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

Area of Science:

• Radiochemistry and Nanomedicine
• Development of novel radiopharmaceuticals
• Targeted alpha-therapy (TAT) applications

Background:

• Radium-223 (²²³Ra) is an alpha-emitter limited to bone metastases due to challenges in stable chelation.
• Existing chelating agents struggle with ²²³Ra's recoil energy and decay daughters.
• Ultrasmall gold nanoclusters (AuNCs) offer favorable pharmacokinetics for drug delivery.

Purpose of the Study:

• To engineer AuNCs capable of stably encapsulating ²²³Ra and its decay products.
• To develop a targeted delivery system for ²²³Ra-based TAT.
• To evaluate the therapeutic efficacy and potential for immunotherapy synergy of the developed radiopharmaceutical.

Main Methods:

• Density functional theory (DFT) simulations to predict ²²³Ra encapsulation in AuNCs.
• Engineering of α_vβ₃-targeted AuNCs co-labeled with ⁶⁸Ga and ²²³Ra (⁶⁸Ga/²²³Ra@AuNCs-RGD).
• Molecular docking, in vitro/in vivo studies, PBPK, and Monte-Carlo simulations for targeting and efficacy assessment.

Main Results:

• AuNCs, particularly Au₁₀, demonstrated favorable energy dynamics for encapsulating ²²³Ra and daughters.
• ⁶⁸Ga/²²³Ra@AuNCs-RGD exhibited tumor-specific targeting and prolonged circulation (t_1/2β = 139.4 min).
• The platform achieved complete tumor regression and stimulated antitumor immunity.

Conclusions:

• AuNCs provide a stable platform for ²²³Ra encapsulation, overcoming previous limitations.
• The ⁶⁸Ga/²²³Ra@AuNCs-RGD system shows significant potential for clinical translation in targeted alpha-therapy.
• This approach opens avenues for synergistic TAT-immunotherapy strategies.