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The purpose of this investigation has been to determine the characteristics of the immune response to 1-fluoro-2,4-dinitrobenzene when this hapten is conjugated with various types of proteins.

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.

The Enhanced Permeability and Retention (EPR) effect has seen considerable exploration by many researchers since it’s discovery by Maeda et al in 1985. Polymers and nanoparticles with a long blood residence half-life can accumulate in some tumour tissues, allowing for the delivery of either diagnostic or therapeutic payloads. We have contributed to this field by the development of methodology to prepare radiolabeled dendrimers which are suitable for EPR effect accumulation with a variety of peripheral functionalities. The first of these was a 99mTc-labeled fifth generation dendron which was peripherally functionalized with low molecular weight poly(ethylene glycol) chains, which was observed to accumulate in xenograft mouse tumours over the course of 6 hours. This work led to the development of improved synthetic means for the preparation of high generation dendrimers with complex peripheral functionality, which hinged on the use of the Strain Promoted Alkyne-Azide Cycloaddition reaction to give high generation dendrimers by a convergent approach. This resulted in the facile preparation of dendrimers with challenging peripheral functionality in reaction times as short as 5 minutes. This SPAAC based convergent synthesis approach was used to prepare 99mTc labeled sulfobetaine and carboxybetaine dendrons of the sixth generation, and these compounds were found to have a size greater than the renal clearance threshold of ~ 5 nm, though it was found that labeling with [99mTc(CO)3]+ was not possible without extensive degradation of the zwitterionic dendrimers. Finally, the dendritic architecture explored for imaging was adapted for use in shielding an enzyme from macromolecules while retaining activity against the native small molecule substrate, and we found that conjugation of high-generation bis-MPA dendrons to α-chymotrypsin was an effective way to eliminate enzyme activity against macromolecules while preserving efficacy against small substrates, indicating this approach may be an effective way to shield proteins from the immune system without interfering with their desired function. This work illustrates the ability to radiolabel polyester dendrimers for tumour imaging through the EPR effect. In addition, it has demonstrated that polymer architecture has a large impact on the properties of polymer-protein conjugates and gives evidence of unique properties that are imparted by the conjugation of high-generation dendrimers onto a protein. / Thesis / Doctor of Science (PhD)

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