铁金属氧簇在放射动力学/免疫治疗中的应用研究

【作者】 陈杨；

【导师】 周治国；

【作者基本信息】 上海师范大学 ， 无机化学， 2022， 硕士

【摘要】 放射治疗（RT）作为最有效的肿瘤局部治疗方法之一,被广泛用于临床肿瘤患者治疗。RT通过高能电离辐射可直接导致肿瘤细胞内DNA受损,或者间接与水分子作用产生羟基自由基（·OH）,进而引起肿瘤细胞死亡。然而,大量的临床和临床前证据表明,肿瘤细胞的免疫原性较低,体内只有少数T细胞能够识别肿瘤细胞。由于低氧肿瘤对电离辐射的吸收较低,单独放射治疗产生的活性氧（ROS）少,只能诱导低水平的免疫原性细胞死亡（ICD）,无法实现抗原呈递和抗肿瘤免疫激活。因此,放大氧化应激诱导ICD启动免疫响应,是一个很好的提高RT效果策略。与此同时,结合检查点阻断免疫疗法（CBI）,通过使用免疫检查点抑制剂靶向免疫检查点,恢复T细胞活力,进而增强全身抗肿瘤免疫应答。这种提高放射免疫治疗效果的策略,能够引发远端效应,对原发、远端肿瘤的生长都有着一定的抑制作用。在本论文中,我们合成了一种铁金属氧簇化合物K₂₁Na₈[KFe₁₂（OH）₁₈(α-1,2,3-P₂W₁₅O₅₆)₄]·70H₂O(Fe₁₂-POM),它具有超小分子尺寸（3 nm）以及良好的水溶性。溶液实验表明在过氧化氢（H₂O₂）存在下,该化合物可以发生Fenton反应,产生·OH。同时,Fe₁₂-POM结构中含有高原子序数的钨原子,作为放射增敏剂增加了X射线能量沉积,促进RT产生更多的·OH。更重要的是,我们证明了在X射线辐照下,Fe₁₂-POM结构中发生了分子内电子转移,导致Fe³⁺向Fe²⁺部分转化,促进了化学动力学治疗效果,实现放射动力学治疗（RDT）。细胞实验进一步证明了Fe₁₂-POM和X射线共同作用放大了氧化应激,有效地诱导ICD,促进树突状细胞的成熟以及T细胞的浸润。最后,活体实验结合免疫检查点抑制剂α-PD-1协同治疗,引发全身抗肿瘤免疫,对原位和远端肿瘤的生长都起到了抑制作用。更多还原

【Abstract】 Radiation therapy（RT）,as one of the most effective local tumor treatment methods,has been widely used in the clinical treatment of tumor patients.RT can directly cause DNA damage in tumor cells through high-energy ionizing radiation,or indirectly interact with water molecules to generate hydroxyl radicals（·OH）,thereby causing tumor cell death.However,substantial clinical and preclinical evidence suggests that tumor cells have low immunogenicity and only a few T cells in the body can recognize tumor cells.Due to the low absorption of ionizing radiation by hypoxic tumors,radiotherapy alone generates less reactive oxygen species（ROS）and can only induce low levels of immunogenic cell death（ICD）,failing to achieve antigen presentation and antitumor immune activation.Therefore,amplifying oxidative stress-induced ICD to initiate an immune response is a good strategy to improve the effect of RT.At the same time,combined with checkpoint blockade immunotherapy（CBI）,T cell viability is restored by targeting immune checkpoints with immune checkpoint inhibitors,thereby enhancing the systemic antitumor immune response.This strategy to improve the effect of radioimmunotherapy can induce distal effects and inhibit the growth of both primary and distant tumors to a certain extent.In this paper,we synthesized an iron metal-oxygen cluster compound K₂₁Na₈[KFe₁₂（OH）₁₈(α-1,2,3-P₂W₁₅O₅₆)₄]·70H₂O(Fe₁₂-POM)with ultra-small molecular size（3 nm）and good water solubility.Solution experiments show that in the presence of hydrogen peroxide（H₂O₂）,the compound can undergo a Fenton reaction to produce·OH.At the same time,the Fe₁₂-POM structure contains tungsten atoms with high atomic number,which act as radiosensitizer to increase the X-ray energy deposition and promote RT to generate more·OH.More importantly,we demonstrated that under X-ray irradiation,intramolecular electron transfer occurred in the Fe₁₂-POM structure,resulting in the partial conversion of Fe³⁺to Fe²⁺,which promoted the chemodynamic therapy effect and realized radiodynamic therapy（RDT）.Cellular experiments further demonstrated that the combined action of Fe₁₂-POM and X-ray amplified oxidative stress,effectively induced ICD,and promoted the maturation of dendritic cells and the infiltration of T cells.Finally,in vivo experiments combined with immune checkpoint inhibitorα-PD-1 synergistic therapy triggered systemic antitumor immunity and inhibited the growth of both in situ and distant tumors.更多还原