UMD Theses and Dissertations
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Item LEVERAGING SELF-ASSEMBLY AND BIOPHYSICAL DESIGN TO BUILD NEXT-GENERATION IMMUNOTHERAPIES(2022) Froimchuk, Yevgeniy; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The immune system has evolved mechanisms to respond not only to specific molecular signals, but also to biophysical cues. Interestingly, research at the interface of biomaterials and immunology has also revealed that the biophysical properties and form of vaccines and immunotherapies impact immunological outcomes. For example, the intermolecular distance between antigen molecules on the surface of nanoparticles can impact formation of T cell receptor clusters that are critical during T cell activation. Despite the importance of biophysical cues in tuning the immune response, the connections between these parameters and immunological outcomes are poorly understood in the context of immunotherapy. Immunotherapies harness an individual’s immune system to battle diseases such as autoimmunity. During autoimmune disease, the immune system malfunctions and mistakenly attacks self-tissue. Immunotherapies can help tailor and guide more effective responses in these settings, as evidenced by recent advances with monoclonal antibodies and adoptive cell therapies. However, despite the transformative gains of immunotherapies for patients, many therapies are not curative, work only for a small subset of patients, and lack specificity in distinguishing between healthy and diseased cells, which can cause severe side effects. To overcome these challenges, experimental strategies are attempting to co-deliver self-antigens and modulatory cues to reprogram dysfunctional responses against self-antigens without hindering normal immune function. These strategies have shown exciting potential in pre-clinical models of autoimmune disease but are unproven in clinical research. Understanding how biophysical features are linked to immunological mechanisms in these settings would add a critical dimension to designing translatable, antigen-specific immunotherapies. Self-assembling materials are a class of biomaterials that spontaneously assemble in aqueous solution. Self-assembling modalities are useful technologies to study the links between biophysical parameters and immune outcomes because they offer precise control and uniformity of the biophysical properties of assembled moieties. Our lab leveraged the benefits of self-assembly to pioneer development of “carrier-free” immunotherapies composed entirely of immune signals. The therapies are composed of self-antigens modified with cationic amino acid residues and anionic, nucleic acid based modulatory cues. These signals are self-assembled into nanostructured complexes via electrostatic interactions. The research in this dissertation utilizes this platform as a tool to understand how tuning the biophysical properties of self-antigens impacts molecular interactions during self-assembly and in turn, how changes in biophysical features are linked to immunological outcomes. Surface plasmon resonance studies revealed that the binding affinity between signals can be tuned by altering overall cationic charge and charge density of self-antigen, and by anchoring the self-antigen with arginine or lysine residues. For example, the binding affinity between signals can be increased by increasing the total cationic charge on the self-antigen, and by anchoring the self-antigen with arginine residues rather than lysine residues. Computational modeling approaches generated insights into how molecular interactions between signals, such as hydrogen bonding, salt-bridges, and hydrophobic interactions, change with different design parameters. In vitro assays revealed that a lower binding affinity between self-assembled signals was associated with greater reduction of inflammatory gene expression in dendritic cells and more differentiation of self-reactive T cells towards regulatory phenotypes that are protective during autoimmunity. Taken all together, these insights help intuit how to use biophysical design to improve modularity of the self-assembly platform to incorporate a range of antigens for distinct disease targets. This granular understanding of nanomaterial-immune interactions contributes to more rational immunotherapy design.Item Bringing New Chemistry to Guanosine Hydrogels(2020) Xiao, Songjun; Davis, Jeffery T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Molecular self-assembly is a powerful method to construct functional materials such as supramolecular hydrogels. Hydrogels