Engineered etoposide-prednisolone co-nanocrystals for synergistic antitumor efficacy enhancement.

The present work involves the development of new organic crystalline nanomedicines, namely, co-nanocrystals (co-NCs), that combine a chemotherapeutic agent with an anti-inflammatory active pharmaceutical ingredient (API), both in their nanocrystalline forms. These mixed systems were formulated to improve their anticancer efficiency. For this purpose, formulations composed of etoposide (ETO) and prednisolone (PRD) NCs were prepared. The co-formulations were optimized with the stabilizing agent poloxamer P407. The average size obtained was 191.9 ± 6.5 nm with a polydispersity index of 0.28 ± 0.09 and a zeta potential of -5.0 ± 0.7 mV for the fresh formulations. The drug loading was determined to be at 71.9% ± 0.6% for PRD and 84.1% ± 3.9% for ETO. The obtained co-NCs presented a long-term stability of at least 70 days after storage at 4 °C. Dialysis experiments showed that both APIs were released from the co-formulations following 1st-order kinetics. In addition, the NCs exhibited stronger antitumoral activities in vitro on Lewis lung carcinoma cells compared to the free ETO formulation or the ETO mono-NCs. Moreover, the anti-angiogenic properties tested on endothelial cells using capillary tube formation and the effect against cell migration analyzed by the scratch healing assay were enhanced by the ETO/PRD NCs co-formulation. The effect of the addition of PRD to the nanocrystalline formulation was shown by the greater reduction in inflammatory cytokine IL-6 levels in vitro when endothelial cells were incubated with the co-NCs as opposed to the mono-NCs. These results open the way for the preparation of stable co-formulations and better-tolerated combined therapies.