Ultrasmall Au_10–12 Nanoclusters: A Novel Platform for ²²³Ra-Targeted Tumor α-Therapy

Abstract

²²³Ra, a potent α-emitting radionuclide, is currently limited to treating bone metastases in clinical practice. This constraint stems from the lack of stable chelating agents capable of withstanding its high recoil energy and the five decay daughters produced during decay, hindering its application in targeted α-therapy (TAT). Ultrasmall gold nanoclusters (AuNCs) exhibit favorable pharmacokinetics, featuring tunable blood half-life, renal clearance, and low hepatic/splenic sequestration. Given gold's high atomic number and structural flexibility, we hypothesized that AuNCs could encapsulate ²²³Ra and its decay progeny, serving as an effective carrier for tumor TAT. Density functional theory simulations revealed that Au_10–12 nanoclusters, particularly a catenane-structured Au₁₀, could incorporate ²²³Ra and its daughters with favorable energy dynamics. We then engineered α_vβ₃-targeted AuNCs co-labeled with ²²³Ra and ⁶⁸Ga (⁶⁸Ga/²²³Ra@AuNCs-RGD). Molecular docking confirmed receptor specificity, while in vitro and in vivo studies demonstrated tumor-specific targeting. PBPK modeling and Monte–Carlo simulations showed prolonged circulation (t_1/2β = 139.4 min), renal clearance, sustained tumor retention, and efficient tumor energy deposition. The ⁶⁸Ga/²²³Ra@AuNCs-RGD platform achieved complete tumor regression and stimulated antitumor immunity, suggesting potential for TAT–immunotherapy synergy. This study establishes a theoretical foundation for stably doping ²²³Ra into gold clusters and provides a framework for developing novel ²²³Ra-based α-radiopharmaceuticals with significant clinical translation potential.

Keywords

²²³Ra labeling / DFT simulation / gold nanoclusters / PET imaging / targeted alpha therapy

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