Atomically-precise Au22(Lys-Cys-Lys)16 nanoclusters for radiation sensitization

Elham Zeinizade; Goonay Yousefalizideh; Parimah Aminfar; Matthew Horn; Lili Ding; Layla Pires; Alina Jaglanian; Lucie Malbeteau; Kristen Harrington; Carla Calçada; Mohamad Dukuray; Brian C Wilson; Marianne Koritzinsky; Juan Chen; Kevin G Stamplecoskie; Gang Zheng

doi:10.1186/s12951-025-03256-7

Atomically-precise Au₂₂(Lys-Cys-Lys)₁₆ nanoclusters for radiation sensitization

J Nanobiotechnology. 2025 Mar 7;23(1):185. doi: 10.1186/s12951-025-03256-7.

Authors

Elham Zeinizade^{1

2}, Goonay Yousefalizideh³, Parimah Aminfar³, Matthew Horn¹, Lili Ding¹, Layla Pires¹, Alina Jaglanian¹, Lucie Malbeteau¹, Kristen Harrington³, Carla Calçada¹, Mohamad Dukuray¹, Brian C Wilson^{1

2}, Marianne Koritzinsky^{1

2

4

5}, Juan Chen⁶, Kevin G Stamplecoskie⁷, Gang Zheng^{8

9

10}

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
² Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
³ Department of Chemistry, Queen's University, Kingston, ON, K7L 3N6, Canada.
⁴ Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
⁵ Institute of Medical Science, University of Toronto, Toronto, ON, M5G 1L7, Canada.
⁶ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. juan.chen@uhn.ca.
⁷ Department of Chemistry, Queen's University, Kingston, ON, K7L 3N6, Canada. kevin.stamplecoskie@queensu.ca.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. gang.zheng@uhn.ca.
⁹ Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada. gang.zheng@uhn.ca.
¹⁰ Institute of Medical Science, University of Toronto, Toronto, ON, M5G 1L7, Canada. gang.zheng@uhn.ca.

Abstract

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, Au₂₂(Lys-Cys-Lys)₁₆, 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 Au₂₂(Lys-Cys-Lys)₁₆ 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, t₁_/₂ = 10.4 h) and renal clearance. In a KB tumor-bearing mouse model, Au₂₂(Lys-Cys-Lys)₁₆ significantly delayed tumor progression and prolonged survival under 8 Gy irradiation without observed side-effects. These findings establish Au₂₂(Lys-Cys-Lys)₁₆ nanoclusters as a potentially translatable radiosensitizer, advancing cancer radiotherapy strategies.

Keywords: Atomically precise; Biocompatibility; Cancer radiation therapy; Gold nanoclusters; Radiosensitizer; Renal clearance; Ultra small size.

MeSH terms

Animals
Cell Line, Tumor
DNA Damage / drug effects
Female
Gold* / chemistry
Gold* / pharmacology
Humans
Metal Nanoparticles* / chemistry
Mice
Mice, Inbred BALB C
Radiation-Sensitizing Agents* / chemistry
Radiation-Sensitizing Agents* / pharmacokinetics
Radiation-Sensitizing Agents* / pharmacology
Tissue Distribution

Substances

Radiation-Sensitizing Agents
Gold

Grants and funding

NFRFT-2020-00573/New Frontiers in Research Program