Lim, Young (2015-07). Development of Polyphosphoester-Based Polymeric Nanoparticles as Delivery Carriers for Silver-Based Antimicrobial Agents for Treatment of Infectious Diseases. Doctoral Dissertation.
Thesis
The development of well-defined polymeric nanoparticles (NPs) as delivery carriers for antimicrobials targeting human infectious diseases requires rational design of the polymer template, an efficient synthetic approach and fundamental understanding of the developed NPs, e.g., drug loading/release, particle stability, and other characteristics. In order to develop potentially fully biodegradable, biocompatible polymeric NPs with the capability to deliver silver-based antimicrobials, a series of anionic degradable NPs (dNPs) were prepared from block copolymers having polyphosphoester (PPE) and poly(L-lactide) block segments, designed specifically for silver loading into the hydrophilic shell and/or the hydrophobic core. With the use of three different types of silver-based antimicrobials - silver acetate (AgOAc) or one of two silver carbene complexes (SCCs), comparative studies of the selection of proper dNP templates for silver-loading and release were undertaken. Then, the comprehensive degradation studies, including evaluation of hydrolytic or enzymatic degradability and identification of the degradation products, were performed for the fundamental understanding of the developed dNPs as potential delivery carriers for silver-based antimicrobials. Finally, in vitro antimicrobial efficacy of the selected Ag-dNPs was compared with that of inherent silver compounds against 10 contemporary epidemic strains of Staphylococcus aureus and eight uropathogenic strains of Escherichia coli. Organocatalyzed ring-opening polymerization (ROP) of ethylene glycol vinyl ether-containing cyclic phosphotriester monomer, as an initial fundamental study toward unique degradable, functional polymer materials, was described. After demonstrating the well-controlled homopolymerization of the monomer with predetermined molecular weights and narrow molecular weight distributions, the resulting vinyl ether-functionalized PPE scaffold was conjugated with hydroxyl- or thiol-containing model small molecules via three different types of conjugation chemistries - thiol-ene "click" reaction, acetalization, or thio-acetalization reaction - revealing efficient routes for postpolymerization modifications of functional polymers. Furthermore, amphiphilic diblock copolymers containing the ethylene glycol vinyl ether-functionalized PPE as a hydrophobic block segment, also prepared by ROP, afforded well-defined micelles that showed a pH-dependent hydrolytic core degradability of both backbone and side chains in aqueous solutions. The degradation products, as identified by mass spectrometry, were found to be nontoxic toward two standard cell lines: RAW 264.7 mouse macrophages and OVCAR-3 human ovarian adenocarcinoma cells.
