Overcoming Barriers in the Gastrointestinal Tract with Ionic Liquids
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CitationPeng, Kevin. 2020. Overcoming Barriers in the Gastrointestinal Tract with Ionic Liquids. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.
AbstractThe oral delivery of biologic drugs is significantly limited by the impact of the GI environment on drug stability, transport, and absorption. Effective strategies to deliver therapeutics must enable drug penetration through both a dynamic intestinal mucus layer and an underlying epithelium that is largely impermeable to macromolecules. Many technologies such as nanoparticles and chemical permeation enhancers fail to enable the transport of drugs across both of these barriers, or result in damage to the mucus or epithelial layer. Therefore, successful approaches for the oral delivery of biologics must address the combination of mucosal and epithelial barriers without inducing unwanted biological toxicity. In this dissertation, I first investigate the use of ionic liquids (ILs) as mucus modulating agents for enhancing oral drug delivery. Ionic liquids have recently been shown to effectively open intestinal tight junctions, and their highly tunable nature offers potential for their tailored use in conjunction with a variety of drugs. We find that choline-based ionic liquids in particular significantly enhance the diffusion of cationic molecules through mucus. The dramatic increase in diffusivity of positively charged dextrans used as model drugs here reveals the role of choline in these ionic liquids in shielding charge interactions between the diffusing molecule and mucus. We further investigated the effect of ionic liquids on mucus rheology, which showed that ionic liquids can be used to reduce mucus viscosity without severely impacting the natural mucus viscoelastic properties. These effects on molecular diffusivity and mucus rheology are explained in part by the wide shifts in pH and ionic strength induced by ionic liquids added to aqueous solution, which we observe can be tuned by varying the molar ratio of cation to anion in the ionic liquids. In vitro studies in a mucus-secreting co-culture model further demonstrate the specific impact of ionic liquids on mucus, wherein cationic dextran molecules experienced a significantly greater increase in transport across the cultured epithelial cell layer when in the presence of mucus. These findings provide guidelines for the rational design of ionic liquid-based drug delivery systems for enhanced oral delivery of charged therapeutics. After investigating ionic liquid effects on barrier properties, I then focus on the development of a mucoadhesive ionic liquid gel (CAGE-patch) for enabling sustained IL and drug delivery to the intestinal epithelium. We find that ionic liquids can be encapsulated into crystallized PVA, forming a gel that is both mucoadhesive and swellable. We then demonstrate a sustained release of IL and insulin along similar timeframes, allowing for localized co-delivery to the intestine. Cell viability results show that cells incubated with CAGE-patches result in significantly higher cell viability compared to solution, demonstrating the reduction of potential toxicity via controlled release. Finally, we show in vitro that CAGE-patches enable significantly enhanced insulin transport across mucus-secreting co-cultures compared to control and equivalent concentrations of IL in solution. We believe that the findings reported here can inform the rational selection and design of ionic liquids for modulating mucus and epithelial barriers, and we highlight a potential strategy for incorporating ionic liquids into oral drug delivery systems with controlled release and minimal toxicity.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37369487
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