Ambient Aqueous Synthesis of Ultrasmall Ni_0.85Se Nanoparticles for Noninvasive Photoacoustic Imaging and Combined Photothermal-Chemotherapy of Cancer

Large-size-induced long-term retention in the body has hampered the translational applications of many reported nanomedicines. Herein, we reported a multifunctional theranostic agent composed of ultrasmall poly(acrylic acid)-functionalized Ni 0.85 Se nanoparticles (PAA–Ni 0.85 Se NPs), which were successfully obtained through a facile ambient aqueous precipitation strategy. Without exhibiting any noticeable toxicity, the as-prepared PAA–Ni 0.85 Se NPs (average diameter of 6.40 ± 1.89 nm) showed considerable absorption in near-infrared (NIR) region and high photothermal conversion efficiency of 54.06%, which could induce remarkable photoacoustic signals for tumor imaging and heat for localized ablation of cancerous cells upon exposure to NIR light. Notably, the ultrasmall PAA–Ni 0.85 Se NPs, unlike conventional nanomaterials with larger sizes, showed reasonable body clearance within 8 h after intravenous injection. Furthermore, ascribed to protonation process of amino groups in DOX molecules and carboxyl groups in PAA molecules in an acidic microenvironment, the drug-loaded (doxorubicin hydrochloride, DOX·HCl) PAA–Ni 0.85 Se NPs (PAA–Ni 0.85 Se–DOX NPs) revealed promoted drug release at acidic pH, which could be useful for acidic tumor microenvironment responsive drug delivery. Evident from the results of cell-killing assay in vitro and tumor treatment study in vivo, PAA–Ni 0.85 Se–DOX NPs exhibited evident synergistic effects on killing 4T1 breast cancer cells. Thus, this study presents a multifunctional theranostic agent composed of ultrasmall PAA–Ni 0.85 Se NPs for potential cancer treatment without long-term toxicity concerns.