Master of Engineering Science
Gillies, Elizabeth R.
Microcomputed tomography (micro-CT) is a micro-imaging modality used for small animal imaging given its high resolution, rapid scan times and quantifiable data. When studying soft tissues, a high-density material (contrast agent) is injected to help attenuate X-rays and provide contrast between these structures. Creation of new contrast agents is limited by short circulation times and localization in reticuloendothelial system (RES) organs. This thesis involves the development of two new contrast agents, which both employ tunable, degradable, self-immolative polymers (SIP). The first project studied a small library of poly(chelate) molecules with varying degradation rates. The second approach was based on PEtG-poly(ethylene glycol) (PEG) diblock copolymers that encapsulated 10 nm diameter nanoparticles. Both contrast agents were synthesized, and the poly(chelate) system was evaluated for in vivo efficacy. Overall results demonstrated successful prolonged vascular circulation along with excretion from the body over time by tuning the polymer’s molar mass and degradation rate.
Summary for Lay Audience
Small animal models are an important tool when trying to understand human diseases. The need to analyze these animal models non-invasively is important in long-term studies, and this can be achieved through medical imaging methods such as microcomputed tomography (micro-CT). When trying to image soft tissues such as blood vessels or organs with CT, their similar density makes it difficult to distinguish different structures in the image. By introducing a material known as a contrast agent, we can illuminate these soft tissues and organs, allowing the extraction of otherwise unavailable information. Advances in science have aided in the emergence of nanomedicines, medicine in the nanometer (10-9 m) size range, which have been developed for use in CT such as polymer-coated metal nanoparticles (NPs). Polymers are most commonly found in materials like plastics. Advances such as polymer-coated NPs continue to push boundaries, but still see limitations in the form of poor animal survival rates, localization of heavy metal materials and short circulation times. In this thesis, we propose two entirely different and novel contrast agents which both rely on a special class of degradable polymer known as a self-immolative polymer (SIP), namely poly(ethyl glyoxylate) (PEtG). Based on its non-toxic degradation products, we hypothesized that by incorporating this degradable polymer into a) an existing nanoparticle-based system and b) an entirely novel polymer-based system, we could influence the route that the drugs take in leaving an animal’s body. The overall results from this research demonstrate the preparation and successful testing of one contrast agent for blood vessel micro- CT imaging, and show promise for the development of a contrast agent that could (ideally) be injected multiple times before an animal would have to be euthanized.
Grolman, Eric, "Long-Circulating, Degradable Lanthanide-Based Contrast Agents for Pre-Clinical Microcomputed Tomography of the Vasculature" (2021). Electronic Thesis and Dissertation Repository. 8272.
Available for download on Wednesday, March 02, 2022