Control of Ultrasmall Sub-10 nm Ligand-Functionalized Fluorescent Core-Shell Silica Nanoparticle Growth in Water

Ultrasmall fluorescent silica nanoparticles (SNPs) and core-shell SNPs surface functionalized with polyethylene glycol (PEG), specific surface ligands, and overall SNP size in the regime below 10 nm are of rapidly increasing interest for clinical applications, because of their favorable biodistribution and safety profiles. Here, we present an aqueous synthesis methodology for the preparation of narrowly size-dispersed SNPs and core-shell SNPs with size control below 1 nm, i.e., at the level of a single atomic layer. Different types of fluorophores, including near-infrared (NIR) emitters, can be covalently encapsulated. Brightness can be enhanced via addition of extra silica shells. This methodology further enables synthesis of <10 nm sized fluorescent core and core-shell SNPs with previously unknown compositions. In particular, the addition of an aluminum sol gel precursor leads to fluorescent aluminosilicate nanopartides (ASNPs) and core-shell ASNPs. Encapsulation efficiency and brightness of highly negatively charged NIR fluorophores is enhanced, relative to the corresponding SNPs without aluminum. Resulting particles show quantum yields of similar to 0.8, i.e., starting to approach the theoretical brightness limit. All particles can be PEGylated providing steric stability. Finally, heterobifunctional PEGs can be employed to introduce ligands onto the PEGylated particle surface of fluorescent SNPs, core-shell SNPS, and their aluminum-containing analogues, producing ligand-functionalized <10 nm NIR fluorescent nanoprobes. In order to distinguish these water-based-synthesis-derived materials from the earlier alcohol-based modified Stober process derived fluorescent core-shell SNPs referred to as Cornell dots or C dots, the SNPs and ASNPs described here and synthesized in water will be referred to as Cornell prime dots or C' dots and AlC' dots. These organic-inorganic hybrid nanomaterials may find applications in nanomedicine, including cancer diagnostics and therapy (theranostics).