Abstract

Magnetic Resonance Imaging (MRI) is a widely used, highly effective imaging method for diagnosing cancer and guiding treatment. MRI contrast agents enhance image quality, with higher relaxivity (r1) contrast agents providing the best utility. Attaching a cancer-specific-targeting group enhances the image further. Therefore, a high-relaxivity cancer-targeted contrast agent is a highly desirable tool for diagnosis and treatment. Our group previously synthesized a peptide-based MRI contrast agent with the Ala(Gd-DO3A) chelator that targeted the prostate cancer biomarker PSMA using the small-molecule ligand DCL. While this agent displayed nominal relaxivity, it was serendipitously found that the relaxivity of a synthetic intermediate containing Fmoc-protected tryptophan (Trp) increased dramatically. This was hypothesized to occur due to intermolecular self-assembly above a critical aggregation concentration (CAC). The first goal was to expand upon this finding by designing peptide-based MRI contrast agents using the simpler Lys(Gd-DOTA) chelator developed earlier in our lab. Di- and tripeptides were synthesized to test the effect of peptide length, net charge, and relative location and stereochemistry of Fmoc, Trp, and Lys(Gd-DOTA) on self-assembly through measuring r1 at 1.0 Tesla. Self-assembly was found to increase r1 from 3-7 to 13-17 mM-1s-1 in H2O and PBS and 11-13 mM-1s-1 in FBS, with remarkably low CACs in FBS. The second goal was to investigate self-assembly using other motifs, including Cbz-protected Trp, two adjacent Trp residues, and other Fmoc-protected aromatic amino acids. The third goal was to apply these findings to synthesize high-relaxivity cancer-targeted MRI contrast agents. Two prostate-cancer-targeted self-assembling MRI contrast agents containing DCL and a breast-cancer-targeted MRI contrast agent containing the peptide 18-4 were synthesized. This work represents the first example of self-assembly in MRI contrast agents induced by Fmoc and aromatic amino acids, and in the broader scope, the synthetic approach is amenable to a wide variety of self-assembling cancer-targeted MRI contrast agents.

Library of Congress Subject Headings

Contrast media (Diagnostic imaging); Prostate--Cancer--Diagnosis; Peptides; Magnetic resonance imaging

Publication Date

11-2023

Document Type

Thesis

Student Type

Graduate

Degree Name

Chemistry (MS)

Department, Program, or Center

Chemistry and Materials Science, School of

College

College of Science

Advisor

Hans Schmitthenner

Advisor/Committee Member

Emiliano Brini

Advisor/Committee Member

Joseph Hornak

Campus

RIT – Main Campus

Plan Codes

CHEM-MS

Download

Share

COinS