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

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 (χFH) 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 χFH 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 ±â€¯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.

Stable loading and delivery of disulfiram with mPEG-PLGA/PCL mixed nanoparticles for tumor therapy.

Disulfiram (DSF) showed great potential in an in vitro tumor therapy study; however, those results could not be applied to an in vivo study due to the extreme instability of DSF in blood. Here, we describe a system of methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide)/poly(ε-caprolactone) (mPEG-PLGA/PCL) mixed nanoparticles (NPs) for DSF loading and delivery. By adjusting the mPEG-PLGA/PCL content ratios, the DSF loading capacity increased to 7.8%, while the hydrodynamic radii of the NPs were around 50-100nm. The DSF-loaded NPs showed high stability in distilled water and 10% serum-containing phosphate buffered saline. The NPs efficiently protected DSF from degradation while maintaining its anti-tumor properties. Furthermore, a pharmacokinetics study demonstrated that NP delivery system enhanced the DSF concentration in the blood after tail vein injection. Finally, DSF delivery using this model effectively slowed the growth of a 4T1 murine xenograft tumor. FROM THE CLINICAL EDITOR: The anti-tumor efficacy of the anti-alcoholic drug disulfiram has been known for some time. However, its use in the clinical setting is limited due to the underlying instability of the drug. In this study, the authors utilized a nanocarrier system of mPEG-PLGA/PCL for the delivery of this drug. The promising results may allow encapsulation of other drugs.