Crystallization of supersaturated PEG-b-PLA for the production of drug-loaded polymeric micelles

In this study, we propose the “crystallization from supersaturated solution” method for producing drug-loaded polymeric micelles. This method involves the formation of solid drug-encapsulating crystals of a diblock copolymer through isothermal crystallization from a supersaturated solution of the copolymer in low molecular weight PEGs containing the drug, followed by dissolution of the crystals to obtain drug-loaded micelles. We fabricated and characterized micelles loaded with several model drugs (paclitaxel, rapamycin, and docetaxel) and their oligo(lactic acid)₈-prodrugs using PEG_4kDa-b-PLA_2.2kDa as the micelle-forming copolymer and PEGs of varying molecular weights (200, 400, and 600 Da) as solvents.

Our findings indicate that the molecular weight of the solvent PEG and the target drug loading significantly influence the physicochemical properties of the resulting micelles, including loading efficiency and particle size distribution. Micelles produced with PEG200 as the solvent exhibited the highest loading efficiency, followed by those made with PEG600 and PEG400 for all the drugs and prodrugs tested. Increasing the target drug loading enhanced both the loading efficiency and average particle size across all formulations. Furthermore, prodrug-loaded micelles showed higher loading efficiency and improved stability in aqueous solutions compared to their parent drug counterparts. Crystals encapsulating both parent drugs and prodrugs could be stored at room temperature for extended periods, producing micelles with no significant differences in loading efficiency and particle size distribution compared to freshly prepared micelles. Additionally, the crystals demonstrated a rapid dissolution rate, forming uniform micelles after just 5 s of hydration and agitation. Cytotoxicity studies against 4 T1 and MDA-MB-231 breast cancer cell lines revealed that the molecular weight of the PEG used as the solvent impacts the cytotoxicity of the resulting micelles, with those produced using PEG200 displaying the highest cytotoxicity, followed by PEG400 and PEG600.

Overall, the crystallization from supersaturated solution method proves to be an effective platform for prolonged storage and rapid formation of stable, drug-loaded polymeric micelles. It has the potential to eliminate the need for freeze-drying in the formulation and storage of drug-loaded polymeric micelles. These findings highlight the method's potential for advancing drug delivery systems, particularly for the solubilization of hydrophobic drugs using micellar formulations.