contain mostly water but show solid-like rheology. Nucleosides and nucleotides contain rich recognition information, which opens up opportunities for gelator design. Hydrogels derived from these natural products have seen a resurgence in the past decade due to the high biodegradability and biocompatibility. Guanosine (G 1) and its analogs are powerful supramolecular hydrogelators. The structural basis for most guanosine hydrogels is G4•M+ quartet with K+ being the best metal to stabilize such a structure. These hydrogen-bonded macrocycles further stack to form 1D G-quadruplex that traps water to give hydrogels. Guanosine hydrogels have been used for applications such as bioactive molecule trap and release, environmental remediation, sensing and cell culture. While the H-bonded G-quadruplex is critical for gelation, G 1 can be synthetically modified to introduce new functions. The work presented here is focused on G-quartet hydrogels made from synthetic guanosine analogs. Guanosine analogs containing sulfur on 8- and 5ʹ-position are purified and their hydrogelation properties in water were examined. The resulting hydrogels can potentially be applied to environmental remediation. Substitution of 5ʹ-OH in G 1 into a hydrazine group in HG 2 significantly improves the hydrogelation properties. The resulting HG 2 KCl hydrogel can be used to non-covalently bind anionic dyes and covalently trap toxic electrophiles such as acrolein. A binary mixture of G 1 and HAG 15 forms a stable hydrogel with KCl. The hydroxamic acid group in HAG 15 serves as a pH-switchable group that can be applied as a carboxylic acid substitute in hydrogelator design. Furthermore, the hydrogel serves as a supramolecular siderophore and binds Fe3+ to generate patterns on the gel surface. The surface can be erased with a reducing agent and rewritten with Fe3+.Item DESIGN OF HYBRID POLYMER- INORGANIC NANOASSEMBLIES FOR BIOMEDICAL APPLICATIONS(2018) Yang, Kuikun; Nie, Zhihong; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Assembly of inorganic nanoparticles (NPs) can give rise to novel collective properties due to the coupling between adjacent subunits, which are not accessible from individual nanoparticles. Among them, hybrid polymer-inorganic nanoassemblies (HPINs) are particularly attractive by combining the complementary strengths of inorganic NPs and polymers. This dissertation describes the design of HPINs with elaborately tailored physicochemical properties and the applications of HPINs in tumor diagnosis and therapy. First, we introduced the design principles and representative morphologies of HPINs. Size, shape, surface charge and coatings are crucial properties to be considered before the design of HPINs. Among various types of HPINs, we focused on the hybrid vesicles assembled from polymer-tethered inorganic NPs due to their synergistic properties that surpass their constituent components. We also summarized recent advances in the development of HPINs as attractive platforms for cancer imaging and therapy. Second, we developed an enzyme-free signal amplification technique, based on gold vesicles encapsulated with Pd−Ir NPs as peroxidase mimics, for colorimetric assay of disease biomarkers with significantly enhanced sensitivity. Third, we introduced a universal approach to attach amphiphilic block copolymers onto oleic acid or/and oleylamine capped NPs to trigger their assembly. Various NPs including Fe3O4, Cu9S5, MnO and upconversion NPs were assembled into hollow vesicles with novel physicochemical properties for a variety of biomedical applications. Finally, we described the fabrication of nanosized magneto-vesicles comprising tunable layers of densely packed superparamagnetic iron oxide nanoparticles (SPIONs) in membranes via cooperative assembly of polymer-tethered SPIONs and free poly(styrene)-b-poly(acrylic acid). Due to the high packing density of SPIONs, the magneto-vesicles showed enhanced signal in magnetic resonance imaging as well as improved efficiency in magnetic-guided drug delivery both in vitro and in vivo.Item Tailoring Guanosine Hydrogels for Various Applications(2018) Plank, Taylor Nicole; Davis, Jeffery T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Supramolecular hydrogels are of current interest for their ease of use, potential biocompatibility, and reactivity to stimuli. These gel materials have found use in a number of fields ranging from drug delivery and tissue engineering to sensing and environmental remediation. For over a century, guanosine (G 1) and its derivatives have been known to form hydrogels based on self-assembled