Turning On/Off the Anti-Tumor Effect of the Au Cluster via Atomically Controlling Its Molecular Size

Abstract

We reported two Au clusters with precisely controlled molecular size (Au₅Peptide₃ and Au₂₂Peptide₁₀) showing different antitumor effects. In vitro, both Au₅Peptide₃ and Au₂₂Peptide₁₀ were well taken up by human nasopharyngeal cancer cells (CNE1 cells). However, only Au₅Peptide₃ significantly induced CNE1 cell apoptosis. Further studies showed that CNE1 cells took up Au₅Peptide₃ (1.98 × 10^-15 mol/cell), and 9% of them entered mitochondria (0.186 × 10^-15 mol/cell). As a comparison, the uptake of Au₂₂Peptide₁₀ was only half the amount of Au₅Peptide₃ (1.11 × 10^-15 mol/cell), and only 1% of them entered mitochondria (0.016 × 10^-15 mol/cell). That gave 11.6-fold more Au₅Peptide₃ in mitochondria of CNE1 cells than Au₂₂Peptide₁₀. Further cell studies revealed that the antitumor effect may be due to the enrichment of Au₅Peptide₃ in mitochondria. Au₅Peptide₃ slightly decreased the Mcl-1 (antiapoptotic protein of mitochondria) and significantly increased the Puma (pro-apoptotic protein of mitochondria) expression level in CNE1 cells, which resulted in mitochondrial transmembrane potential change and triggered the caspase 9-caspase 3-PARP pathway to induce CNE1 cell apoptosis. In vivo, CNE1 tumor growth was significantly suppressed by Au₅Peptide₃ in the xenograft model after 3 weeks of intraperitoneal injection. The TUNEL and immuno-histochemical studies of tumor tissue verified that CNE1 cell apoptosis was mainly via the Puma and Mcl-1 apoptosis pathway in the xenograft model, which matched the aforementioned CNE1 cell studies in vitro. The discovery of Au₅ but not Au₂₂ suppressing tumor growth via the mitochondria target was a breakthrough in the nanomedical field, as this provided a robust approach to turn on/off the nanoparticles' medical properties via atomically controlling their sizes.