ORCID
https://orcid.org/0000-0002-1770-4245
Date of Award
12-17-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Intellectual Gaps: As the drug delivery field evolves, various release methods present distinct advantages and limitations, influencing the choice of platforms for specific applications. However, a significant gap persists in the field. At present, there are few drug delivery systems comprised of a stable carrier to help avoid premature breakdown in circulation before reaching the target site, a reversible loading mechanism that ensures the cargo is not released until required, and a biocompatible strategy that enables precise spatiotemporal control over cargo release. Intellectual Merit: This research resulted in the development of new cationic, viologen-based drug delivery system capable of electrostatic loading and photo-accelerated release of a wide variety of anionic cargo applicable to hydrogel and nanoparticles. Oligoviologen-crosslinked nanoparticles were synthesized via ring-opening metathesis polymerization (ROMP). Photo-accelerated release of anionic drugs was achieved from the aforementioned hydrogels and nanoparticles using a near IR light-absorbing boron-dipyrromethene (BODIPY) photocatalyst and a photoredox-based mechanism of electron transfer from the photocatalyst to the oligoviologen crosslinkers. Abstract: Drug delivery is a continuously growing area of research in the scientific community. A web of science search for “drug delivery” yields hundreds of thousands of individual results, two hundred of which have been published over the past eight years. Across all drug delivery platforms, loading of the therapeutic cargo is performed either though physical encapsulation, covalent conjugation, or specific non-covalent interactions. Drug release rate, depending on the platform, is often dictated by (i ) the pore size relative to the cargo and thus occurs passively via diffusion, (ii) on the progressive degradation of the carrier to release the cargo over time, or (iii) the dissociation of drugs from the carrier. While passive drug release methods have their advantages, stimuli responsive materials are often sought after for the control they offer when activated external environmental cues. Light is a particularly attractive stimulus because of spatiotemporal control it affords. In this dissertation photo-responsive, oligoviologen-crosslinked hydrogels and nanoparticles are described where anionic molecular cargo – such as a dye, antibiotics, a cyclic dinucleotide, or an oligonucleotide – was loaded electrostatically and its release accelerated through a photoinduced electron-transfer process involving photoirradiation of an integrated Aza-BODIPY photocatalyst with red light (660nm). In both platforms, the photoexcited Aza-BODIPY transfers an electron to the oligoviologen-based crosslinkers, resulting in a one-electron reduction of the viologen (V2+ to V●+). This reversible V2+ to V●+ transition has been leveraged in various applications, however, in our materials, the Aza-BODIPY is regenerated on the benchtop by a sacrificial reductant, triethylamine (TEOA) and in vitro by the reductants present in the intracellular environment. At the end of this PET cycle, the viologen radical cation is reoxidized to its dicationic oxidation state upon exposure to ambient O2. With constant irradiation, this dynamic process results in continuous viologen reduction/oxidation, and release of the cargo in its entirety is possible. We envision that this photoredox-based delivery platform, once optimized, can be used for the delivery of anionic drugs or prodrugs in treatments ranging from wound care to gene therapy.
Language
English (en)
Chair and Committee
Jonathan Barnes
Committee Members
Alexander Stegh; Courtney Reichhardt; John-Stephen Taylor; Timothy Wencewicz
Recommended Citation
Dorsainvil, Jovelt Marie, "Electrostatic Drug Loading and Photo-Accelerated Release: Exploring Viologen-Based Materials as Drug Carriers Across Nano, Micro, and Macro Scales" (2024). Arts & Sciences Electronic Theses and Dissertations. 3371.
https://openscholarship.wustl.edu/art_sci_etds/3371