Multi spectroscopic investigation of maisine-based microemulsions as convenient carriers for co-delivery of anticancer and anti-inflammatory drugs

Lipid-based drug delivery systems are very promising in addressing critical medical needs associated with cancer because they are able to enhance the efficacy of the therapeutic agents loaded in. Yet, their transferability from bench to bedside is still a challenge as it hits many barriers. Among them, the absence of a clear design made on the deeper understanding of the intermolecular forces underlying the formation of the drug-carrier system and the controlled release of the drug is relevant. In this contribution, we rationally designed and prepared lipid-based formulations of an anticancer drug, fluorouracil (FU - hydrophilic) and an anti-inflammatory drug, ibuprofen (IBU - hydrophobic) to thoroughly characterize the specific intermolecular interactions between drugs and components of the carrier matrix. Microemulsions (ME) were selected as the main carriers for this study, but a comparison with liposomes was performed to observe if different organization of the lipophilic and hydrophilic compartments influences the loading capacity and controlled release of these two drugs. Using Maisine CC, a biocompatible oil, and Tween 20 as the surfactant, normal oil-in-water ME loaded with FU and IBU (1:1, 1:3, 1:6, wt:wt) were prepared by the water titration method. MEs were characterized by DLS, Zeta potential, and DOSY spectroscopies to assess their droplet size, surface charge, structure and type of emulsion. Intermolecular interactions between drugs and components of the ME's matrix were investigated by FT-IR, RAMAN and ¹H-NMR spectroscopies. The experimental results of DOSY revealed that all components of MEs are gathered in normal oil-in-water ME. Due to their different affinities for the main components of the ME, FU, and IBU were mainly distributed in the aqueous and oily phases, respectively, as supported by the droplet size measured by DLS. It was observed that co-loading the two drugs impacted the release behavior, assessed by the dialysis bag method, as compared with the mono-drug formulations. Based on the findings of this work, a release mechanism for FU and IBU was proposed, as well. Overall, the ME proved to be more suitable nanocarriers since the drugs, which were loaded in higher amounts as compared to liposomes, followed a controlled and sustained release of at least 96 h.