Fundamental Chemistry Advances Toward the Development of Degradable Polymer-Based Nanoparticles for the Treatment of Infectious Diseases
Abstract
Microorganisms, including bacteria, viruses, fungi, or parasites, give rise to infectious diseases, which can spread between people, and can even transfer from animals or insects to humans. Infectious diseases are common, sometimes fatal, health issues. To date, the treatment of infectious diseases has largely relied on antibiotics. However, the therapeutic outcomes of current treatments need to be enhanced due to the emergence of drug-resistant microorganisms and the decline in the development of new antibiotics. Nanotechnology could help improve the efficacy of currently available antibiotics via changing the pharmacokinetics and biodistribution of drugs, which could enhance bioavailability, reduce side effects, help overcome physical and biological barriers for the efficient delivery to the site of infection, and so on. This dissertation aims to explore a novel treatment method to treat infectious diseases using degradable polymer-based nanoparticles.
In a first project, bacterial adhesin, FimHA-targeted polymeric nanoparticles were developed for the delivery of antimicrobials to bacteria hiding inside the cells by mimicking the bacterial mode of cell invasion in order to treat and eradicate recurrent urinary tract infections. Amidation between carboxylic acids located in the shell of the poly(acrylic acid)-block-polystyrene-based polymeric nanoparticles and primary amine groups of lysine residues on FimHA was employed as the conjugation method. We prepared FimHA-polymeric nanoparticle conjugates with varying amounts of adhesins on the surface without free and/or physically-associated proteins under the improved coupling conditions.
In a second direction involving a series of projects, functional polycarbonates were developed in order to expand the pool of degradable polymers and their self-assembled nanostructures, which can be utilized as drug-delivery vehicles. Degradable polycarbonates were synthesized by metal-free organocatalytic ring-opening polymerization of cyclic carbonate monomers. Postpolymerization modifications were also employed to introduce new functionalities onto the same degradable polymer backbone. Water-soluble polycarbonate formed a hydrophilic shell domain of polymeric nanostructures, and reactive aldehyde- and vinyl ether-functionalized polycarbonates were synthesized and their potential for drug delivery systems were demonstrated.
In a third direction, advanced mechanistic understanding of organocatalytic ring-opening polymerization (ROP), which is widely used for syntheses of degradable polymers, was gained by specialized NMR spectroscopy studies. The collection of 13C NMR data in real time during polymerization was enhanced via hyperpolarization of nuclear spins. The “living” characteristics of ring-opening polymerization enabled the observation of NMR resonances associated with an intermediate formed during ROP.
Citation
Heo, Gyu Seong (2016). Fundamental Chemistry Advances Toward the Development of Degradable Polymer-Based Nanoparticles for the Treatment of Infectious Diseases. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /192017.