Gharibkandi Nasrin Abbasi, Wawrowicz Kamil, Walczak Rafał, Majkowska-Pilip Agnieszka, Wierzbicki Mateusz, Bilewicz Aleksander
Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Dorodna 16 St, Warsaw, 03-195, Poland.
Department of Medical Physics, M. Smoluchowski Institute of Physics, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Kraków, Poland.
EJNMMI Radiopharm Chem. 2024 Aug 13;9(1):59. doi: 10.1186/s41181-024-00293-9.
Convenient therapeutic protocols for hepatocellular carcinoma (HCC) are often ineffective due to late diagnosis and high tumor heterogeneity, leading to poor long-term outcomes. However, recently performed studies suggest that using nanostructures in liver cancer treatment may improve therapeutic effects. Inorganic nanoparticles represent a unique material that tend to accumulate in the liver when introduced in-vivo. Typically, this is a major drawback that prevents the therapeutic use of nanoparticles in medicine. However, in HCC tumours, this may be advantageous because nanoparticles may accumulate in the target organ, where the leaky vasculature of HCC causes their accumulation in tumour cells via the EPR effect. On the other hand, recent studies have shown that combining low- and high-LET radiation emitted from the same radionuclide, such as Tb, can increase the effectiveness of radionuclide therapy. Therefore, to improve the efficacy of radionuclide therapy for hepatocellular carcinoma, we suggest utilizing radioactive palladium nanoparticles in the form of Pd/Ag in-vivo generator that simultaneously emits β particles and Auger electrons.
Palladium nanoparticles with a size of 5 nm were synthesized using Pd produced through neutron irradiation of natural palladium or enriched Pd. Unlike the Pd-cyclam complex, where the daughter radionuclide diffuses away from the molecules, Ag remains within the nanoparticles after the decay of Pd. In vitro cell studies using radioactive Pd nanoparticles revealed that the nanoparticles accumulated inside cells, reaching around 50% total uptake. The Pd-PEG nanoparticles exhibited high cytotoxicity, even at low levels of radioactivity (6.25 MBq/mL), resulting in almost complete cell death at 25 MBq/mL. This cytotoxic effect was significantly greater than that of PdNPs labeled with β (I) and Auger electron emitters (I). The metabolic viability of HCC cells was found to be correlated with cell DNA DSBs. Also, successful radioconjugate anticancer activity was observed in three-dimensional tumor spheroids, resulting in a significant treatment response.
The results indicate that nanoparticles labeled with Pd can be effectively used for combined β - Auger electron-targeted radionuclide therapy of HCC. Due to the decay of both components (β and Auger electrons), the Pd/Ag in-vivo generator presents a unique potential in this field.
由于肝癌（HCC）诊断较晚且肿瘤异质性高，便捷的治疗方案往往效果不佳，导致长期预后不良。然而，最近的研究表明，在肝癌治疗中使用纳米结构可能会提高治疗效果。无机纳米颗粒是一种独特的材料，体内引入后往往会在肝脏中积累。通常，这是一个主要缺点，阻碍了纳米颗粒在医学上的治疗应用。然而，在肝癌肿瘤中，这可能是有利的，因为纳米颗粒可能会在靶器官中积累，肝癌的渗漏血管会通过增强渗透和滞留（EPR）效应导致它们在肿瘤细胞中积累。另一方面，最近的研究表明，将同一放射性核素（如铽）发射的低线性能量传递（LET）和高线性能量传递辐射相结合，可以提高放射性核素治疗的效果。因此，为了提高肝癌放射性核素治疗的疗效，我们建议使用Pd/Ag体内发生器形式的放射性钯纳米颗粒，其同时发射β粒子和俄歇电子。
使用通过天然钯或富集钯的中子辐照产生的钯合成了尺寸为5纳米的钯纳米颗粒。与子放射性核素从分子中扩散出去的钯-环胺配合物不同，钯衰变后银仍保留在纳米颗粒内。使用放射性钯纳米颗粒的体外细胞研究表明，纳米颗粒在细胞内积累，达到总摄取量的50%左右。即使在低放射性水平（6.25 MBq/mL）下，钯-聚乙二醇纳米颗粒也表现出高细胞毒性，在25 MBq/mL时导致几乎完全的细胞死亡。这种细胞毒性作用明显大于用β（I）和俄歇电子发射体（I）标记的钯纳米颗粒。发现肝癌细胞的代谢活力与细胞DNA双链断裂（DSB）相关。此外，在三维肿瘤球体中观察到了成功的放射性缀合物抗癌活性，产生了显著的治疗反应。
结果表明，用钯标记的纳米颗粒可有效地用于肝癌的β-俄歇电子靶向联合放射性核素治疗。由于两种成分（β和俄歇电子）的衰变，Pd/Ag体内发生器在该领域具有独特的潜力。
