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ItemProtein Nanoparticles For Applications In Chemical Biology And Immunology(Georgia Institute of Technology, 2022-09-02) Hincapie, RobertThroughout this thesis, I leverage the properties of virus-like particles (VLPs) – their highly organized structure, immunogenicity, optimal size for trafficking to lymph nodes, their ability to undergo dense surface chemical modification, and overall stability– to produce a series of targeted platforms for cellular targeting, imaging, and vaccinology. The copper(I)-catalyzed azide-alkyne cycloaddition is used to direct surface modification of VLPs with ligands that imbue the resulting particles with selected functional properties. Multivalent carbohydrate ligands are used to direct selective uptake of particles in hepatic cells in vitro or in vivo; oligonucleotide ligands are used to generate VLP-spherical nucleic acids, with enhanced non-specific uptake properties and reduced immunogenicity in vivo; pathogen-associated carbohydrate antigens are displayed on VLPs towards the development of potent monoclonal antibodies; finally, multifunctional particles bearing dendritic cell-targeting glycan ligands and model peptide antigens are used as potent immunogens to generate antigen-specific cellular immunity. The collaborative and interdisciplinary projects described within this thesis compliment previous work towards the manipulation and engineering of protein nanoparticles, and provide several starting points for further efforts.
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ItemPEG (Polyethylene Glycol)-PCL (Polycaprolactone) Block Copolymers For 3D Printing Of Medical Devices(Georgia Institute of Technology, 2022-01-18) Yang, RuyiPCL polymers have been widely used in 3D printing of scaffolds over the past few decades, which can be applied in a variety of medical devices. However, PCL has intrinsic defects, such as high hydrophilicity which causes low biocompatibility. The research reported in this thesis aims to modify existing PCL polymers by developing a series of PEG-PCL block copolymers with different ratios of blocks and investigate their potential as implants for soft tissue engineering and airway reconstruction. The introduction of PEG blocks to PCL enhanced biocompatibility towards mammalian cells compared to the commercially available PCL with same molecular weight, without compromising the 3D printability. Moreover, some PEG-PCL copolymers showed significantly better resistance towards bacterial adhesion, which is desirable for both applications. The various mechanical properties of these copolymers make them promising candidates to devise patient-specific medical devices with various needs.
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ItemOxanorbordienes and Azanorbordienes as thiol cleavable linkers(Georgia Institute of Technology, 2021-05-06) De Pascalis, LucreziaOxa/ Azanorbornadienes (ONDs/ ZNDs) are potent electrophiles that undergo Michael addition with thiols, and then fragment by retro-Diels-Alder (rDA) reaction, a unique two-step sequence among thiol-reactive linkages. Modifications can be made which change adduct stability toward rDA over a very wide range. The structure-activity of rDA rates to substituents was explored. The rDA reaction rate was found to be highly sensitive to the substitution pattern, with half-lives spanning a large range. Since the cleavage mechanism is not traceless, leaving a furan unit behind, the consequences of this were tested. A series of furan conjugates of metabolically stable drugs was synthesized. The microsomal stability of the furan derivatives was tested to explore the potential for adverse metabolic processing. Lastly, ONDs were used as cleavable linkers for delivery and stimuli responsive release of cargo using a virus-like particle (VLP). The work described in this dissertation will aid the development of this linker technology for future applications in drug delivery and biomaterials, which is widely useful to applications requiring controlled release over hours or months.
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ItemDiscovery of Monoclonal Antibodies for Diagnostics and Therapies Using Conjugate Virus-like Particle Vaccines(Georgia Institute of Technology, 2021-05) Schroeder, MichelleMonoclonal antibodies (mAbs) are highly specific antigen binding proteins that are used as biological reagents, therapeutics, and in rapid diagnostics. While mAbs have extensive potential applications, their means production for small molecules and conformationally specific peptides is difficult. Here, we use a method of mAb production in which we pair conjugate virus-like particle (VLP) vaccine with hybridoma technology to produce high-affinity mAbs against three classes of molecules 1) fentanyl derivatives, 2) SARS-CoV-2 peptides, and 3) α-amanitin and microcystin LR cyclic peptide toxins. We successfully produced broad and derivative-selective mAbs against eight fentanyl derivatives. We also showed early signs of success targeting neutralizing and mutant SARS-CoV-2 peptides with conformational specificity using a heterologous prime-boost strategy. Lastly, we produced high affinity mAbs for both α-amanitin and microcystin LR, two highly toxic cyclic peptides. The early success of mAb production against the variety of targets presented in this thesis shows the viability and exceptional versatility of conjugate VLP vaccines as a means to producing mAbs.
