Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Chemistry

Supervisor(s)

Dr. Elizabeth R. Gillies

Abstract

Self-immolative spacers are a unique class of molecules employed in a variety of applications, particularly in the biomedical field. Most commonly, they are molecules containing two reactive termini with a capping group at one terminus and a substrate of interest at the other. Upon removal of the capping group, the spacer undergoes an intramolecular reaction that results in its removal from the molecule and liberation of the substrate. These spacers have been extensively studied in monomeric form within prodrugs, as well as to form dendrimers that have been used for applications such as signal amplification, molecular logic gates and amplified drug release. Their use to form polymeric systems, however, remains largely unexplored and undeveloped. The work described in this thesis serves to expand this particular area of research, exploring the use of amine-based self-immolative spacers in the context of self-immolative polymers.

Two new polymeric systems were developed using N,N-dimethylethylenediamine in conjunction with first 4-hydroxybenzyl alcohol and then 2-mercaptoethanol. In the first example, when a poly(ethylene glycol) end cap was used a block copolymer was formed that self-assembled in an aqueous environment and was capable of encapsulating a hydrophobic molecule and releasing it upon polymer degradation. The second polymeric system was the first fully aliphatic self-immolative polymer, and when a disulfide end cap was employed polymer degradation could be triggered by the addition of dithiothreitol.

Following this work, a series of novel self-immolative spacers derived from 4-aminobutyric acid were developed in efforts to gain access to more rapidly cyclizing amine-based spacers. Carrying out modifications to the N and a positions, a series of spacers were developed with half-lives of cyclization ranging from 2 – 39 s. Lastly, these spacers were then combined with 4-hydroxybenzyl alcohol and 2’-hydroxyhydrocinnamic acid in efforts to develop novel 4-aminobutyric acid-based self-immolative polymers.


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