Tuning the Surface Chemistry of Second-Harmonic-Active Lithium Niobate Nanoprobes Using a Silanol–Alcohol Condensation Reaction

The surface functionalization of nanoparticles (NPs) is of a great interest for improving the use of NPs in, for example, therapeutic and diagnostic applications. The conjugation of specific molecules with NPs through the formation of covalent linkages is often sought to provide a high degree of colloidal stability and biocompatibility, as well as to provide functional groups for further bioconjugation. Nanoparticles of lithium niobate (LiNbO3) have been explored for use in second harmonic generation (SHG) based bioimaging, expanding the applications of SHG based microscopy techniques. The efficient use of SHG active LiNbO3 NPs as probes will, however, require the functionalization of their surfaces with molecular reagents such as polyethylene glycol and fluorescent molecules to enhance their colloidal and chemical stability, and to enable a correlative imaging platform. Herein, we demonstrate the surface functionalization of LiNbO3 NPs through the covalent attachment of alcohol-based reagents through a silanol-alcohol condensation reaction. Alcohol-based reagents are widely available and can have a range of terminal functional groups such as carboxylic acids, amines, and aldehydes. Attaching these molecules to NPs through the silanol-alcohol condensation reaction could diversify the reagents available to modify NPs, but this reaction pathway must first be established as a viable route to modifying NPs. This study focuses on the attachment of a linear alcohol functionalized with carboxylic acid and its use as a reactive group to further tune the surface chemistry of LiNbO3 NPs. These carboxylic acid groups were reacted to covalently attach other molecules to the NPs using copper-free click chemistry. This derivatization of the NPs provided a means to covalently attach polyethylene glycols and fluorescent probes to the NPs, reducing NP aggregation and enabling multimodal tracking of SHG nanoprobes, respectively. This extension of the silanol-alcohol condensation reaction to functionalizing the surfaces of LiNbO3 NPs can be extended to other types of nanoprobes for use in bioimaging, biosensing, and photodynamic therapies.