Ionic liquids (ILs) and deep eutectic solvents (DESs) are unique classes of liquids with remarkable properties. Traditionally they have been used in industrial settings and as green solvents, however, their use in drug delivery has been a topic of recent interest (Mitragotri 2024; Shukla et al. 2023).
While very similar, ILs and DESs are separate phenomena (Figure 1). ILs are salts that exist in liquid phase below 100 °C, typically consisting of weakly interacting organic–often heterocyclic–cations and organic or inorganic anions (Mitragotri 2024; Shukla et al. 2023; Adawiyah et al. 2016). ILs are the “parents” of DESs, which are mixtures of compounds with a melting point lower than that of their respective original components and are primarily coordinated by hydrogen bonding (Li et al. 2022; Tanner, Ibsen, and Mitragotri 2018; Płotka-Wasylka et al. 2020).
Figure 1. A comparison of the similarities and differences in the defining characteristics of ILs and DESs (Płotka-Wasylka et al. 2020). While they are very similar, the most pertinent difference (aside from melting point characteristics) lies in the type of coordination between constituent molecules, with ILs involving an ionic bond between an anion and cations, while DESs involve hydrogen bonding due to the constituents acting as hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA). Note that many ILs can be biodegradable and/or non-hazardous, however this is less likely than with DESs.
ILs and DESs have garnered a lot of attention because of their unusual and tailorable physicochemical properties (Shukla et al. 2023; Adawiyah et al. 2016). All of these liquids inherently exhibit high thermal stability, low vapour pressure, and high solvating power for both organic and inorganic solutes, while properties such as hydrophobicity, toxicity, and biodegradability can be tuned via component selection. This makes ILs and DESs very valuable in a variety of applications, and the selection of biocompatible components has enabled their use in drug delivery, showing improvements in drug pharmacokinetics and pharmacodynamics (Adawiyah et al. 2016; Mitragotri 2024).
Choline geranate (CAGE) is a notable biocompatible IL/DES used for drug delivery (Mitragotri 2024). CAGE consists of choline (a common dietary supplement) and geranic acid (a common food flavoring agent), ensuring CAGE is highly tolerable by the body. The ability of CAGE to remain tolerable while still being an effective solvent is exceptional as the two are often contradictory–a significant limitation and consideration when selecting constituents. Whether CAGE is considered an IL or a DES depends on the ratio of components (Riaz et al. 2022). It is considered an IL when the choline:geranate ratio is 1:1, however, when this ratio is varied, the resulting mixture isn’t solely ionically coordinated and is therefore considered a DES.
CAGE has shown increased efficacy in multiple routes for drug discovery, notably transdermal administration (Mitragotri 2024). This route is particularly challenging due to the barrier of the stratum corneum (SC), the outer layer of the epidermis, which is composed of tightly packed cells and lipids (Li et al. 2022).
CAGE has been demonstrated to be superior to traditional chemical permeation enhancers in both potency and safety, and is remarkably able to deliver macromolecules across the dermal barrier (Mitragotri 2024; Neville et al. 2024). 1:2 CAGE appears to be the most effective variant at penetrating the skin, however, there is uncertainty surrounding the mechanism. The ability of CAGE to interact with membranes is generally attributed to its amphiphilicity, and one putative mechanism involves CAGE penetrating into the skin and interacting with the lipids of the SC, causing them to be extracted and fluidized. Another hypothesis for the mechanism is that CAGE travels through the intercellular lipids of the SC as well as through its cells by creating small transient openings in the phospholipid membranes through which drugs can permeate (Boscariol et al. 2021).
While there is still much to be uncovered about CAGE and its mechanism of assisting drugs in transdermal permeation, it is clear that ILs and DESs are very promising and robust solutions to the most preeminent issue in drug delivery.
References
Adawiyah, Noorul, Muhammad Moniruzzaman, Siti Hawatulaila, and Masahiro Goto. 2016. “Ionic Liquids as a Potential Tool for Drug Delivery Systems.” MedChemComm 7 (10): 1881–97. https://doi.org/10.1039/C6MD00358C.
Boscariol, Rodrigo, Érika A. Caetano, Erica C. Silva, Thais J. Oliveira, Raquel M. Rosa-Castro, Marta M. D. C. Vila, and Victor M. Balcão. 2021. “Performance of Choline Geranate Deep Eutectic Solvent as Transdermal Permeation Enhancer: An In Vitro Skin Histological Study.” Pharmaceutics 13 (4): 540. https://doi.org/10.3390/pharmaceutics13040540.
Li, Xiaodan, Nannan Ma, Lijing Zhang, Guixia Ling, and Peng Zhang. 2022. “Applications of Choline-Based Ionic Liquids in Drug Delivery.” International Journal of Pharmaceutics 612 (January):121366. https://doi.org/10.1016/j.ijpharm.2021.121366.
Mitragotri, Samir. 2024. “Choline Geranate (CAGE): A Multifaceted Ionic Liquid for Drug Delivery.” Journal of Controlled Release 376 (December):593–600. https://doi.org/10.1016/j.jconrel.2024.10.034.
Neville, George M., Ana-Maria Dobre, Gavin J. Smith, Samantha Micciulla, Nick J. Brooks, Thomas Arnold, Tom Welton, and Karen J. Edler. 2024. “Interactions of Choline and Geranate (CAGE) and Choline Octanoate (CAOT) Deep Eutectic Solvents with Lipid Bilayers.” Advanced Functional Materials 34 (2): 2306644. https://doi.org/10.1002/adfm.202306644.
Płotka-Wasylka, Justyna, Miguel de la Guardia, Vasil Andruch, and Mária Vilková. 2020. “Deep Eutectic Solvents vs Ionic Liquids: Similarities and Differences.” Microchemical Journal 159 (December):105539. https://doi.org/10.1016/j.microc.2020.105539.
Riaz, Mubeshar, Maida Akhlaq, Sadia Naz, and Maliha Uroos. 2022. “An Overview of Biomedical Applications of Choline Geranate (CAGE): A Major Breakthrough in Drug Delivery.” RSC Advances 12 (40): 25977–91. https://doi.org/10.1039/D2RA03882J.
Shukla, Monu Kumar, Harshita Tiwari, Rachna Verma, Wen-Liang Dong, Shavkatjon Azizov, Brajesh Kumar, Sadanand Pandey, and Deepak Kumar. 2023. “Role and Recent Advancements of Ionic Liquids in Drug Delivery Systems.” Pharmaceutics 15 (2): 702. https://doi.org/10.3390/pharmaceutics15020702.
Tanner, Eden E. L., Kelly N. Ibsen, and Samir Mitragotri. 2018. “Transdermal Insulin Delivery Using Choline-Based Ionic Liquids (CAGE).” Journal of Controlled Release 286 (September):137–44. https://doi.org/10.1016/j.jconrel.2018.07.029.