Date of Award
1-1-2025
Document Type
Dissertation
Degree Name
Ph.D. in Chemistry
First Advisor
Eden E.L. Tanner
Second Advisor
Susan D. Pedigo
Third Advisor
Thomas A. Werfel
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Despite their potential for targeted and non-toxic delivery of systemically administered drugs, very few intravenous (IV) nanoparticle (NP) delivery systems, and no polymer-based NPs, have successfully made it into the clinic. A primary challenge remains the premature clearance of polymeric nanoparticles by the immune system soon after intravenous (IV) injection, initiated by mononuclear phagocytic system (MPS) components within the blood. The mechanism of this clearance is driven by opsonization—the process of serum proteins rapidly adsorbing to NP surfaces and triggering the immune system via a series of monocyte and protein-signaling cascades. In addition to phagocytosis, this system shuttles NPs to off-target accumulation sites, such as the kidneys, spleen, and liver, acting as filtration systems for rapid clearance. This creates a significant challenge in designing bioresponsive and targeted injectable NP systems, as, despite the surface functionalization strategy, fewer than 5% currently reach their destination after IV injection. Re-engineering of NP bio-interactions in the bloodstream via cellular hitchhiking is a new and recent approach that allows for biocompatible and facile re-directing of systemic NPs to desired tissues without significant interaction with the MPS. However, these bioinspired systems are also limited as they involve extraction of blood cells, combination, and re-injection back into the bloodstream, creating a challenge for streamlining accessible clinical translation. Ionic liquids are liquid salts under 100 ℃, composed of bulky and asymmetric cations and anions, which have novel potential to act as drug delivery biomaterials, seen in transdermal, antimicrobial, transbuccal, oral, and intravenous systems. With high structural tunability of either cationic or anionic partner, the resulting physicochemical and biophysical properties can be controlled both within the IL and with its interfacing environment to modulate biophysical interactions. A choline and trans-2-hexenoate IL has been used to electrostatically coat PLGA surfaces in order to repel serum proteins as well as direct affinity to RBC membranes in situ, thereby significantly extending circulation half-life and redirecting biodistribution to the first encountered capillary bed post-IV injection in a BALB/c mouse in vivo model. Herein, we demonstrate that by engineering the anion identity around that of trans-2-hexenoic acid in choline carboxylate ILs, we can identify new analog structures that drive selective affinity to white blood cell subpopulations, platelets, as well as RBCs, in whole blood. By engineering cellular hitchhiking affinity in whole blood, the targeting for diseased tissue sites can be significantly enhanced in an unprecedented way for virtually any disease manifesting at those locations, and in systemic circulation. This dissertation has been divided into 3 chapters: 1) Conception of the IL-NP nanoformulation platform and identification of top candidates for in situ cellular hitchhiking, 2) Study of the underlying physicochemical mechanisms between top candidate IL-NPs and red blood cell (RBC) membranes governing in situ cellular hitchhiking, and 3) Application of in situ RBC hitchhiking for nanotherapeutic delivery.
Recommended Citation
Hamadani, Christine, "Elucidating the Physicochemical Interactions of Ionic Liquid-coated Polymeric Nanoparticles with Blood Cells to Achieve Organ-Targeted Delivery After Intravenous Administration" (2025). Electronic Theses and Dissertations. 3288.
https://egrove.olemiss.edu/etd/3288