Copper(II)-Complexed Polyethylenimine-Entrapped Gold Nanoparticles Enable Targeted CT/MR Imaging and Chemodynamic Therapy of Tumors

Transition-metal ion copper(II) (Cu(II)) has drawn increasing attention as a small-molecular cancer theranostic agent. However, delivering a sufficient dosage of Cu(II) to the tumor site and integrating multiple imaging modalities to achieve precise and effective cancer theranostics remains a critical challenge. Herein, an emerging Cu(II)-based nanocomposite has been synthesized for targeted tumor computed tomography (CT)/magnetic resonance (MR) dual-mode imaging and chemodynamic therapy (CDT). Briefly, 2-picolinic acid (PA-COOH), polyethylene glycol (PEG)-linked folic acid (FA), and fluorescein isothiocyanate (FI) were sequentially conjugated with polyethylenimine (PEI.NH₂) and then in situ fabrication of gold nanoparticles (Au NPs) occurred within the PEI.NH₂ internal cavity. After acetylation of PEI.NH₂ terminal amines and Cu(II) complexation, the Cu(II)-based nanocomposites FA-Au/Cu(II) PENPs with a mean diameter of 2.87 nm were generated. The synthesized FA-Au/Cu(II) PENPs showed favorable stability of colloidal dispersion, sustainable Cu(II) release properties in a pH-dependent manner, and Fenton-like catalytic activity specifically. With the FA-mediated targeting pathway, FA-Au/Cu(II) PENPs can specifically accumulate in cancer cells with high expression of FA receptors. Meanwhile, the complementary CT/MR dual-mode imaging in vitro and in vivo can be afforded by FA-Au/Cu(II) PENPs based on the excellent X-ray attenuation properties of Au NPs and the applicable r₁ relaxivity (0.7378 mM^-1s^-1) of Cu(II). Notably, the Cu(II)-mediated CDT mechanism enables FA-Au/Cu(II) PENPs to elicit the generation of toxic hydroxyl radicals (·OH), depletion of glutathione (GSH), promotion of lipid peroxidation (LPO), and induction of cancer cell apoptosis in vitro, and further demonstrates remarkable anti-tumor efficacy in a xenograft tumor model. With the illustrated targeted theranostic capacity of FA-Au/Cu(II) PENPs towards tumors, this Cu(II)-based nanocomposite paradigm inspires the construction of advanced theranostic nanoplatforms incorporating alternative transition metal ions.