C);Figure 6 is (A) the schematic diagram of the isolated tumor tissue of the tumor-bearing nude mice in different treatment groups at 12 days; the tumor volume (B) and the body weight change (C) of the tumor-bearing nude mice during the treatment;
图7为不同治疗组荷瘤裸鼠在12d时,离体肿瘤组织的苏木精和伊红(H&E)染色图;Figure 7 is a graph of hematoxylin and eosin (H&E) staining of tumor-bearing nude mice in different treatment groups at 12 days;
图8为不同治疗组荷瘤裸鼠在12d时,离体肿瘤组织Ki-67染色图(A)和其定量值(B)示意图;Figure 8 is a schematic diagram of Ki-67 staining (A) and its quantitative value (B) in isolated tumor tissue of tumor-bearing nude mice in different treatment groups at 12 days;
图9为不同治疗组荷瘤裸鼠在12d时,离体肿瘤组织中GPX-4表达的Western blot图。Figure 9 is the Western blot chart of GPX-4 expression in tumor tissues of tumor-bearing nude mice in different treatment groups at 12 d.
具体实施方式Detailed ways
以下实施方式旨在说明本发明而不是对本发明的进一步限定。在背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段。The following embodiments are intended to illustrate the present invention rather than to further limit the present invention. Modifications or substitutions made to the methods, steps or conditions of the present invention without departing from the spirit and essence of the present invention all belong to the scope of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art.
实施例1 :铁死亡在放射治疗A549、MCF-7和HepG2细胞中的作用Example 1: Effect of ferroptosis in radiotherapy of A549, MCF-7 and HepG2 cells
将A549、MCF-7和HepG2细胞分别接种于96孔板,每组设6个复孔。四周用PBS缓冲液(200μL每孔)填满,预防周边效应。37℃、5 % CO2培养箱中孵育。细胞贴壁后,弃掉旧培基,每孔加入200 μL新培养,然后分别做如下处理:A549, MCF-7 and HepG2 cells were seeded in 96-well plates, with 6 replicate wells in each group. Four weeks were filled with PBS buffer (200 μL per well) to prevent peripheral effects. Incubate in a 37°C, 5% CO2 incubator. After the cells adhered, discard the old medium, add 200 μL of new culture to each well, and then do the following treatments:
Control:10 μL生理盐水Control: 10 μL normal saline
治疗组1:放疗治疗(2、4和6 Gy)Treatment Group 1: Radiation Therapy (2, 4, and 6 Gy)
治疗组2:10 μL Erastin 12 h + 放射治疗(2、4和6 Gy)Treatment Group 2: 10 μL Erastin 12 h + radiation therapy (2, 4, and 6 Gy)
治疗组2:10 μL Fer-1 12 h + 放射治疗(2、4和6 Gy)Treatment group 2: 10 μL Fer-1 12 h + radiation therapy (2, 4 and 6 Gy)
培养箱中继续孵育48 h。 48h后弃掉旧培基,利用 CCK-8试剂盒测定各组细胞活性。Continue to incubate for 48 h in the incubator. After 48h, the old medium was discarded, and the cell viability of each group was measured by CCK-8 kit.
将A549、MCF-7和HepG2细胞分别接种于96孔板,每组设6个复孔。四周用PBS缓冲液(200 μL每孔)填满,预防周边效应。37℃、5 % CO2培养箱中孵育。细胞贴壁后,弃掉旧培基,每孔加入200 μL新培养,然后分别做如下处理:A549, MCF-7 and HepG2 cells were seeded in 96-well plates, with 6 replicate wells in each group. Four weeks were filled with PBS buffer (200 μL per well) to prevent peripheral effects. Incubate in a 37°C, 5% CO2 incubator. After the cells adhered, discard the old medium, add 200 μL of new culture to each well, and then do the following treatments:
Control:10 μL生理盐水Control: 10 μL normal saline
治疗组1: 6 GyTreatment Group 1: 6 Gy
治疗组2:10 μL Z-VAD 12 h + 放射治疗(6 Gy)Treatment group 2: 10 μL Z-VAD for 12 h + radiation therapy (6 Gy)
治疗组2:10 μL Fer-1 12 h + 放射治疗(6 Gy)Treatment group 2: 10 μL Fer-1 12 h + radiation therapy (6 Gy)
培养箱中继续孵育48 h。 48h后弃掉旧培基,利用 CCK-8试剂盒测定各组细胞活性。Continue to incubate for 48 h in the incubator. After 48h, the old medium was discarded, and the cell viability of each group was measured by CCK-8 kit.
