Zeinizade Elham, Yousefalizideh Goonay, Aminfar Parimah, Horn Matthew, Ding Lili, Pires Layla, Jaglanian Alina, Malbeteau Lucie, Harrington Kristen, Calçada Carla, Dukuray Mohamad, Wilson Brian C, Koritzinsky Marianne, Chen Juan, Stamplecoskie Kevin G, Zheng Gang
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
J Nanobiotechnology. 2025 Mar 7;23(1):185. doi: 10.1186/s12951-025-03256-7.
Radiotherapy is a leading method for cancer treatment, effectively eliminating cancer cells but often causing collateral damage to surrounding healthy tissue. Radiosensitizers aim to enhance the therapeutic effects of radiotherapy while minimizing harm to normal cells. We recently reported atomically-precise gold nanoclusters, Au(Lys-Cys-Lys), synthesized via a photochemical method coupled with a novel accelerated size-focusing procedure. These nanoclusters exhibit a distinct luminescence emission profile, reflecting exceptional optical purity and the absence of contamination from other nanocluster species. They demonstrate efficient oxygen radicals generation under light irradiation. In this study, we comprehensively evaluated the radiosensitization potential of Au(Lys-Cys-Lys) nanoclusters in vitro and in vivo, alongside their pharmacokinetics, biodistribution and toxicity. The nanoclusters demonstrated high stability under physiological conditions and efficient internalization in tumor cells, achieving dose enhancement factors of 2.0 and 1.6 in KB and 4T1 tumor cells, respectively, under 225 kVp X-ray irradiation. Mechanistic investigations revealed enhanced radiation-induced DNA damage and disruption of DNA repair pathways. The radiosensitizing effects were further validated in radioresistant pancreatic ductal adenocarcinoma cells using the clonogenic assay and γH2AX analysis of double-strand breaks, as well as in a duck chorioallantoic membrane model. With ultra small size (~ 1.7 nm) and favorable surface framework, the nanoclusters exhibited relevant pharmacokinetics (circulation half-life, t₁₂ = 10.4 h) and renal clearance. In a KB tumor-bearing mouse model, Au(Lys-Cys-Lys) significantly delayed tumor progression and prolonged survival under 8 Gy irradiation without observed side-effects. These findings establish Au(Lys-Cys-Lys) nanoclusters as a potentially translatable radiosensitizer, advancing cancer radiotherapy strategies.
放射治疗是癌症治疗的主要方法，能有效消除癌细胞，但常常会对周围健康组织造成附带损害。放射增敏剂旨在增强放射治疗的效果，同时将对正常细胞的损害降至最低。我们最近报道了通过光化学方法结合一种新型加速尺寸聚焦程序合成的原子精确金纳米团簇Au(Lys-Cys-Lys)。这些纳米团簇呈现出独特的发光发射谱，反映出卓越的光学纯度以及不存在其他纳米团簇物种的污染。它们在光照下能高效产生活性氧。在本研究中，我们全面评估了Au(Lys-Cys-Lys)纳米团簇在体外和体内的放射增敏潜力，以及它们的药代动力学、生物分布和毒性。这些纳米团簇在生理条件下表现出高稳定性，并能在肿瘤细胞中有效内化，在225 kVp X射线照射下，在KB和4T1肿瘤细胞中分别实现了2.0和1.6的剂量增强因子。机制研究揭示了辐射诱导的DNA损伤增强以及DNA修复途径的破坏。使用克隆形成试验和双链断裂的γH2AX分析，以及在鸭胚绒毛尿囊膜模型中，对耐辐射的胰腺导管腺癌细胞进一步验证了放射增敏作用。由于尺寸超小（约1.7纳米）且表面结构良好，这些纳米团簇呈现出相关的药代动力学（循环半衰期，t₁₂ = 10.4小时）和经肾清除。在携带KB肿瘤的小鼠模型中，Au(Lys-Cys-Lys)在8 Gy照射下显著延缓了肿瘤进展并延长了生存期，且未观察到副作用。这些发现确立了Au(Lys-Cys-Lys)纳米团簇作为一种潜在可转化的放射增敏剂，推动了癌症放射治疗策略的发展。
