目的:实体恶性肿瘤的经典近距离放射治疗是一种侵入性方法,通常会导致剂量分布不均,同时需要在一定时间后手术去除密封的放射性种子源。为了规避这些问题,我们报道了作为新型纳米级近距离放射治疗剂的内在放射性标记和阿拉伯树胶糖蛋白功能化的[169Yb]Yb2O3纳米种子的合成,可以通过肿瘤内注射直接给药用于肿瘤治疗。
方法:169Yb(T½=32天)是通过在核反应堆中对富集的(在168Yb中为15.2%)Yb2O3靶进行中子辐照而产生的,放射化学转化为[169Yb]YbCl3并用于纳米颗粒(NP)合成。通过在阿拉伯树胶糖蛋白培养基中控制Yb3离子的水解来合成固有的放射性标记的NP。体内SPECT/CT成像,放射自显影,在肿瘤内注射放射性标记的NP后,对携带B16F10肿瘤的C57BL/6小鼠进行了生物分布研究。进行系统肿瘤消退研究和组织病理学分析以证明在相同小鼠模型中的治疗功效。
结果:纳米制剂是具有高胶体和放射化学稳定性的澄清溶液。通过SPECT/CT成像和放射自显影研究观察到放射性标记的纳米制剂在肿瘤块中的均匀分布和保留。在肿瘤消退研究中,与对照组相比,用不同剂量的放射性标记的NP显着阻止了肿瘤的生长,并且在〜27.8MBq剂量下观察到了最佳的治疗效果。在组织病理学分析中,有丝分裂细胞的损失在治疗组的肿瘤组织中是明显的,而肾脏没有明显损伤,肺,观察肝脏组织形态。
结论:这些结果有望使纳米级近距离放射治疗成为无法切除的实体癌的临床实用治疗方式。
OBJECTIVE: Classical brachytherapy of solid malignant tumors is an invasive procedure which often results in an uneven dose distribution, while requiring surgical removal of sealed radioactive seed sources after a certain period of time. To circumvent these issues, we report the synthesis of intrinsically radiolabeled and gum Arabic glycoprotein functionalized [169Yb]Yb2O3 nanoseeds as a novel nanoscale brachytherapy agent, which could directly be administered via intratumoral injection for tumor therapy.
METHODS: 169Yb (T½ = 32 days) was produced by neutron irradiation of enriched (15.2% in 168Yb) Yb2O3 target in a nuclear reactor, radiochemically converted to [169Yb]YbCl3 and used for nanoparticle (NP) synthesis. Intrinsically radiolabeled NP were synthesized by controlled hydrolysis of Yb3+ ions in gum Arabic glycoprotein medium. In vivo SPECT/CT imaging, autoradiography, and biodistribution studies were performed after intratumoral injection of radiolabeled NP in B16F10 tumor bearing C57BL/6 mice. Systematic tumor regression studies and histopathological analyses were performed to demonstrate therapeutic efficacy in the same mice model.
RESULTS: The nanoformulation was a clear solution having high colloidal and radiochemical stability. Uniform distribution and retention of the radiolabeled nanoformulation in the tumor mass were observed via SPECT/CT imaging and autoradiography studies. In a tumor regression study, tumor growth was significantly arrested with different doses of radiolabeled NP compared to the control and the best treatment effect was observed with ~ 27.8 MBq dose. In histopathological analysis, loss of mitotic cells was apparent in tumor tissue of treated groups, whereas no significant damage in kidney, lungs, and liver tissue morphology was observed.
CONCLUSIONS: These results hold promise for nanoscale brachytherapy to become a clinically practical treatment modality for unresectable solid cancers.