将A549、MCF-7和HepG2细胞分别接种于96孔板,每组设6个复孔。四周用PBS缓冲液(200 μL每孔)填满,预防周边效应。37℃、5 % CO2培养箱中孵育。细胞贴壁后,弃掉旧培基,每孔加入200 μL新培养,然后分别做如下处理:A549, MCF-7 and HepG2 cells were seeded in 96-well plates, with 6 replicate wells in each group. Four weeks were filled with PBS buffer (200 μL per well) to prevent peripheral effects. Incubate in a 37°C, 5% CO2 incubator. After the cells adhered, discard the old medium, add 200 μL of new culture to each well, and then do the following treatments:
Control:10 μL生理盐水Control: 10 μL normal saline
治疗组1: 6 GyTreatment Group 1: 6 Gy
治疗组2:10 μL Erastin 12 h + 放射治疗(6 Gy)Treatment group 2: 10 μL Erastin 12 h + radiation therapy (6 Gy)
治疗组2:10 μL Fer-1 12 h + 放射治疗(6 Gy)Treatment group 2: 10 μL Fer-1 12 h + radiation therapy (6 Gy)
培养箱中继续孵育48 h。 48h后弃掉旧培基,利用还原型谷胱甘肽(GSH)含量测定试剂盒测定各组细胞中GSH含量;利用western blotting测定各组中GPX-4表达变化;利用脂质过氧化物(LPO)检测试剂盒测定各组细胞中LPO含量。Continue to incubate for 48 h in the incubator. After 48 h, the old culture medium was discarded, and the GSH content in the cells of each group was determined by the reduced glutathione (GSH) content assay kit; the expression changes of GPX-4 in each group were determined by western blotting; lipid peroxide ( LPO) detection kit to measure the LPO content in cells of each group.
如图2和3所示,在549、MCF-7和HepG2细胞中,给予不同剂量放射治疗,可诱导细胞死亡。在加入铁死亡诱导剂Erastin后,细胞死亡明显增加。然而,在加入铁死亡抑制剂Fer-1的治疗组中,细胞死亡受到抑制;作为对照的,相应的加入细胞凋亡抑制剂Z-VAD,细胞死亡抑制相对较弱。这些研究结果表明,在放射治疗过程中发生了铁死亡,铁死亡诱导剂可以增敏放射治疗。As shown in Figures 2 and 3, different doses of radiation therapy induced cell death in 549, MCF-7 and HepG2 cells. After the addition of the ferroptosis inducer Erastin, cell death was significantly increased. However, in the treatment group with the addition of the ferroptosis inhibitor Fer-1, cell death was inhibited; as a control, the corresponding addition of the apoptosis inhibitor Z-VAD, the inhibition of cell death was relatively weak. These findings suggest that ferroptosis occurs during radiotherapy and that ferroptosis inducers can sensitize radiotherapy.
如图4所示,在放疗治疗后48 h,各种细胞中GSH含量显著降低,GPX-4表达增加,LPO含量增多。在给予铁死亡诱导剂Erastin治疗组中,GSH含量进一步降低,GPX-4表达降低,LPO含量显著增多;在给予铁死亡抑制剂Fer-1的治疗组中,GSH和GPX-4含量都会增高,LPO含量降低。这些结果表明,在放射治疗中,尽管会发生铁死亡,但也会诱导GPX-4表达增加,抵抗放射治疗。在给予铁死亡诱导剂后,会显著下调GPX-4表达,进一步诱导铁死亡的发生。因此,铁死亡诱导和放射治疗会产生协同作用。铁死亡诱导剂可作为放疗增敏剂,在放射治疗中起到增敏作用。As shown in Figure 4, 48 h after radiotherapy treatment, GSH content in various cells was significantly decreased, GPX-4 expression increased, and LPO content increased. In the treatment group given the ferroptosis inducer Erastin, the content of GSH was further decreased, the expression of GPX-4 was decreased, and the content of LPO was significantly increased; in the treatment group given the ferroptosis inhibitor Fer-1, the content of GSH and GPX-4 increased, The LPO content decreased. These results suggest that during radiotherapy, although ferroptosis occurs, it also induces increased GPX-4 expression that is resistant to radiotherapy. After administration of ferroptosis inducers, the expression of GPX-4 was significantly down-regulated, further inducing the occurrence of ferroptosis. Therefore, ferroptosis induction and radiation therapy would have a synergistic effect. Iron death inducers can be used as radiosensitizers and play a sensitizing role in radiotherapy.
