Physical Sciences and Mathematics Commons^™

Development Of Biomolecule Nanoparticle Conjugate For Targeted Delivery Of Therapeutics, Peidong Wu

Doctoral Dissertations

Delivery of therapeutics specifically to the disease site is the final goal for the field of drug discovery. Considerable efforts in understanding disease biology have contributed to identifying novel therapeutics such as small molecules, proteolysis targeting chimeras (PROTACs), peptides, proteins, and nucleic acids. However, improving their efficacy as well as minimizing their off-target toxicity remains challenging. Developing vectors that could not only efficiently encapsulate these therapeutics but also direct these therapeutics to the target site is a potential solution to address these challenges. In this dissertation, a block-copolymer-based nanoparticle platform has been developed optimized, and decorated with various kinds of …

Frontiers In The Self-Assembly Of Charged Macromolecules, Khatcher O. Margossian

Doctoral Dissertations

The self-assembly of charged macromolecules forms the basis of all life on earth. From the synthesis and replication of nucleic acids, to the association of DNA to chromatin, to the targeting of RNA to various cellular compartments, to the astonishingly consistent folding of proteins, all life depends on the physics of the organization and dynamics of charged polymers. In this dissertation, I address several of the newest challenges in the assembly of these types of materials. First, I describe the exciting new physics of the complexation between polyzwitterions and polyelectrolytes. These materials open new questions and possibilities within the context …

Development Of Stimuli-Responsive Liposomes For Drug Delivery Applications, Jinchao Lou

Doctoral Dissertations

Liposomes are spherical nano-assemblies that are proven to be effective drug delivery vehicles. Due to their unique bilayer structures, they are able to encapsulate both hydrophilic and hydrophobic drugs in their aqueous inner core and membrane bilayers, respectively. While liposomal delivery platforms exbibit numerous advantages, the therapeutic efficacy of these platforms would be enhanced by developing triggered release strategies such that one can tune the timing and location of the cargo release in a controlled manner. In this dissertation, we mainly present the development of stimuli-responsive liposomes targeting different disease-associated metabolites utilizing rationally designed synthetic lipid switches.

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Enhancing The Intracellular Availability Of Protein Cargoes In Polymer-Mediated Delivery, Christopher R. Hango

Doctoral Dissertations

Protein drugs, including antibodies, are rapidly emerging as the top-selling pharmaceuticals worldwide owing to their unparalleled specificity and biocompatibility. However, none of the currently-approved protein therapeutics act intracellularly, despite the vast majority of potential drug targets residing within the cell. This is due mainly to the paramount challenge of transporting hydrophilic macromolecular cargoes across the plasma membrane. As such, effective protein carriers are essential for the advancement of modern medicine. Despite significant advances, many challenges still plague protein delivery. Following membrane transduction, delivery vectors must preserve the structure and activity of their cargoes while transporting them to the correct subcellular …

Design And Synthesis Of Stimuli-Responsive Polymeric Nanogels Towards Therapeutic Translation, Mallory R. Gordon

Doctoral Dissertations

In the application of delivery of therapeutics, nanostructures of various composition have been employed due to their capacity to act as a host for lipophilic payloads. Advances in the synthetic preparation, size, morphology, and chemical or physical characteristics of polymers have impacted their development and versatility. A detailed understanding of polymeric nanoparticle host-guest properties is crucial to their practical translation to specific delivery applications. Further, these features must be highly tailorable to overcome biological barriers, stably encapsulate their therapeutic contexts, and exhibit payload release selectively in the target environment. In this dissertation, we aim to rationally design polymeric nano-scale assemblies …

Nanoparticle As Supramolecular Platform For Delivery And Bioorthogonal Catalysis, Gulen Yesilbag Tonga

Doctoral Dissertations

Nanoparticles (NPs) are being investigated widely for many applications including imaging, drug delivery, therapeutics, materials, and catalysis due to their unique and tunable physical and chemical properties. Among NPs, gold nanoparticles (AuNPs) have attracted great attention due to ease of synthesis and surface functionalization, inertness of the core, biocompatibility, and functional versatility. Introducing supramolecular chemistry into the nanoparticle-based platforms brings out controllable properties, dynamic self assembly processes, and adjustable performance. My research has focused on the synthesis of AuNPs bearing different surface functionalities and their host-guest interactions with synthetic small molecules or commercially available hydrophobic catalysts for delivery and therapeutic …

Stimuli Responsive Polymeric Nanogels For Hydrophobics & Hydrophilics Delivery, Kishore Raghupathi

