Dual-drug delivery system based on cubosomes for glioblastoma therapy: electrochemical, structural and biological...

Monotherapy using a single drug exhibits significant limitations in the treatment of complex diseases, particularly cancer, where tumor heterogeneity often restricts therapeutic efficacy. Dual-drug delivery systems enable the co-administration of therapeutics with distinct and complementary mechanisms of action, offering a promising strategy to overcome these limitations. In this study, we developed a dual-drug delivery system based on lipid liquid-crystalline cubic phases (LCPs) co-loaded with temozolomide (TMZ) and doxorubicin (DOX). TMZ induces DNA alkylation, whereas DOX inhibits topoisomerase II, thereby reducing the likelihood of developing resistance by tumor. Electrochemical methods were employed to investigate drug release kinetics from mono- and dual-drug-loaded cubosomes and to detect any interactions between the drugs or with the lipid forming the carrier that affect the release behavior of each drug from the nanocarrier system. They also allowed monitoring of the hydrolysis of TMZ and proposal of the optimal ratio of drugs in the carrier, taking into account this degradation process. The simultaneous administration of TMZ and DOX may improve treatment efficacy through synergistic effects and permit dose reduction compared with monotherapy. The structural properties of the nanoparticles were characterized using small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS). Biological evaluation demonstrated that combination treatment with a standard concentration of TMZ and a lower concentration of DOX resulted in improved therapeutic outcomes in A172 glioblastoma-derived and HeLa cell lines.