Enhancement of\nTemozolomide Stability and Anticancer\nEfficacy by Loading in Monopalmitolein-Based Cubic Phase Nanoparticles

Temozolomide (TMZ)\nis a prodrug possessing a wide spectrum\nof anticancer\nactivities. TMZ is pharmacologically inactive, but at a physiological\npH, it is quickly converted to an active metabolite, 5-aminoimidazole-4-carboxamide,\nand a methyldiazonium cation. Due to its chemical nature, TMZ presents\nsome capability of crossing the blood-brain barrier and therefore\nis used as a first-line agent in the treatment of gliomas. Here, we\naimed to improve the anticancer effectiveness of TMZ by loading it\ninto cubosomes, which are lipid nanoparticles recognized as efficient\nnano-based drug delivery systems. TMZ was incorporated into the monoolein\n(MO)- and monopalmitolein (MP)-derived cubic phases to improve its\nstability and half-life. It was considered that the drug release rate\nmay vary between the MO and MP cubosomes, as the water channels of\nMP phases are larger than those of MO cubosomes. Therefore, we expected\nthat due to the MPs’ ability to entrap more drug molecules\ninside the mesophase, the concentration of TMZ available to cancer\ncells would be enhanced. This assumption was supported by biological\nanalyses using the A-172 and drug-resistant T98G glioma-derived cell\nlines. The strongest reduction in viability was observed for A-172\ncells treated with TMZ-loaded MP nanoparticles. Importantly, the TMZ-loaded\nMPs also caused a significant anticancer effect in the drug-resistant\nT98G glioma-derived cells. Both MO and MP empty cubic phases did not\naffect the survival of the tested cells. Concluding, TMZ-loaded cubosomes\npresent strong anticancer properties. Encapsulating the drug within\nthe lipid nanostructure helps to protect the drug from degradation\nand allows for greater accumulation of TMZ at the tumor site. Together\nwith chemical-based features of mesophases related to increased cargo\nsize and kinetic properties, we imply that MPs may be considered as\na highly efficient nano-based drug delivery system to treat poorly\ncurable tumors including gliomas.