G4-quartet structures. Recent research has focused on extending the lifetime stability of these hydrogels and modifying their properties to better suit the gels for applications in multiple fields. One such method involves the mixing of G 1 (or G-derivatives) with 0.5 eq of KB(OH)4, which results in the formation of guanosine-borate (GB) diesters. The GB-diesters self-assemble into G4-quartets stabilized by K+, the G4-quartets then stack to form wires that entangle to make a fibrous hydrogel network. This thesis details modifications of this GB-hydrogel system and explores applications of the resulting hydrogels. Modification of the 5ʹ-OH group of G 1 to form 5ʹ-deoxy-5ʹ-iodoguanosine (5ʹ-IG 2) results in a hydrogel that self-destructs via intramolecular cyclization to 5ʹ-deoxy-N3,5ʹ-cycloguanosine (5ʹ-cG 3). Guanine analog drugs can be incorporated into this hydrogel network and then released upon self-destruction of the gel. Substitution of boric acid with benzene-1,4-diboronic acid (BDBA 4) to form hydrogels with G 1 and K+ results in hydrogels that can be crosslinked with Mg2+. These G-BDBA-Mg hydrogels have a lower critical gelator concentration (cgc) than their non-crosslinked counterparts and can be used for cell growth applications. Utilizing binary mixtures of 8-aminoguanosine (8AmG 5) with G 1 allows for the formation of hydrogels with various salts. Hydrogels made of different salts preferentially absorb either cationic or anionic dyes from water, making them candidates for use in environmental remediation. Other 8-substituted G-analogs, including, 8-bromoguanosine (8BrG 6), 8-iodoguanosine (8IG 7), and 8-morpholinoguanosine (8morphG 8) can be used in binary mixtures with G 1 to form gels at room temperature upon mixing with KB(OH)4. Room temperature hydrogels have potential applications in enzyme immobilization, drug encapsulation, and environmental cleanup.Item DESIGN AND HIERARCHICAL ASSEMBLY OF AMPHIPHILIC SUPRACOLLOIDS THAT MIMIC BIMOLECULAR COMPOUNDS(2018) Zhang, Shaoyi; Nie, Zhihong; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Self-assembly of nanoparticles (NPs) into desired structures with precisely controlled NP organization is crucial to the property discovery and application of inorganic NPs. Despite tremendous efforts made in the past decades, little progress has been achieved in controlled hierarchical assembly of NPs. My dissertation is focused on the multi-level assembly of inorganic NPs into various hierarchical structures by tethering NPs with functional block copolymers (BCPs). First, one versatile strategy was developed to design monodisperse amphiphilic supracolloids with defined valence and chemical patches by co-assembly of binary disparate hybrid building blocks composed of BCP-functionalized NPs. The binary BCP is composed of a hydrophilic/hydrophobic block and a Lewis base-containing/Lewis acid-containing block. The resulting supracolloids consist of two different types of inorganic NPs precisely arranged in space, which mimics the geometric shape and valence of bimolecular compounds containing two elements. By varying the size, chemical composition and feeding ratio of NPs, as well as the length of BCP combinations, supracolloids with different valences, compositions and localized chemical patches (which are determined by the BCP tethers) were produced in high yield. Second, the amphiphilic supracolloids were demonstrated to assemble into a range of two-dimensional (2D) hierarchical structures at the liquid/liquid interface. Depending on the quality of solvent, amphiphilic dimers were found to assemble into petal-like structures with different numbers of dimers. Moreover, amphiphilic trimers underwent side-by-side or end-to-end association to form ribbon or chain structures, depending on the arrangement of hydrophilic and hydrophobic domains (chemical patches). Third, the effect of polymer length of BCP tethers within supracolloids was systematically studied on the ribbon formation of trimer-like supracolloids with hydrophobic center and hydrophilic ends. It was found that longer hydrophobic block and shorter hydrophilic BCP tethers facilitate the formation of ribbon. The results were summarized in a product diagram. Finally, the pH effect on the assembly of amphiphilic supracolloidal trimers was investigated. A transition of assembly morphologies from ribbons to chains was observed, with changing pH of the water phase. This can be attributed to the change on the amphiphilicity of supracolloidal trimers upon the addition of acid or base.Item Immobilized Seed-mediated Growth of Two Dimensional Arrays