Deep Eutectic-Mediated Parenteral Drug Delivery Systems for Therapeutic Macromolecules

Abstract

The past 100 years have seen an evolution of drug payloads that have expanded the number of treatment options for an increasing number of treatable diseases. With this progression, it has become increasingly necessary to develop specialized drug delivery systems that can achieve the goal of getting the drug to the correct target at the correct dose for the correct amount of time. However, some systems have become narrowly focused limiting these systems' broad applicability for incorporation of new therapeutic modalities or disease targets. Deep eutectic solvents, mixtures of acids and bases that cause a depression in the melting temperature, are a class of compounds that can be extensively tuned to give rise to a variety of properties like amphiphilicity, viscosity, and charged interactions. The modular nature of these compounds makes them an exciting choice for creating broadly applicable drug delivery systems. In my dissertation, I explore the use of deep eutectic solvents to create modular drug delivery systems for 3 of the most widely used drugs today, insulin, monoclonal antibodies, and messenger RNA. Using a library screening approach, I assess the ability to create formulations that allow for sufficient protein therapeutic stability. I investigate the improvements that these formulations have on the pharmacokinetics and bioavailability of both protein therapeutics when administered subcutaneously. With the same DES generating a faster insulin absorption into the bloodstream and increasing monoclonal antibody absorption by over 100 percent. I also confirm that these formulations are non-toxic utilizing histological assessment of both the injection site and vital organs as well as over 30 blood cell and biochemistry metrics. I highlight the potential role that the chosen DES is playing in penetrating the subcutaneous barrier by identifying its inhibitory nature on non-specific collagen-therapeutic protein binding. In a separate study, I identify a DES that can be formulated across a wide range of concentrations to give optimal lipid nanoparticle stability for messenger RNA encapsulation. This range of DES concentrations allows for linear control of expression percentages at the injection site when the formulations are administered intramuscularly. I also show the ability to choose a formulation along this continuum to significantly increase muscle expression and decrease liver expression kinetics.