Preparation of copper-doped calcium phosphate nanoclusters to enhance copper-mediated catalytic activity

Abstract

Calcium phosphate (CaP), a critical bone mineral in mammals, exhibits promising potential for application in biomedicine. In this study, we report a biomimetic mineralization strategy, based on a stoichiometric polyacrylic acid (PAA) complexation–precipitation method, to prepare copper-doped calcium phosphate nanoclusters (Cu–CaP NCs). This systematic investigation focuses on the effect of nanocluster structure on copper-mediated catalytic activity. A series of Cu–CaP NCs (5%, 10%, 15%, 20%, and 25%) were successfully synthesized, demonstrating good mono-dispersity and a particle size of <10 nm. Molecular dynamics (MD) simulations were performed to elucidate the mechanism by which the nanoclusters are formed. Cu²⁺ ions (∼10 ns) exhibited faster complexation with PAA than Ca²⁺ ions whereas the Cu²⁺–PAA interaction featured characteristic intramolecular five-membered chelate rings via quadruple coordination; in contrast, Ca²⁺ tended to engage in nonspecific ionic crosslinking. The presence of HPO₄²⁻ ions further promoted the assembly of stable nanoclusters. PAA also played a role in the ligand-mediated spontaneous reduction of Cu(II) to Cu(I) within the nanocluster structure; accordingly, Cu-catalyzed Fenton-like reactivity was markedly enhanced. In addition, Cu–CaP NCs exhibited higher levels of responsiveness to glutathione (GSH). Hemolysis and cytotoxicity assays indicated a good biosafety profile for these novel NCs. More importantly, the growth of tumor cells (4T1, MG63, and Hep G2) was suppressed by Cu–CaP NCs in a dose-dependent manner. In summary, PAA-based Cu–CaP NCs represent an easily synthesized and low-toxicity therapeutic agent that utilizes Fenton-like reactivity for antitumor efficacy, thus providing a promising novel strategy for tumor treatment.