of Shaped Metallic Nanocrystals(2017) Perez Cardenas, Maria Teresa; Nie, Zhihong; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Acknowledging that the optical properties of noble metal nanocrystals (NMNCs) are largely determined by their size, composition, and shape, the demand for NMNCs with controlled shapes is expected to increase. To expand the property discovery and application development of polyhedral NMNCs, it is pivotal to understand the key factors involve in the nucleation and growth processes of NMNCs for better control over the crystal facets. Furthermore, to implement polyhedral NMNCs into functional devices for applications in such as chemical sensors, photovoltaics, and catalysis, it is essential to design cost-effective methods to assemble NMNCs into two-dimensional arrays with controlled orientation and particle distance. This dissertation describes the stability and interaction of molecular species formed during the reduction of gold metal precursor, as well as factors that influence the formation of nanocrystals with different shapes. Our study suggests that during the Au reduction step, an intermediate complex is formed. Over time the complex degrades decreasing the concentration of gold ions and subsequently slowing down or inhibiting the nucleation; thereby, affecting the reproducibility of synthetic methods. My findings will provide guidance for the development of more simple, reliable methods to control the shapes of the nanocrystals. Additionally, I developed an immobilized seed-mediated growth strategy for the fabrication of two-dimensional arrays of mono- and bi-metallic polyhedral nanocrystals with well-defined shapes and orientations on a substrate. This method relies on the controlled solution-phase deposition of gold and palladium metals on a selectively exposed surface of self-assembled seed nanoparticles that are immobilized on a substrate through collapsed polymer brushes. The synthetic approach I developed presents an important addition to current tools for the fabrication of substrate-supported functional nanocrystals as new materials and devices.Item Self-assembly of inorganic nanoparticle amphiphiles for biomedical applications(2015) Liu, Yijing; Nie, Zhihong; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Ensembles of interacting nanoparticles (NPs) can exhibit novel collective properties ─ arising from the coupling between NPs ─ that can be radically different from individuals. Realizing the enormous potential of NPs in biomedical applications requires the organization of NPs into hierarchically ordered structures. My dissertation is focused on the design of NP amphiphiles (NPAMs) and the use of NPAMs as building blocks to construct polymer-inorganic hybrid materials. The NPAMs are made from NPs surface-grafted with amphiphilic block copolymers (BCPs). In this way, the NPAMs synergistically combine the properties of both inorganic NPs and grafted BCPs, such as optical and magnetic properties of NPs, and flexibility of BCPs. First, we demonstrated that NPAMs with relatively low polymer ligand densities (~0.03 chain/nm2) self-assembled into vesicular nanostructures composed of a single layer of NP chains in the membrane. The decrease in the interparticle distance between NPAMs in the chain vesicles led to strong plasmon coupling of NPs and hence enhanced efficiency in photoacoustic imaging. Second, we fabricated hybrid vesicles with well-defined shapes and surface patterns by co-assembling amphiphilic BCPs and NPAMs, which include Janus-like vesicles (JVs) with different shapes, patchy vesicles, and homogeneous vesicles. Third, we prepared magneto-plasmonic hybrid vesicles with various structures through concurrent self-assembly of NPAMs, free BCPs, and hydrophobic magnetic NPs. The hybrid vesicles were demonstrated for both light-triggered release of payload and magnetic resonance imaging. Particularly, the magnetic manipulation of vesicles to specific location can be used to enhance the photothermal effect of the vesicles in cancer imaging and therapy. Finally, we reported that the use of a microfluidic flow-focusing device for the self-assembly of JVs that can act as vesicular motors. The vesicles can be used to encapsulate active compounds, and the release of this payload can be effected using near-infrared light. This systematic study will help us gain deeper understanding of the self-assembly of NPAMs into controllable nanostructures and control the collective properties of NP ensembles for various applications. This research will also provide new insights into the fundamental questions