Click-Functionalized SERS Nanoprobes with Improved Labeling Efficiency and Capability for Cancer Cell Imaging

Precise identification and detection of cancer cells using nanoparticle probes are critically important for early cancer diagnosis and subsequent therapy. We herein develop novel folate receptor (FR)-targeted surface-enhanced Raman scattering (SERS) nanoprobes for cancer cell imaging based on a click coupling strategy. A Raman-active derivative (5,5'-dithiobis(2-nitrobenzoic acid)-N₃ (DNBA-N₃)) is designed with a disulfide bond for covalently anchoring to the surface of hollow gold nanoparticles (HAuNPs) and a terminal azide group for facilitating highly efficient conjugation with the bioligand. Modification of HAuNPs with DNBA-N₃ yields monolayer coverage of Raman labels absorbed on the nanoparticle surface (HAuNP-DNBA-N₃) and strong SERS signals. HAuNP-DNBA-N₃ can be simply and effectively conjugated with folate bicyclo[6.1.0]nonyne derivatives via a copper-free click reaction. The synthesized nanoprobes (HAuNP-DNBA-folic acid (FA)) exhibit excellent targeted capacities to FR-positive cancer cells relative to FR-negative cells through SERS mappings. The receptor-mediated delivery behaviors are confirmed by comparison with the uptake of HAuNP-DNBA-N₃ and free FA competition experiments. In addition to its good stability and benign biocompatibility, the developed SERS nanoprobes have great potential for applications in targeted tumor imaging.