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

Abstract

Previous studies have shown that calcium tungstate (CaWO 4 ) nanoparticles (NPs) can be used as a radiosensitizing/Xray 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.

Synthesis of weakly-agglomerated luminescent CaWO4:Nd3+ particles by modified Pechini method

“…All luminescence decay curves of CaWO4:Nd 3+ measured for intense 4 F3/2 -4 I11/2 transition (1066 nm) displayed mono-exponential behavior. 4 F3/2 lifetime monotonically decreased along with an increase of calcination temperature Т2 (from 139 to 110 s) and calcination duration in the salt melt (from 96 to 86 s). Based on the obtained results, the optimal conditions of synthesis of CaWO4:Nd 3+ crystalline particles in salt melt were determined to be Т1= 600 о С; t1=2 hours (the stage of polymer gel thermal treatment), Т2= 800 о С; t2=1 hour (the stage of thermal treatment in salt melt, KCl).…”

“…One of the most promising luminophores doped with rare earth ions (REI) are metal oxides because of their thermal stability over a wide temperature range, chemical inertness, stability of optical and mechanical properties, and biocompatibility. The combination of these properties makes these materials interesting for use in instrumentation, display, sensor technology, and, of course, medical applications [1][2][3][4]. Functional properties and small particle size of the oxide luminophores are the most important parameters for the field of biomedicine (luminescent sensors, nanothermometers, etc.).…”

Radiation-induced photodynamic therapy using calcium tungstate nanoparticles and 5-aminolevulinic acid prodrug

“…The PEG–PLA block copolymer used in this study was synthesized using ring-opening polymerization of racemic lactide with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the catalyst and monomethoxy-terminated PEG as the macroinitiator. 18 4.47 g of monomethoxy, monohydroxy-terminated PEG ( M n = 2000 Da, Sigma-Aldrich) and 4.47 g of racemic lactide (Sigma-Aldrich) were melted together in a round bottom flask at 60 °C. A strong vacuum was applied till no bubble formation could be observed (approximately for 30 minutes), after which the flask was purged with nitrogen and cooled to room temperature.…”