Pilot-Scale Optimization of the Solvent Exchange Production and Lyophilization Processing of PEG–PLA Block Copolymer-Encapsulated CaWO4 Radioluminescent Nanoparticles for Theranostic Applications

Previous studies have shown that calcium tungstate (CaWO4) nanoparticles (NPs) can be used as a radiosensitizing/X-ray contrast agent for cancer treatment. However, due to the propensity of calcium tungstate to agglomerate in physiological solutions, there is a need to encapsulate these NPs within poly­(ethylene glycol)-poly­(d,l-lactic acid) (PEG–PLA) polymeric micelles through a solvent exchange process. Several parameters including solvent type, polymer to NP ratio, mixing method, and lyophilization were studied to optimize the encapsulation and storage procedures for future scale-up. Herein, we report that the cosolvent that was previously used in this procedure (dimethylformamide) can be replaced with a less toxic cosolvent (acetone), the polymer to NP ratio can be reduced from 600:1 to 50:1 without increasing the particle size by 20%, and mixing methods that create a more uniform flow field produce a more homogenous and less polydisperse particle distribution. In addition, our results indicate that sucrose as a lyophilization excipient produces less agglomeration during freeze-drying compared to mannitol. The smaller molecular weight 2 kDa and 2 kDa (“2 k–2 k”) PEG–PLA was less prone to agglomeration during freeze-drying compared to 5 k–5 k PEG–PLA.