The objective of molecular imaging is to noninvasively visualize biochemical events in a living system at the cellular level. Magnetic resonance imaging (MRI) is a promising modality for this goal due to its excellent resolution, unlimited depth penetration, and absence of harmful ionizing radiation. MRI techniques frequently use Gd(III)-based contrast agents (CAs) to enhance signal and illuminate differences in biological tissues. However, the sensitivity limits of MRI preclude widespread molecular imaging applications. This thesis describes three approaches to address this sensitivity challenge and improve the performance of Gd(III) MRI probes. The first strategy reduces the background signal of bioresponsive CAs by modulating the electronic relaxation time (T1e) of Gd(III), accomplished through magnetic coupling interactions in coordination complexes. Redox-switching of the coupled species offers an activatable handle and the ability to study dynamic processes through MRI. Synthetic approaches and challenges are described in Chapter 2. Future work for this T1e approach involves further synthesis and characterization to evaluate complex stability and biological relevance. The second and third strategies use nanoconjugate CAs to target the MRI sensitivity problem. These platforms offer a high local concentration of Gd(III), improving sensitivity through signal amplification. Chapter 3 describes a self-reporting, combination therapy-diagnostic (theranostic) carbon nanodiamond construct. Macrocyclic Gd(III) chelates were conjugated to the nanodiamond surface for MRI functionality and the drug doxorubicin was incorporated for chemotherapy. The theranostic was evaluated in vitro and in vivo, with further work needed to successfully translate of the promising cellular results to an animal model. Chapter 4 explores Gd(III)-nanoconjugate CA performance in metal-organic frameworks (MOFs). Previous research has demonstrated that both the structure and surface chemistry of the nanomaterial substantially influence contrast. Through the study of Zr-based MOFs, NU-1000 (nano and micron size particles) and NU-901, we investigated the impact of particle size and pore shape on proton relaxivity. Zr-MOFs were functionalized with Gd(III) chelates through solvent-assisted ligand incorporation (SALI). Through robust physical characterization of these hybrid materials, we demonstrated that SALI is a promising method for incorporating Gd(III) complexes into MOF materials and identified crucial design parameters for the preparation of next generation Gd(III)-MOF MRI contrast agents.

Creator

• McLeod, Shaunna M.

DOI

• https://doi.org/10.21985/n2-wmef-t295

Subject

• Nanoscience
• Molecular chemistry
• Chemistry

Language

• en

Alternate Identifier

• etdadmin_upload_769217
• http://dissertations.umi.com/northwestern:15316

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright