Organizational Unit:

School of Chemistry and Biochemistry

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https://hdl.handle.net/1853/70752

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College of Sciences

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https://finding-aids.library.gatech.edu/agents/corporate_entities/153

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Now showing 1 - 10 of 11

Exciton and Charge Carrier Nonlinear Dynamics in Hybrid Organic-Inorganic Metal Halides

(Georgia Institute of Technology, 2024-04-27) Rojas Gatjens, Jorge Esteban

Hybrid-organic inorganic metal-halide semiconductors pose an interesting photophysical scenario. Due to the ionic and dynamic nature of the structure, their excited-state properties are highly correlated with the structure's vibrations, distortions, and solvation dynamics. This thesis studies the interactions between excited states (nonlinear dynamics), their manifestation in physical observables, and their relation to the material's structure and fabrication. We explore the exciton and charge carrier nonlinear dynamics, via incoherent and coherent spectroscopy, in hybrid organic-inorganic mixed-halide lead perovskites, Ruddlesden-Popper metal halides, and perovskite nanocrystals. The many-body interactions manifest in incoherent spectroscopy as nonlinearities in the photoluminescence and/or photocurrent and, in two-dimensional coherent spectroscopy lineshapes, in the spectral linewidth, phase, and many-particle state feature (e.g. biexcitons, trions). For bulk hybrid organic-inorganic mixed-halide lead perovskites, we resolve incoherent nonlinear dynamics with sub-picosecond resolution in the photoluminescence and photocurrent. We were able to characterize the competition between defect-assisted recombination, Auger recombination, and amplified spontaneous emission. For the Ruddlesden-Popper metal halide perovskites and perovskite nanocrystals, we used two-dimensional coherent spectroscopy to explore ultrafast exciton scattering events and exciton-carrier coupling dictating the exciton-quantum dynamics. The work of this thesis sheds light on the many-body interactions in hybrid-organic inorganic metal-halide semiconductors and provides the tools to transition from the description to the control of nonlinear dynamics.
Probing nonlinear phenomena with multidimensional and entangled photon spectroscopies

(Georgia Institute of Technology, 2024-04-25) Malatesta, Ravyn Alysha

This dissertation is concerned with understanding what is learned from novel spectroscopic techniques using entangled photon pairs and how they compare to coherent multidimensional spectroscopy. With both theory and experiment, it considers what is learned by treating the light in light-matter interactions semi-classically (as a periodic perturbation of a quantum system) versus treating light fully quantum-mechanically, taking advantage of quantum characteristics of light such as polarization or time-frequency entanglement.
Versatile Design Strategies of Protein Nanoparticles for Vaccines and Drug Delivery

(Georgia Institute of Technology, 2023-04-25) Bhattacharya, Sonia Bholanath

The broad theme of this thesis is designing protein nanoparticles with applications in vaccination and targeted delivery. We bring focus to three protein nanoparticle scaffolds in this thesis- bacterial sourced encapsulins and viral sourced PP7 and Qb - all with variety of applications in the literature. We establish the natural immunological properties of the encapsulin scaffold for engineering peptide nanoparticle vaccines. For further vaccine development efforts using these particles, we delve into ideas about optimum peptide antigen conformations that can be displayed on these particles along with heterologous combination vaccine therapies. We take cues from peptide’s native design and evaluate heterologous vaccination strategies with epitope focusing in mind in two ways. We immunofocus on peptide epitope’s sequence and conformation to develop monoclonal antibodies by sequentially priming and boosting with PP7-displaying linear or loop conformation peptide sequence then with whole protein containing the same peptide sequence in native conformation. Alternately, we design a similar vaccination strategy that displays same peptide antigen in a biologically relevant loop conformation but put them on two scaffold- PP7 and Enc- to improve peptide recognition. We inquire into the effects of directionality of introducing the scaffold to the immune system on antigenic peptide responses. Additionally, I discuss our preliminary efforts at targeting multiple epitopes for leishmaniasis vaccine with no commercial precedence. Finally, we explore the glycan ligand multivalency on surface functionalized Qb particles and show improved targeted delivery in hepatocytes. The collective work presented here is meant to guide the vaccine and drug delivery community on optimum design strategies of the plug-and-play particles.
Protein Nanoparticles For Applications In Chemical Biology And Immunology

(Georgia Institute of Technology, 2022-09-02) Hincapie, Robert

Throughout 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.
PEG (Polyethylene Glycol)-PCL (Polycaprolactone) Block Copolymers For 3D Printing Of Medical Devices

(Georgia Institute of Technology, 2022-01-18) Yang, Ruyi

PCL 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.
Oxanorbordienes and Azanorbordienes as thiol cleavable linkers

(Georgia Institute of Technology, 2021-05-06) De Pascalis, Lucrezia

Oxa/ 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.
Discovery of Monoclonal Antibodies for Diagnostics and Therapies Using Conjugate Virus-like Particle Vaccines

(Georgia Institute of Technology, 2021-05) Schroeder, Michelle

Monoclonal 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.
Directing the immune response using nanoparticle vaccines and drug delivery systems

(Georgia Institute of Technology, 2021-04-28) Chapman, Asheley Poole

Virus-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.
MICROPOROUS 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.
DISCOVERY OF NOVEL DRUGS WITH TISSUE AND CELL-TYPE SELECTIVITY FOR CANCER AND INFLAMMATION

(Georgia Institute of Technology, 2021-04-26) Wu, Bocheng

Uncontrolled 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.