Voltammetric and biological studies of folate-targeted non-lamellar lipid mesophases.

Folate-targeted lipid nanostructures are promising strategies for the development of biocompatible drug delivery systems. The objective of this study was to evaluate the efficacy of drug delivery to cancer cells by folate-targeted lipid mesophases, cubosomes (CUB) and hexosomes (HEX), loaded with doxorubicin (DOX). Three cancer-derived cell lines (KB, HeLa, T98G) exhibiting different expressional levels of folate receptor protein (FR) were used. DOX-loaded folate-targeted CUB and HEX dispersions were characterized via small angle X-ray scattering and dynamic light scattering to assess their physicochemical properties. DOX release characteristics were evaluated by electrochemical methods and demonstrated structure-dependent release capabilities. A slow release rate was observed for hexosomes, while cubosomes offered more rapid drug transport. Analysis of the release kinetics revealed that the total amount of DOX released from cubosomes is linearly dependent on the square root of time, implying that the release process follows the Higuchi diffusion model. Assessment of drug uptake performed on cancer-derived cell lines demonstrated that DOX accumulation in cancer cell depends not only on the release capability of the applied mesophase, but also, on the level of folate receptor protein present in the cancer cells. FR-functionalized CUB and HEX enabled faster drug delivery to cancer cells as a result of receptor-ligand interactions. In addition, doxorubicin encapsulated into FR-cubosomes demonstrated significantly improved anti-tumor activity promoting the necrosis of tumor cells, while DOX-loaded FA-hexosomes acted via induction of the apoptotic state. Overall, our data indicates that folate-modified formulations are promising drug delivery systems and can be considered as potential therapeutic tools in the targeted therapy of FR-positive tumors.