Intelligent gold nanoparticles for malignant tumor treatment via spontaneous copper manipulation and on-demand photothermal therapy based on copper induced click chemistry

The excessive copper in tumor cells is crucial for the growth and metastasis of malignant tumor. Herein, we fabricated a nanohybrid to capture, convert and utilize the overexpressed copper in tumor cells, which was expected to achieve copper dependent photothermal damage of primary tumor and copper-deficiency induced metastasis inhibition, generating accurate and effective tumor treatment. The nanohybrid consistsed of 3-azidopropylamine, 4-ethynylaniline and N-aminoethyl-N’-benzoylthiourea (BTU) co-modified gold nanoparticles (AuNPs). During therapy, the BTU segment would specifically chelate with copper in tumor cells after endocytosis to reduce the intracellular copper content, causing copper-deficiency to inhibit the vascularization and tumor migration. Meanwhile, the copper was also rapidly converted to be cuprous by BTU, which further catalyzed the click reaction between azido and alkynyl on the surface of AuNPs, resulting in on-demand aggregation of these AuNPs. This process not only in situ generated the photothermal agent in tumor cells to achieve accurate therapy avoiding unexpected damage, but also enhanced its retention time for sustained photothermal therapy. Both in vitro and in vivo results exhibited the strong tumor inhibition and high survival rate of tumor-bearing mice after application of our nanohybrid, indicating that this synergistic therapy could offer a promising approach for malignant tumor treatment. Statement of Significance: The distinctive excessive copper in tumor cells is crucial for the growth and metastasis of tumor. Therefore, we fabricated intelligent gold nanoparticles to simultaneously response and reverse this tumorigenic physiological microenvironment for the synergistic therapy of malignant tumor. In this study, for the first time we converted and utilized the overexpressed Cu²⁺ in tumor cells to trigger intracellular click chemistry for tumor-specific photothermal therapy, resulting in accurate damage of primary tumor. Moreover, we effectively manipulated the content of Cu²⁺ in tumor cells to suppress the migration and vascularization of malignant tumor, resulting in effective metastasis inhibition.