Mitoxantrone-loaded lipid nanoparticles for breast cancer therapy - Quality-by-design approach and efficacy assessment in 2D and 3D in vitro cancer models

Abstract

Breast cancer is the leading cause of cancer-related deaths among women worldwide. The conventional chemotherapeutic regimens used in the treatment of this disease often lead to severe side-effects and reduced efficacy. In this study, a novel drug delivery system for the chemotherapeutic drug mitoxantrone (Mito) was developed using solid lipid nanoparticles (SLN). The production of the SLN was carried out using an organic-solvent-free, low-cost method and optimized using a Box-Behnken design. SLN presented adequate size for cancer-related applications, more than 90% of EE% and remained stable for at least 6 months. A much higher drug release was obtained at acidic pH (mimicking the endosomal compartment) than plasmatic pH, highlighting the potential of the nanosystem for tumor drug delivery. Additionally, SLN were non-hemolytic and cytocompatible, even at high concentrations of lipid. A significantly higher anti-cancer efficacy was obtained for Mito-loaded SLN comparing to the free drug at different concentrations in MCF-7 2D models. Finally, the nanoformulation was evaluated in heterotypic breast cancer spheroids showing capacity to penetrate the tridimensional structure and ability to induce a high anti-tumoral effect, similarly to the free drug. Overall, these results support that the developed SLN are effective Mito nanocarriers for the treatment of breast cancer.

Keywords: Box-Behnken design; Breast cancer; Chemotherapy; Mitoxantrone; Solid lipid nanoparticles (SLN); Tumor spheroids.