OPTIMIZED SYNTHESIS AND PURIFICATION STEPS FOR ULTRASMALL FLUORESCENT CORE-SHELL SILICA NANOPARTICLES WITH APPLICATIONS IN NANOMEDICINE
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Ultrasmall PEGylated core-shell silica nanoparticles (C′ dots) are promising platforms for molecular imaging and therapeutic delivery due to their sub-10 nm size, renal clearance, and robust dye encapsulation. However, scaling up their synthesis without compromising narrow size distribution, structural integrity, or purification efficiency remains a significant challenge. In this study, we developed an optimized, scalable synthesis workflow by increasing precursor concentration fivefold while elevating the reaction pH to counteract increased silicic acid formation and maintain controlled condensation kinetics. Standard bioanalytic techniques were used to characterize the C’dot variants. Fluorescence correlation spectroscopy (FCS) was used to monitor C’dot hydrodynamic diameters across variants, guiding early PEGylation at 15 min, 1 h, and 2 h intervals to tune particle size and growth arrest. Tangential flow filtration (TFF) was implemented for purification, replacing time-intensive spin filtration and enabling high-throughput removal of unencapsulated dye. The resulting particles were characterized by GPC and HPLC, confirming the formation of dominant 7-cluster silica core structures across all modifications introduced in the workflow. Across synthesis variants, particles exhibited narrow size distributions and high dye encapsulation uniformity. This modular workflow integrates synthesis, process control, and purification strategies to enable reproducible, scalable production of high-purity C′ dots, addressing a critical bottleneck in their clinical and translational advancement.