Doctoral Dissertations

Stimuli responsive nanoparticles have gained significant interest in the drug delivery research. The essential goal of drug delivery is to improve the efficacy of drugs by increasing their stability and bioavailability. Small molecule hydrophobic drugs face limited bioavailability due to their poor water solubility. Biologic drugs on the other hand, lack bioavailability because of their degradation by various enzymes encountered during blood circulation. For a systemic delivery approach, depending on site of drug action, delivery vehicles must pass through several contrasting micro environments before delivering the cargo selectively at the target site. Therefore, it is essential that a delivery vehicle …

Engineering The Nano-Bio Interface Of Gold Nanoparticles For Biomedical Applications, Ying Jiang

Doctoral Dissertations

Gold nanoparticles (AuNPs) have emerged as a promising platform for a myriad of biomedical applications, including sensing, drug delivery, and antibiotics. In this thesis, I have studied and engineered the interface of AuNPs with different biological systems, demonstrating a large variety of biomedical applications by modulation of these interfaces. My research was initially focused on systematically tuning the physicochemical properties of nanoparticles to understand nano-bio interactions at the cellular level. The results demonstrate that size and surface charge of AuNP interact in an interrelated fashion to modulate nanoparticle internalization by cells, providing an engineering strategy for designing nanomaterials for drug …

Responsive Supramolecular Assemblies Based On Amphiphilic Polymers And Hybrid Materials, Longyu Li

Doctoral Dissertations

The design and synthesis of responsive supramolecular assemblies are of great interest due to their applications in a variety of areas such as drug delivery and sensing. We have developed a facile method to prepare self-crosslinking disulfide-based nanogels derived from an amphiphilic random copolymer containing a hydrophilic oligo-(ethylene glycol)-based side-chain functionality and a hydrophobic pyridyl disulfide functional group. This thesis first provides a concept of studying the influence of Hofmeister ions on the size and guest encapsulation stability of a polymeric nanogel. The size and core density of nanogel can be fine-tuned through the addition of both chaotropes and kosmotropes …

Transferrin-Based Therapeutics And Analytical Methods To Characterize Them, Son N. Nguyen

Doctoral Dissertations

Modern development of medicine requires detailed characterization by state-of-the art analytical techniques that can be used to analyze covalent structure, conformations and protein-receptor interaction to quantitatively measure biodistribution of protein therapeutics. Mass spectrometry has already become an indispensable tool facilitating all stages of protein drug development. Particularly, this work has demonstrated the tremendous potential of electrospray ionization (ESI) mass spectrometry (MS) in this arena by providing invaluable information beyond mass measurement that can be used to optimize protein drug conjugate structures during early stages of development, and to further catalyze drug design efforts. Additionally, a new sensitive and selective method …

Nanoparticle Building Blocks For Functional Structures, Youngdo Jeong

Doctoral Dissertations

A major goal in material science is achieving a desired function using structures fabricated with designed building blocks. Advanced synthetic and self-assembly techniques allow various nanomaterials to become promising building blocks, providing the control of the interaction between building blocks. The unique properties of nanomaterials can be transferred to structured systems. Among nanomaterials, inorganic nanoparticles such as gold nanoparticles (AuNPs), magnetic particles, and quantum dots (QDs) provide useful physical properties stemming from their inorganic core, large surface areas, and oriented surface functionalities. My research has focused on fabricating functional systems using gold nanoparticles (AuNPs), manipulating the interaction between AuNPs, bio-entities, …

Functional Phosphorylcholine Polymers: Prodrugs And Biomaterials, Samantha B.M. Page

Doctoral Dissertations

This thesis describes the synthesis and applications of multifunctional, hydrophilic polymers consisting of a methacrylate backbone and zwitterionic phosphorylcholine (PC) pendent groups, prepared by free radical polymerization of the zwitterionic monomer, 2-methacryloyloxyethyl phosphorylcholine (MPC). Advances in polymer chemistry, applied to PC polymers, allowed for the preparation of well-defined structures with controlled molecular weight, narrow polydispersity, and facile incorporation of functional comonomers, giving breadth to the range of materials accessible for different applications. Built-in functionality included fluorophores and reactive groups for post-polymerization transformations, such as drug conjugation or cross-linking. The ability to form well-defined structures based on the polyMPC backbone is …

Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego Amado Torres

Doctoral Dissertations

Proteins have the capacity to bind specific sets of compounds known as ligands, these are small molecules with a recurrent theme in their molecular design that is a characteristic exploited here to (i) identify particular affinities of small molecules for proteins with the aim of using them as ligands, inhibitors, or targeting moieties in more complex systems by means of a methodology that screens small molecules based on protein affinity; (ii) decorate a self-assembling supramolecular system at different positions, making it responsive to a complementary protein with the aim of exploring differences in disassembly and sensitivity of the release of …