(685f) Mechanism of Transdermal Delivery of Macromolecules Assisted By Ionic Liquids

Skin is a strong diffusive barrier especially to the permeation of large hydrophilic molecules owing to its anatomy, posing a great challenge to utilizing the transdermal route for various drug delivery applications. Using ionic liquids (IL) to chemically enhance the transport of macromolecules is a novel technique attracting immense research interests recently^1,2,3. A fundamental understanding of the role of IL underlying this process is still lacking and is essential to broadening its applications for pharmaceutically-relevant macromolecules. In this talk, we discuss the complex interactions among skin (barrier), IL (solvent) and drugs (macromolecules) and unravel this transport enhancement mechanism.

Using dextrans at varying molecular weights as the model molecule and choline-geranate (CAGE) as the model IL, we performed both experiments and theoretical modelling to investigate the transport mechanism. At the macroscopic scale, we measured skin permeabilities ex vivo, and for the first time, report remarkable enhancement for dextran up to 150kDa. At the microscopic scale, we probed CAGE-induced structural changes in both the lipid and protein components of the stratum corneum layer using spectroscopic methods. In addition to lipid extraction previously reported, we also observed changes in the protein secondary structure. Inspired by these new experimental findings, we theoretically model the transport of macromolecules via both intercellular and transcellular pathways and the predicted permeation enhancement agrees with experimental measurements. In the end, we discuss the scaling of molecular weight versus permeability, which shows a slower decay in the presence of CAGE. This striking change of scaling relationship sheds light on the advantage of IL over other enhancement techniques for large molecules in particular.

1. Ibsen, K. N., Ma, H., Banerjee, A., Tanner, E. E., Nangia, S., & Mitragotri, S. (2018). Mechanism of Antibacterial Activity of Choline-Based Ionic Liquids (CAGE). ACS Biomaterials Science & Engineering, 4(7), 2370-2379.
2. Tanner, E. E., Ibsen, K. N., & Mitragotri, S. (2018). Transdermal insulin delivery using choline-based ionic liquids (CAGE). Journal of Controlled Release, 286, 137-144.
3. Zakrewsky, M., & Mitragotri, S. (2016). Therapeutic RNAi robed with ionic liquid moieties as a simple, scalable prodrug platform for treating skin disease. Journal of Controlled Release, 242, 80-88.