Enhancement of Temozolomide Stability and Anticancer Efficacy by Loading in Monopalmitolein-Based Cubic Phase Nanoparticles

Temozolomide (TMZ) is a prodrug possessing a wide spectrum of anticancer activities. TMZ is pharmacologically inactive, but at a physiological pH, it is quickly converted to an active metabolite, 5-aminoimidazole-4-carboxamide, and a methyldiazonium cation. Due to its chemical nature, TMZ presents some capability of crossing the blood-brain barrier and therefore is used as a first-line agent in the treatment of gliomas. Here, we aimed to improve the anticancer effectiveness of TMZ by loading it into cubosomes, which are lipid nanoparticles recognized as efficient nano-based drug delivery systems. TMZ was incorporated into the monoolein (MO)- and monopalmitolein (MP)-derived cubic phases to improve its stability and half-life. It was considered that the drug release rate may vary between the MO and MP cubosomes, as the water channels of MP phases are larger than those of MO cubosomes. Therefore, we expected that due to the MPs' ability to entrap more drug molecules inside the mesophase, the concentration of TMZ available to cancer cells would be enhanced. This assumption was supported by biological analyses using the A-172 and drug-resistant T98G glioma-derived cell lines. The strongest reduction in viability was observed for A-172 cells treated with TMZ-loaded MP nanoparticles. Importantly, the TMZ-loaded MPs also caused a significant anticancer effect in the drug-resistant T98G glioma-derived cells. Both MO and MP empty cubic phases did not affect the survival of the tested cells. Concluding, TMZ-loaded cubosomes present strong anticancer properties. Encapsulating the drug within the lipid nanostructure helps to protect the drug from degradation and allows for greater accumulation of TMZ at the tumor site. Together with chemical-based features of mesophases related to increased cargo size and kinetic properties, we imply that MPs may be considered as a highly efficient nano-based drug delivery system to treat poorly curable tumors including gliomas.