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|Title:||The Synthesis and Characterization of Dendronized Biomacromolecules|
|Department:||Chemistry and Chemical Biology|
|Abstract:||Dendrimers are a unique class of polymer characterized by their structural perfection, monodisperse nature, and well defined, multi-valent periphery. These reasons, among others, make dendrimers an attractive polymer for use in biological systems, particularly in the field of polymer- protein therapeutics. While many therapeutics make use of a native enzyme, tethering a polymer to the therapeutic has many advantages such as increasing the lifetime of the therapeutic, and its overall efficacy. Polymer-protein therapeutics however must be selective to which biomolecules they interact with. While small molecule interactions are important to the regulation of the therapeutic, larger macromolecular interactions can often have a negative impact. It therefore becomes a challenge to construct polymer protein therapeutics that can selectively control these substrate interactions. The molecular sieving effect investigates this idea through the preparation of polymer-protein conjugates that can selectively interact with biomolecules of certain sizes. While it has recently been shown that the molecular sieving effect can be achieved using high generation dendrimers that are quite large in size, these dendrimers are time consuming, and laborious to construct. In this work we sought out to further explore the molecular sieving effect using a series of novel linear-dendritic hybrid polymers. We hypothesized that appending a linear polymer to a lower generation dendrimer would help to prepare the larger polymeric constructs necessary for molecular sieving, in a more time- and labour-efficient manner. Furthermore, the addition of a linear polymer onto a dendrimer can have a beneficial effect the overall behaviour of the eventual conjugate. Herein, we describe the synthesis of a library of linear-dendritic hybrid polymers and their conjugations to a model enzyme. This library consists of 9 novel linear-dendritic hybrid polymers, each varying in the generation of dendrimer used, and the size of linear polymer, PEG, appended to the dendrimer’s periphery. We first prepared these dendrimers using divergent synthesis approach, however, dendrimer core modifications post-PEGylation were unable to be performed due to complete core isolation within our dendrimers. We then developed a convergent synthesis approach to prepare these dendrimers which proved to be a better alternative as core modifications before PEGylation circumvented the issues we faced with the divergent approach. Each PEGylated dendrimer was functionalized to obtain a reactive DBCO moiety that would allow for simple conjugation to our model enzyme using click chemistry. Upon full characterization of each linear- dendritic hybrid polymer, select analogs were then conjugated to our model protein, a- chymotrypsin, which was functionalized with azide residues. SPAAC chemistry allowed for full conjugation to proceed quickly, and with minimal purification. After a full characterization of each conjugate, it was concluded that each conjugate was fully dendronized as intended.|
|Appears in Collections:||Open Access Dissertations and Theses|
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