Disulfiram-loaded mixed nanoparticles with high drug-loading and plasma stability by reducing the core crystallinity...

To develop an injectable formulation and improve the stability of disulfiram (DSF), DSF was encapsulated into mixed nanoparticles (DSF-NPs) through a high-pressure homogenization method. The Flory-Huggins interaction parameters (χ_FH) were calculated to predict the miscibility between DSF and the hydrophobic core, resulting in PCL₅₀₀₀ selected as the hydrophobic block to encapsulate the DSF, as PCL₅₀₀₀ had a lower χ_FH 3.39 and the drug loading of the nanoparticles prepared by mPEG₅₀₀₀-PCL₅₀₀₀ was relatively higher. mPEG₅₀₀₀-PCL₅₀₀₀ and PCL₅₀₀₀ were blended to reduce the leakage of DSF during preparation, as well as increase the stability of the nanoparticles. The cargo-loading capacity of the nanoparticles was improved from 3.35% to 5.50% by reducing the crystallinity of the PCL nanoparticle core, and the crystallinity decreased from 51.13% to 25.15% after adding medium chain triglyceride (MCT). The DSF-NPs prepared by the above method had a small particle size of 98.1 ± 10.54 nm, with a polydispersity index (PDI) of 0.036, as well as drug loading of 5.50%. Furthermore, DSF-NPs containing MCT showed higher stability than DSF-NPs without MCT and DSF-sol (DSF dissolved in Cremophor EL and ethanol) in water and 90% plasma-containing PBS. The pharmacokinetics proved that DSF-NPs containing MCT enhanced the DSF concentration in the blood. Finally, DSF-NPs effectively inhibited H22 xenograft tumor growth in vivo.