实施例2 : 铁死亡诱导剂增敏A549移植瘤放射治疗的实验研究Example 2: Experimental study of ferroptosis inducers sensitizing A549 xenografts to radiotherapy
选取周龄为4-5周BALB/c裸鼠,皮下接种约107个A549细胞,建立肺癌移植瘤模型,待肿瘤体积达到100-200 mm3时,随机分为4组,分别做如下处理(图 5):A 每天腹腔注射生理盐水;B 10 Gy放射治疗;C 10 Gy放射治疗后,每天给予腹腔注射Erastin (15 mg/kg);D 10Gy放射治疗后,每天给予腹腔注射Fer-1 (10 mg/kg)。每2 天监测一次荷瘤裸鼠体重和肿瘤体积大小,连续监测12 d。在12 d处死裸鼠,取肿瘤组织,苏木精和伊红(H&E)和Ki-67染色;Western blot检测GPX-4含量变化。BALB/c nude mice aged 4-5 weeks were selected and subcutaneously inoculated with about 107 A549 cells to establish a lung cancer xenograft model. When the tumor volume reached 100-200 mm3, they were randomly divided into 4 groups and treated as follows (Fig. 5): A daily intraperitoneal injection of normal saline;
如图6所示, A549肺癌肿瘤经过10 Gy放射治疗12 d后,肿瘤体积减小;进一步给予铁死亡诱导剂组,肿瘤体积明显减小;相反地,进一步给予铁死亡抑制剂组,肿瘤体积变大。在治疗过程中,各组荷瘤裸鼠体重略微降低。H&E和Ki-67染色表明,在放射治疗联合铁死亡诱导剂组中,肿瘤细胞坏死明显,增殖指数显著降低(图7和8)。Western blot检测GPX-4表达实验表明,在放射治疗后,GPX-4表达上调,进一步给予铁死亡诱导剂可显著下调GPX-4的表达(图 9)。这些结果表明,铁死亡诱导和放射治疗会产生协同作用。铁死亡诱导剂可作为放疗增敏剂,在放射治疗中起到增敏作用。As shown in Figure 6, after 12 d of 10 Gy radiotherapy for A549 lung cancer tumor, the tumor volume decreased; in the ferroptosis inducer group, the tumor volume decreased significantly; on the contrary, in the ferroptosis inhibitor group, the tumor volume decreased significantly. get bigger. During the treatment, the body weight of tumor-bearing nude mice in each group decreased slightly. H&E and Ki-67 staining showed that tumor cell necrosis was evident and the proliferation index was significantly decreased in the radiation therapy combined with ferroptosis inducer group (Figures 7 and 8). Western blot detection of GPX-4 expression showed that after radiotherapy, the expression of GPX-4 was up-regulated, and further administration of ferroptosis inducers could significantly down-regulate the expression of GPX-4 (Figure 9). These results suggest that ferroptosis induction and radiation therapy work synergistically. Iron death inducers can be used as radiosensitizers and play a sensitizing role in radiotherapy.
最后应该说明的是,以上所述仅为本发明的优选实例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神和实质的基础之上所做的任何修改或改进,均属于本发明要求保护的范围。Finally, it should be noted that the above are only preferred examples of the present invention, and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still Modifications are made to the technical solutions described in the foregoing embodiments, or equivalent replacements are made to some of them. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention. The present invention has been described in detail above with general description and specific embodiments, but on the basis of the present invention, some modifications or improvements can be made, which will be obvious to those skilled in the art. Therefore, any modification or improvement made on the basis of not departing from the spirit and essence of the present invention shall fall within the protection scope of the present invention.
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CN114984230A (en) * | 2022-06-30 | 2022-09-02 | 杭州博医生物医药科技有限责任公司 | Composition for enhancing tumor sensitivity in treatment of iron death and application thereof |
CN116099010A (en) * | 2022-07-20 | 2023-05-12 | 天津医科大学第二医院 | Biocompatible magnetic resonance nanoprobes for tumor-induced ferroptosis and their preparation and application |
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CN112933078A (en) * | 2021-04-14 | 2021-06-11 | 广西大学 | Nano compound for inducing iron death, preparation method and application thereof in tumor treatment |
CN114984230A (en) * | 2022-06-30 | 2022-09-02 | 杭州博医生物医药科技有限责任公司 | Composition for enhancing tumor sensitivity in treatment of iron death and application thereof |
CN116099010A (en) * | 2022-07-20 | 2023-05-12 | 天津医科大学第二医院 | Biocompatible magnetic resonance nanoprobes for tumor-induced ferroptosis and their preparation and application |
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