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ItemDirecting the immune response using nanoparticle vaccines and drug delivery systems(Georgia Institute of Technology, 2021-04-28) Chapman, Asheley PooleVirus-like particles (VLPs) are icosahedral protein nanoparticles with inherent immunogenicity qualifying them as ideal carrier proteins for conjugate vaccines. These vaccines have both prophylactic potential and can be used to generate monoclonal antibodies (mAbs) against a wide array of targets. VLPs derived from bacteriophage Q and PP7 are formed from 180 copies of coat protein expressed in Escherichia coli that self-assemble nanoparticles ~30 nm in diameter. Reactive amino acid side chains can be modified to display synthetic antigens using bioconjugation techniques or can be genetically engineered as C-terminal extensions forming multivalent VLP-conjugate vaccines. This dissertation will describe the optimization of several design features of VLP-conjugate vaccines including linker length connecting antigen to carrier protein, route of vaccine administration, and adjuvant incorporation. These findings were incorporated into subsequent VLP-conjugate vaccine design and strategy. The antigenicity of several molecular classes of VLP-presented antigens were evaluated and ultimately produced libraries of rare mAbs targeting bacterial and tumor-associated glycans, fentanyl small molecules, cyclic peptides toxins, and SARS-CoV-2 peptides and proteins. Hybridoma-produced mAbs were characterized and assessed for binding specificity, affinity, cross-reactivity, and function, including their diagnostic potential for incorporation into immunoassays for use at Centers for Disease Control and Prevention. Additionally, a multistage nanoparticle drug delivery platform was explored in order to improve access to adaptive lymphocytes residing in the lymph nodes. This work builds upon previous work exploring the utility of VLP conjugates for vaccine development and polymeric nanoparticles that target lymph nodes for drug delivery, all of which demonstrate promise as technologies for use in the clinic and in diagnostic reagent development.
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ItemMICROPOROUS SPIROCYCLIC POLYMERS FOR MEMBRANE SEPARATIONS OF CRUDE OIL MIXTURES(Georgia Institute of Technology, 2021-04-26) Thompson, Kirstie A.The fractionation of crude oil mixtures via distillation is a large-scale, energy-intensive process. Membrane materials can avoid phase changes in such mixtures and thereby reduce the energy intensity of these thermal separations. However, membrane technologies have not yet been developed for the fractionation of complex organic mixtures. With this application in mind, we developed a modular method for the synthesis of spirocyclic membrane materials, providing a platform to study membrane structure-function relationships. This dissertation explores these structure-function relationships as they pertain to the membrane-based fractionation of complex hydrocarbon and crude oil mixtures.
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ItemDISCOVERY OF NOVEL DRUGS WITH TISSUE AND CELL-TYPE SELECTIVITY FOR CANCER AND INFLAMMATION(Georgia Institute of Technology, 2021-04-26) Wu, BochengUncontrolled inflammation is a key factor in multiple disease types, including tissue fibrosis and cancers. The underlying mechanisms and treatment of several of these diseases are still unsolved medical challenges. The studies described in this thesis focused on developing novel cell-type and tissue-selective anti-inflammation and anti-cancer agents that target microinjuries, fibroblast hyperplasia exaggerated extracellular matrix (ECM) deposition and epigenetic dysfunctions. Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease (ILD) of ambiguous cause. IPF is sustained by inflammation caused by chronic injury that promotes inflammatory cytokines release and the accumulation of these cytokines in the bronchial tubes and airways. IPF is a chronic and fatal disease that progressively declines the lung function. Till date, IPF remains untreatable. The FDA approved drugs - pirfenidone (PFD) and nintedanib – are suboptimal in the management of IPF due to their toxic side effects, low potency, cost ineffectiveness and minimal beneficial effect on the patients’ survival rate. In chapter 2 of this thesis, I described four classes of macrolide-based anti-fibrotic agents (28 final compounds) designed to exploit the excellent PK and selective lungs and/or liver tissues distribution activities of the macrolide templates to arrive at novel anti-fibrotic agents that may selectively accumulate within these tissues. I investigated the effects of these compounds on the viability of four cell lines (MRC-5, A549 Hep-G2 and VERO), NF-κB and TGF-β pathways and the levels of fibrosis markers (FN-1, MMP-9, COL1A1, α-SMA). A cohort of these compounds elicit anti-proliferative and anti-inflammatory effects with potency enhancement as high as 1000-fold relative to the standard of care PFD. Based on the data from these experiments, compound 15c was identified as a lead based while the next best compounds are 10c, 11c and 20e. Inspired by the study described in chapter 2, I designed and synthesized macrolide (azithromycin (AZM) and clarithromycin (CLM)) conjugates of three antioxidants – alpha lipoic acid (ALA), fumarate and piperic acid (PIPE) – in chapter 3. After investigation of the