Date of Award
2017
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biotechnology Science and Engineering
Committee Chair
Carmen Scholz
Committee Member
Robert McFeeters
Committee Member
William Setzer
Committee Member
Bernhard Vogler
Committee Member
Emanuel Waddell
Subject(s)
Polymers--Biotechnology., Polymers in medicine.
Abstract
Poly(α-amino acid)s (PAAs) are a diverse class of polymers that can be synthesized or biologically derived. PAAs have been widely used for biomedical applications due to their biodegradability and biocompatibility. Living polymerization through ring opening polymerization of amino acid N-carboxyanhydrides using a nucleophilic initiator provides the potential to manipulate polymer architecture and physiochemical characteristics. In this study, we investigate the use of amphiphilic block and random PAA tercopolymer constructs that contain ionic and hydrophobic components. The amphiphilic character for each tercopolymer allows for the formation nanoparticles that can be used in gene and drug delivery. Each tercopolymer component provides a specific purpose that is needed to produce biologically relevant gene and drug delivery vectors. Poly(ethylene glycol) (PEG) is used widely as a biomaterial with the ability to lower immunogenicity. PEG has a large excluded volume in aqueous media and repels macromolecules due to an entropic effect which prevents nanoparticle disruption. L-lysine and L-glutamate provide ionicity required due electrostatically bind to DNA and provide tenability for drug encapsulation, respectively. L-leucine was utilized to provide compaction and nanoparticle stability by introduction of hydrophobic moieties. PEGylated PAAs (PEG-PAAs) were successfully synthesized in the presence of urea, yielding products with desired molecular weights and architecture. Gel permeation chromatography (GPC) and proton nuclear magnetic resonance (1H-NMR) displayed polydispersity indexes (PDI) between 1.1 and 1.4 and accurate chain lengths, which are indicative of living polymerization. Higher PDIs were observed with increasing hydrophobic character within block tercopolymers and was minimized when hydrophobicity was spread throughout random tercopolymers. Cationic tercopolymers were shown to bind and condense DNA into nanoparticles less than 200 nm and increased polymer concentrations resulted in a net positive charge. Also, DNA condensation and protection from DNAse I at 37 ℃ was dependent upon the use of either block or random tercopolymers. Transfection and cytotoxicity in COS-1 cells was found to be dependent upon tercopolymer structure and cationic density. Anionic tercopolymers formed drug encapsulates within both a partially soluble and a hydrophobic drug. The size, stability, and loading efficiency of the nanoparticles altered based upon the placement of the hydrophobic components and the loading of each individual drug. This study made two important contributions to the field: 1) PEG-PAA tercopolymers are shown be tunable gene and drug delivery vectors and 2) molecular architecture is a very important factor into the efficiency of these tercopolymers for biomedical applications.
Recommended Citation
Ulkoski, David J., "Synthesis of amphiphilic pegylated poly([alpha]-amino acid) tercopolymers and the impact of molecular architecture on their use as gene and drug delivery vectors" (2017). Dissertations. 122.
https://louis.uah.edu/uah-dissertations/122