Multifunctional Ionic Hydrogel-Based Transdermal Delivery of 5-Fluorouracil for the Breast Cancer Treatment

Transdermal drug delivery systems (TDDS) are a promising and innovative approach for breast cancer treatment, offering advantages such as non-invasiveness, potential for localized and prolonged drug delivery while minimizing systemic side effects through avoiding first-pass metabolism. Utilizing the distinctive characteristics of hydrogels, such as their biocompatibility, versatility, and higher drug loading capabilities, in the present work we prepared ionic hydrogels through synergistic interaction between ionic liquids (ILs), Choline Alanine ([Cho][Ala]) and Choline Proline ([Cho][Pro]) with oleic acid (OA). ILs used in the study are biocompatible and enhance the solubility of 5-Fluorouracil (5-FU), whereas OA is a known chemical penetration enhancer. Concentration dependent (OA) change in morphological aggregates, i.e. from cylindrical micelles to worm-like micelles to hydrogels was formed with both ILs and were characterized by SANS measurement, whereas the interactions involved were confirmed by FTIR spectroscopy. The hydrogels owes excellent mechanical properties, studied by rheology and its morphology through FE-SEM analysis. The in vitro skin permeation study revealed that both hydrogels penetrated 255 times ([Cho][Ala]) and 250 times ([Cho][Pro]) more as compared to PBS after 48 h. Those ionic hydrogels exhibited the capability to change the lipid and keratin arrangements within the skin layer, thereby enhancing the transdermal permeation of the 5-FU. Both ionic hydrogels exhibit excellent biocompatibility with normal cell lines (L-132 cells), as well as cancerous cell lines (MCF-7 cells), demonstrating over 92 % cell viability after 48 h in both cell lines. In vitro, cytotoxicity of the 5-FU loaded hydrogels was evaluated on MCF-7 and HeLa cell lines. These results indicate that the investigated biocompatible and non-toxic ionic hydrogels enable the transdermal delivery of hydrophilic drugs, making them a viable option for effectively treating breast cancer.