Liu William, Mirzoeva Salida, Yuan Ye, Deng Junjing, Chen Si, Lai Barry, Vogt Stefan, Shah Karna, Shroff Rahul, Bleher Reiner, Jin Qiaoling, Vo Nghia, Bazak Remon, Ritner Carissa, Gutionov Stanley, Raha Sumita, Sedlmair Julia, Hirschmugl Carol, Jacobsen Chris, Paunesku Tatjana, Kalapurkal John, Woloschak Gayle E
Department of Radiation Oncology, Northwestern University, Chicago, IL 60611 USA.
Department of Physics and Astronomy, Northwestern University, Evanston, IL 60208 USA.
Cancer Nanotechnol. 2021;12(1):12. doi: 10.1186/s12645-021-00081-z. Epub 2021 May 14.
Neuroblastoma is the most common extracranial solid malignancy in childhood which, despite the current progress in radiotherapy and chemotherapy protocols, still has a high mortality rate in high risk tumors. Nanomedicine offers exciting and unexploited opportunities to overcome the shortcomings of conventional medicine. The photocatalytic properties of FeO core-TiO shell nanocomposites and their potential for cell specific targeting suggest that nanoconstructs produced using FeO core-TiO shell nanocomposites could be used to enhance radiation effects in neuroblastoma. In this study, we evaluated bare, metaiodobenzylguanidine (MIBG) and 3,4-Dihydroxyphenylacetic acid (DOPAC) coated FeO@TiO as potential radiosensitizers for neuroblastoma in vitro.
The uptake of bare and MIBG coated nanocomposites modestly sensitized neuroblastoma cells to ionizing radiation. Conversely, cells exposed to DOPAC coated nanocomposites exhibited a five-fold enhanced sensitivity to radiation, increased numbers of radiation induced DNA double-strand breaks, and apoptotic cell death. The addition of a peptide mimic of the epidermal growth factor (EGF) to nanoconjugates coated with MIBG altered their intracellular distribution. Cryo X-ray fluorescence microscopy tomography of frozen hydrated cells treated with these nanoconjugates revealed cytoplasmic as well as nuclear distribution of the nanoconstructs.
The intracellular distribution pattern of different nanoconjugates used in this study was different for different nanoconjugate surface molecules. Cells exposed to DOPAC covered nanoconjugates showed the smallest nanoconjugate uptake, with the most prominent pattern of large intracellular aggregates. Interestingly, cells treated with this nanoconjugate also showed the most pronounced radiosensitization effect in combination with the external beam x-ray irradiation. Further studies are necessary to evaluate mechanistic basis for this increased radiosensitization effect. Preliminary studies with the nanoparticles carrying an EGF mimicking peptide showed that this approach to targeting could perhaps be combined with a different approach to radiosensitization - use of nanoconjugates in combination with the radioactive iodine. Much additional work will be necessary in order to evaluate possible benefits of targeted nanoconjugates carrying radionuclides.
The online version contains supplementary material available at 10.1186/s12645-021-00081-z.
神经母细胞瘤是儿童期最常见的颅外实体恶性肿瘤，尽管目前放疗和化疗方案取得了进展，但高危肿瘤的死亡率仍然很高。纳米医学为克服传统医学的缺点提供了令人兴奋且尚未开发的机会。FeO核-TiO壳纳米复合材料的光催化特性及其细胞特异性靶向潜力表明，使用FeO核-TiO壳纳米复合材料制备的纳米结构可用于增强神经母细胞瘤的放射效应。在本研究中，我们评估了裸露的、间碘苄胍（MIBG）和3,4-二羟基苯乙酸（DOPAC）包被的FeO@TiO作为神经母细胞瘤体外潜在放射增敏剂的效果。
裸露的和MIBG包被的纳米复合材料的摄取适度地使神经母细胞瘤细胞对电离辐射敏感。相反，暴露于DOPAC包被的纳米复合材料的细胞对辐射的敏感性提高了五倍，辐射诱导的DNA双链断裂数量增加，且出现凋亡性细胞死亡。向MIBG包被的纳米缀合物中添加表皮生长因子（EGF）的肽模拟物改变了它们在细胞内的分布。用这些纳米缀合物处理的冷冻水合细胞进行的低温X射线荧光显微镜断层扫描显示纳米结构在细胞质以及细胞核中均有分布。
本研究中使用的不同纳米缀合物的细胞内分布模式因纳米缀合物表面分子不同而有所差异。暴露于DOPAC包被的纳米缀合物的细胞显示出最小的纳米缀合物摄取量，细胞内大聚集体的模式最为突出。有趣的是，用这种纳米缀合物处理的细胞在与外照射X射线联合使用时也显示出最明显的放射增敏效果。有必要进行进一步研究以评估这种增强的放射增敏效果的机制基础。对携带EGF模拟肽的纳米颗粒的初步研究表明，这种靶向方法可能与另一种放射增敏方法——纳米缀合物与放射性碘联合使用相结合。为了评估携带放射性核素的靶向纳米缀合物的潜在益处，还需要进行大量额外的工作。
在线版本包含可在10.1186/s12645-021-00081-z获取的补充材料。
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