that must be overcome before the hybrid materials can be utilized in effective cancer imaging and treatment.Item Gel Formation by the Self-Assembly of Small Molecules: Insights from Solubility Parameters(2014) Diehn, Kevin; Raghavan, Srinivasa R; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Many small molecules can self-assemble into long fibers and thereby gel organic liquids. However, no capability exists to predict whether a molecule in a given solvent will form a gel, a thin solution (sol), or an insoluble precipitate. In this thesis, we build a framework for gelation via a common gelator based on Hansen solubility parameters (HSPs). Using HSPs, we construct 3-D plots showing regions of solubility (S), slow gelation (SG), instant gelation (IG), and insolubility (I) for DBS in different solvents. Our central finding is that these regions radiate out as concentric shells. The distance (R0) from the central sphere quantifies the incompatibility between gelator and solvent. The elastic moduli of the gels increase with R0, while the time to gelation decreases with R0. Our approach can be used to design organogels of desired strength and gelation time by judicious choice of a solvent or a blend of solvents.Item Self-assembly in aqueous solutions of a non-ionic hydrotrope(2012) Subramanian, Deepa; Anisimov, Mikhail A; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Hydrotropes are amphiphilic molecules, too small to cause spontaneous self-assembly towards equilibrium mesoscale structures in aqueous solutions, but they form dynamic, noncovalent assemblies, which may create microscopic regions of lowered polarity. This enhances the solubilization of hydrophobic compounds, also known as solubilizates, in aqueous solutions and may cause further aggregation to larger structures. In this work, unusual mesoscopic properties of aqueous solutions of a non-ionic hydrotrope, namely tertiary butyl alcohol (TBA) have been investigated by light scattering, microscopy, and chromatography. Aqueous TBA solutions show anomalous thermodynamic and structural properties in the range of concentrations 3-8 mol % TBA and temperatures 0 - 25 °C. These anomalies appear to be associated with short-lived, short-ranged micelle-like structural fluctuations, distinctly different from usual concentration fluctuations in non-ideal solutions. Molecular dynamics simulations and neutron-scattering experiments show clustering of TBA molecules on a nanometer scale, interacting through hydrogen bonds with a shell of water molecules. In this concentration range, TBA aqueous solutions, although macroscopically homogeneous, occasionally show the presence of "mysterious" inhomogeneities on a 100 nm scale. We have found that the emergence of such inhomogeneities strongly correlates with impurities present in commercial TBA samples. Experiments with controlled addition of a third component, such as propylene oxide, isobutyl alcohol, or cyclohexane, reveal the mechanism of formation of these inhomogeneities through stabilization of micelle-like fluctuations by a solubilizate. These structures are long-lived, i.e., stable from a few days up to many months. We have confirmed that mesoscale structures in aqueous solutions can be generated from self-assembly of small molecules, without involvement of surfactants or polymers. This kind of self-assembly may potentially result in the development of novel nanomaterials.Item ACCELERATED SELF-ASSEMBLY OF PEPTIDE-BASED NANOFIBERS USING NANOMECHANICAL STIMULUS(2010) Chang, Jonathan Paul; Seog, Joonil; Material Science and Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)One-dimensional nanostructures are ideal building blocks for functional nanoscale assembly. Peptide-based nanofibers have great potential for building smart hierarchical structures due to their tunable structures at a single residue level and their ability to reconfigure themselves in response to environmental stimuli. In this study, it was observed that a pre-adsorbed silk-elastin-based protein polymer self-assembled into nanofibers through a conformational change on the mica substrate. Furthermore, using atomic force microscopy, it was shown that the rate of the self-assembling process was significantly enhanced by applying a nanomechanical stimulus. The orientation of the newly grown nanofiber was mostly perpendicular to the scanning direction, implying that the new nanofiber assembly was locally activated with a directional control. The method developed as a part of this study provides a novel way to prepare a nanofiber patterned substrate using a bottom-up approach.