A Combinatorial Statistical Design Approach to Optimize the Nanostructured Cubosomal Carrier System for Oral Delivery of Ubidecarenone for Management of Doxorubicin-Induced Cardiotoxicity: In Vitro-In Vivo Investigations.

Present work aims to optimize and characterize orally administered, ubidecarenone (UDC)-loaded glycerylmonooleate-based cubosome (GCBMs) and phytantriol based cubosomes (PCBMs) for effective management of doxorubicin-induced cardiotoxicity and to enhance bioavailability of UDC. Formulations optimized using statistical hybrid-design approach exhibited particle size of 152.0 ± 1.78 and 248.8 ± 1.83 nm, polydispersity index of 0.183 ± 0.021 and 0.225 ± 0.018 with zeta potential of -26.8 ± 0.76 and -23.3 ± 0.22 mV and percentage entrapment efficiency (% EE) of 92.3 ± 4.99% and 94.7 ± 5.67%, for GCBMs and PCBMs, respectively. High-resolution transmission electron microscopy revealed agreement with the particle size and shows the discrete cubic geometry of particles, while small-angle X-ray scattering analysis confirmed the primitive (Im3m) and diamond (Pn3m) type crystalline cubic self-assemble structure of the particles. The comparative bioavailability profiles of UDC from GCBMs and PCBMs (AUC0→∞ = 19,546.8 ± 512.88 ng·h/L for GCBMs and 27,961.99 ± 602.46 ng·h/L for PCBMs) were approximately 6.5- and 7.0-fold higher than that of UDC suspension (AUC0→∞ = 3132.806 ± 405.44 ng·h/L). Cardioprotective assessment showed a significant increase in superoxide dismutase and β-glutathione peroxidase levels, while a decrease in the level of catalase, creatine kinase-MB isoenzyme, lactate dehydrogenase, and lipid peroxidation was observed in animals pre-treated with developed CBMs. Histopathology studies revealed no significant damage, infiltrated cells, and signs of fibrosis in the CBM-treated groups.