氧化铪增强兔原位肝癌放疗疗效并减轻肺部转移负荷

Hafnium Oxide Nanoparticles Enhancing Radiotherapy Efficacy and Reducing Pulmonary Metastatic Burden in Rabbit Orthotopic Hepatocellular Carcinoma

摘要

高原子序数纳米材料因能够在放射线照射下增强局部能量沉积、 放大辐射诱导的物理和化学损伤, 在肿瘤放疗增敏领域受到广泛关注. 为构建适用于肝癌放疗的高效增敏体系, 本研究通过水热法制备了粒径主要分布于50~100 nm且分散性良好的单斜晶相HfO₂纳米颗粒, 并在兔原位肝癌模型中系统评估了其经肝动脉介入灌注后的体内行为、 放疗增敏效果及初步安全性. TEM、 XRD与EDS表征结果表明, 所得HfO₂纳米颗粒形貌规则、纯度高且晶相稳定. ICP-MS、 CT及TEM结果显示, 经肝动脉给药后, HfO₂纳米颗粒在肿瘤组织中实现了较高的富集与一定时间的滞留, 而在心、 肺及肾等主要脏器中的蓄积较低, 仅脾脏因富含吞噬细胞而表现出一定的聚集. 与单纯放疗相比, HfO₂与放疗联合处理显著降低了肿瘤体积和重量, 并在组织学和分子水平上表现为更广泛的坏死区域、 更明显的Ki67阳性率下降以及更高水平的γ-H2AX表达和细胞内活性氧积累, 表明HfO₂纳米颗粒可放大辐射诱导的DNA损伤和氧化应激, 从而增强放疗抑瘤作用. 血清细胞因子检测结果显示, 联合治疗组炎症相关因子水平升高, 同时肺部转移负荷相对减轻, 提示联合治疗除直接放大局部辐射损伤外, 还可能伴随一定程度的系统性免疫应答. 血常规、 血生化及主要脏器病理结果未见明显急性毒性, 说明在本研究剂量和给药条件下HfO₂纳米颗粒具有较好的耐受性. 本工作从材料制备、 体内分布、 放疗增敏效应及初步安全性等方面, 为HfO₂基纳米放疗增敏剂在肝癌治疗中的进一步研究和转化应用提供了依据.

Abstract

High-atomic-number nanomaterials have garnered significant attention in the field of tumor radiosensitization due to their ability to enhance localized energy deposition and amplify radiation-induced physicochemical damage upon irradiation. To establish an efficient radiosensitization system for hepatocellular carcinoma (HCC) radiotherapy, a hydrothermal method was employed to synthesize HfO₂ nanoparticles with a primary size distribution of 50—100 nm, a monoclinic crystal phase, and excellent dispersion. The in vivo behavior, radiosensitization efficacy, and preliminary safety of the test substance were systematically evaluated in a rabbit orthotopic liver cancer model following transarterial infusion. TEM, XRD and EDS characterization indicated that the obtained HfO₂ nanoparticles exhibited regular morphology, high purity, and stable crystalline phases. The results of ICP-MS, CT, and TEM analyses demonstrated that following hepatic arterial administration, HfO₂ nanoparticles achieved high enrichment and sustained retention within tumor tissues over time. Accumulation in major organs such as the heart, lungs, and kidneys was minimal, with only the spleen, which is rich in phagocytes, demonstrating notable aggregation. The combination of HfO₂ and radiotherapy led to a substantial reduction in tumor volume and weight when compared to radiotherapy alone. Histological and molecular analyses revealed that the treatment resulted in extensive necrosis, a significant decrease in Ki-67 positivity, and elevated levels of γ-H2AX expression and intracellular reactive oxygen species accumulation. This finding suggests that HfO₂ nanoparticles augment radiation-induced DNA damage and oxidative stress, thereby potentiating the antitumor effects of radiotherapy. Serum cytokine analysis revealed elevated levels of inflammation-related factors in the combination therapy group, accompanied by a relative reduction in lung metastasis burden. This finding indicates that, in addition to directly amplifying local radiation-induced damage, the combination therapy may elicit a systemic immune response. No significant acute toxicity was observed in hematological assessments, biochemical parameters, or major organ pathology, indicating good tolerability of HfO₂ nanoparticles under the study dosage and administration conditions. This work provides experimental evidence covering material preparation, in vivo distribution, radiosensitization effects, and preliminary safety for the further development and translational application of HfO₂-based nanoradiosensitizers in hepatocellular carcinoma treatment.

关键词

氧化铪纳米颗粒 / 放疗增敏 / 原位肝细胞肝癌 / 肝动脉介入灌注 / 肿瘤转移负荷

Key words

Hafnium dioxide nanoparticle / Radiosensitization / Orthotopic hepatocellular carcinoma / Transarterial hepatic infusion / Tumor metastasis burden

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基金资助

国家自然科学基金(82171988)

山西白求恩医院科研项目(2023RC24)