cytotoxicity of these macrolide-antioxidant conjugates against cancer cells, normal kidney cell line, and fibroblast cell line, I observed that most of novel compounds showed significant enhancement (more than 100-fold) in cytotoxicity and stronger anti-fibrotic effects relative to their unconjugated antioxidants. Specifically, ALA derivatives showed strong STAT 3 inhibition and extracellular matrix (ECM) components production inhibition effects with attenuation of TGF-β stimulation. Fumarate and PIPE derivatives also demonstrated strong anti-fibrotic effects and Nrf-2 activation. In Chapter 4, I report the discovery that macrolide antibiotic clarithromycin (CLM) undergoes tandem dehydration- cyclization-dehydration reactions, involving C-11 and C-12 hydroxyl groups and the C-9 keto moiety, to furnish a dihydrofuranyl macrolide AO-02-63. I observed that AO-02-63 inhibits the activities of prokaryotic and eukaryotic ribosomes and possibly disrupts the activity of hnRNPs. AO-02-63 also inhibits the proliferation of all cell lines in the NCI-60 panel with low micromolar IC50s and elicits anti-inflammatory activity similar to CLM, although with a 10-fold potency enhancement. The broad anti-cancer activity of AO-02-63 could be due to its inhibition of protein synthesis and mRNA processing, two processes that are vital for the survival of cells. The potential of STAT 3 pathway inhibition as an anticancer and anti-inflammatory strategy is under active investigation in preclinical and clinical settings. Chapter 5 of this thesis focused on validating our hypothesis that simultaneous STAT 3 and histone deacetylase (HDAC) inhibition will lead to more durable anti-proliferative effects in STAT 3-addicted cancer cells. Toward this end, I synthesized 5 pyrimethamine (PYM)-derived compounds and tested them against Hep-G2, A549, VERO, MDA-MB-231, and MCF-7 cell lines. I noticed that these compounds inhibited both HDAC and STAT 3 pathway intracellularly. Interestingly, compounds 12b and 12c showed 6- to 10-fold cell-type selectivity for a STAT 3-dependent, TNBC cell line MDA-MB-231. In Chapter 6, I used an in silico molecular docking tool (Autodock vina) to design three classes of PYM derivatives (total of 12 compounds) as putative STAT 3 inhibitors that function by blocking the DNA binding domain of STAT 3. I synthesized these compounds and profiled their STAT 3 inhibition in a cell free assay. Subsequently, they were analyzed against Hep-G2, A549, VERO, MDA-MB-231, and MCF-7 cell line. I found that class II compounds 11b-d showed 100-fold enhanced cytotoxicity relative to PYM and are also 100-fold better STAT 3 pathway inhibitors. Using a p-STAT 3 DNA binding assay, I found that the STAT 3 inhibition activities of these PYM derivatives are largely due to their direct STAT 3 DNA binding interruption. These PYM-HDAC inhibitors and STAT 3 DNA domain inhibitors could be novel anticancer agents that are selective for STAT 3-addicted cancer cells. In chapter 7, I described results from characterization of the anti-proliferative activities and mechanism of action of 19 glycosylated HDAC inhibitors (HDACi). I found that these compounds are selectively cytotoxic to several HCC cell lines possibly due to GLUT2-mediated uptake with lead compound STR-V-53 significantly more selective for HCC cells. In collaboration with the Petros Lab at Emory University, we found that STR-V-53 is non-toxic to healthy mice (MTD > 100 mg/kg) and effectively suppressed tumor growth in orthotopic murine model of HCC. In addition, we identified STR-V-165 and STR-I-195 as back-up compounds. Collectively, these glycosylated HDACi are promising anti-HCC agents.
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ItemThe design and application of functional enyne reagents in metathesis polymerization(Georgia Institute of Technology, 2021-04-19) Zhang, TianqiRing-opening metathesis polymerization (ROMP) using Grubbs-type initiators has become a widespread polymerization technique due to its remarkable functional group tolerance and reliability. This has enabled the synthesis of well-defined materials with applications. However, efficient methods for chain-end modification of ROMP and recycling metal initiators remain significant challenges. The research reported in this thesis explored the design and application of functional enyne reagents to overcome these challenges in ROMP. The key to all of these methods is a terminal alkyne that rapidly reacts with the ruthenium alkylidene and serves as a directing group to promote otherwise inefficient transfer reactions intramolecularly. Using this general relay strategy, different enyne molecules can be designed to give direct polymer-polymer coupling or to generate functional initiators, enabling the functionalization of both ends of the metathesis-derived polymer chain. The enyne derivatives are also capable of recycling the ruthenium catalyst in pulsed-addition ring-opening metathesis polymerization (PA-ROMP) to produce multiple functional chains from single ruthenium initiator with low dispersities. In addition, the terminating type enyne derivatives can be designed as a branching agent, which can be used to synthesize well defined branched ROMP polymers in a convergent synthetic pathway. Overall, the utilities of ROMP for macromolecular construction are widely expanded through these functional enyne reagents and could find broad applications in the design of functional materials.