Synthetic strategies for polysaccharide-protein conjugates, pH-responsive hydrogels, and amorphous solid dispersion (ASD) polymers were developed. Conjugating a polysaccharide to a protein drug via a covalent bond may improve its medical properties including solubility, stability, immunogenicity, circulation time, and targeting ability. Regioselectivity of conjugation is still challenging. We developed a strategy for regioselective conjugation of amino acid esters to polysaccharides, by employing 6-Br-polysaccharides in SN2 substitution reactions with amino acid esters. This work provides a good starting point for the regioselective conjugation of polysaccharides to proteins. Polysaccharides can also serve as hydrogel drug carriers. Most hydrogels employed in drug delivery work by incorporating the drug physically. We synthesized sustained and pH-responsive hydrogels using oxidized hydroxypropyl cellulose (Ox-HPC)/carboxymethyl chitosan (CMCS) crosslinked by imine bond. Phenylalanine as a model amine-containing drug was chemically bonded to the Ox-HPC hydrogel component and was observed to release faster at the pH of a tumor microenvironment. These hydrogels show promise as targeting cancer drug carriers. ASDs are polymeric systems to disperse poorly soluble drugs amorphously and enhance permeation from the gastrointestinal tract (GI tract) to the bloodstream. We synthesized potentially zwitterionic cellulose derivatives by reductive amination of Ox-HPC with ω-aminoalkanoic acids and obtained products with the degree of substitution (cation and anion) up to 1.6, which is difficult to attain using previous methods. The products showed manipulated amphiphilicity and excellent thermostability, exhibiting potential application in ASDs. We anticipate that these strategies will benefit future polysaccharide chemistry research and permit synthesis of a broad variety of more functional biomedical materials. / Doctor of Philosophy / Polysaccharides are long chains of individual sugars ("polymers"). Many natural-sourced polysaccharides are sustainable, biodegradable, and have low toxicity. Polysaccharide-based materials may improve the properties of current drugs, resulting in decreased cost, enhanced absorption efficiency, and continuous and/or targeted delivery. Protein drugs such as human insulin have a significant role in medicine. However, the residence time of a protein drug in the human body is short. To overcome this challenge, we designed a method to link polysaccharides to proteins at controlled reaction sites, and reported herein the first step of this route. The final polysaccharide-protein products will even have the ability to recognize and access target cells, like those of tumors. Tumor tissues are more acidic than normal tissue and can trigger faster release of drug from drug carriers. We developed polysaccharide-based hydrogels, which are gels that bind a great deal of water but won't dissolve in it, as acid-sensitive carriers. In addition, our hydrogels are also injectable, and can spontaneously repair themselves. These properties make our hydrogels promising as cancer targeting drug carriers. Most new drug candidates have poor water solubility and permeation through the gastrointestinal tract to reach the blood stream. Dispersing the insoluble drug into a properly designed polymer network can enhance dissolution, permeation, and absorption. We developed a new family of polymers designed for this purpose using two cheap starting materials. These polymers can interact with the drug, preventing it from forming crystals and simultaneously promoting slow drug release. Overall, we explored ways to modify polysaccharides to create harmless, effective medical materials. We aim to promote science and benefit human health via our research.

Particles that deposit in the respiratory airways can come from many sources, such as environmental pollution, particles created in the workplace, and inhalers that are designed to deliver medicines to the lungs. Once these particles deposit in the respiratory airways, they can interact in a variety of ways. Some particles are toxic and can cause damage to lung tissues, others may have little to no effect on health, and some may provide some benefit or therapy. Once particles land in the respiratory airways, the interactions they have with proteins can impact where they go and how they behave. This thesis explores how particles that are inhaled may impact health through toxicity to lung cells. Aerosols produced from photooxidation of decamethylcyclopenta-siloxane, an ingredient common in personal care products, were exposed to lung cells using an air-liquid interface exposure system to assess if these aerosols impact lung cell health. No significant impacts on lung cell health were observed. Copper oxide, a component of cigarette smoke, urban particulate matter, and e-cigarette vapor, was assessed for its role in lung disease. Copper oxide nanoparticles were exposed to lung cells, and their viability, expression of a platelet activating factor receptor (PAFR), and susceptibility to infection with a pneumonia-causing bacterium (S. pneumoniae) were measured. Copper oxide nanoparticles were found to be toxic to lung cells. At some doses, increases in PAFR were observed, but no clear differences in susceptibility to bacterial infection were observed. This research improves knowledge of how inhaled materials can impact health, providing insight into how particles from human-derived sources affect the lungs. This thesis further explores how particles behave in the thin layer of fluid that covers the respiratory epithelium. This fluid contains a complex mixture of proteins, and this work aims to identify some of the ways these proteins interact with particles and influence behavior. This was accomplished by first investigating how individual proteins from this fluid interact with particles. Particle behavior was studied after exposure to these proteins, as well as the lung cell responses to the particles before and after interaction with individual proteins. These lung proteins were found to induce aggregation, significantly alter surface charge, and reduce cell uptake of particles. After studying how individual proteins might specifically affect particle behavior, particles were exposed to bronchoalveolar lavage fluid (BALF), a diluted lung fluid collected by rinsing lungs with saline. Particle responses to proteins in this fluid were compared to those in serum, a protein-rich blood extract. These studies identified differences in how various surface-functionalized polystyrene particles aggregated in BALF compared to serum. When particles were exposed to serum or BALF, they tended to be less likely to associate with lung cells. With some particle types studied, there were significant differences in how much BALF or serum reduced cell attachment and uptake. In addition to demonstrating that lung fluids impact particle behavior in a manner that differs from serum, a method was developed to increase the concentration of the proteins in BALF to partially undo the dilution that occurs during collection. After studying how protein adsorption can cause aggregation, cover up particle surfaces, and reduce attachment and uptake by lung cells, a polymer coating was synthesized to reduce particle interactions with these proteins and assist in stabilizing particles in lung fluids. This coating was tested in both BALF and serum to demonstrate its general utility at reducing undesired interactions with proteins in biological fluids and was found to enhance particle stability in lung fluids as well as saline. This research enhances understanding of how particles behave in the respiratory airways, providing tools to further study how particles behave in lung fluids and demonstrating a polymer coating that is useful in this environment.

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