Augmented efficacy of nano-formulated docetaxel plus curcumin in orthotopic models of neuroblastoma
Martina Di Francesco, Fabio Pastorino, Miguel Ferreira, Agnese Fragassi, Valentina Di Francesco, Anna Lisa Palange, Christian Celia, Luisa Di Marzio, Michele Cilli, Veronica Bensa, Mirco Ponzoni, Paolo Decuzzi
Abstract
Neuroblastoma is a biologically heterogeneous extracranial tumor, derived from the sympathetic nervous system, that affects most often the pediatric population. Therapeutic strategies relying on aggressive chemotherapy, surgery, radiotherapy, and immunotherapy have a negative outcome in advanced or recurrent disease. Here, spherical polymeric nanomedicines (SPN) are engineered to co-deliver a potent combination therapy, including the cytotoxic docetaxel (DTXL) and the natural wide-spectrum anti-inflammatory curcumin (CURC). Using an oil-in-water emulsion/solvent evaporation technique, four SPN configurations were engineered depending on the therapeutic payload and characterized for their physico-chemical and pharmacological properties. All SPN configurations presented a hydrodynamic diameter of ∼ 185 nm with a narrow size distribution. A biphasic release profile was observed for all the configurations, with almost 90 % of the total drug mass released within the first 24 h. SPN cytotoxic potential was assessed on a panel of human neuroblastoma cells, returning IC 50 values in the order of 1 nM at 72 h and documenting a strong synergism between CURC and DTXL. Therapeutic efficacy was tested in a clinically relevant orthotopic model of neuroblastoma, following the injection of SH-SY5Y-Luc + cells in the left adrenal gland of athymic mice . Although ∼ 2 % of the injected SPN per mass tissue reached the tumor, the overall survival of mice treated with CURC/DTXL–SPN was extended by 50 % and 25 % as compared to the untreated control and the monotherapies , respectively. In conclusion, these results demonstrate that the therapeutic potential of the DTXL/CURC combination can be fully exploited only by reformulating these two compounds into systemically injectable nanoparticles .