Recent efforts in diagnostic imaging have focused not only on improving anatomical imaging but designing approaches to detect molecular changes within a living system. Pioneering work in immuno-PET demonstrates the power of molecular imaging. However, the number of ligands that bind disease specific cell surface biomarkers must be expanded to fully realize the power of molecular imaging. Synthetic peptides have attracted attention as targeting molecules to deliver radioisotopes to in vivo targets for imaging. This has been stimulated in part by advances in screening phage-displayed peptide libraries to identify peptidic ligands that target different cell types. Yet, a flood of peptide guided imaging agents has not occurred. This is partially due to the difficulty in retaining the affinity and actiity of peptides outside of the context of the phage particle. Moreover, peptides typically have short half-lives in the blood because of degradation and rapid renal filtration, which limits their accumulation in their targets. Multimerization can improve affinity, enhance stability, and extend in vivo half-life of peptides. None-the-less, most current multimeric peptide constructs are not systematically designed. We propose to create multivalent peptidic PET imaging agents in which the valency can be layered using a novel bifunctional chelator scaffold (BFCS) and a unique multimeric peptide scaffold for displaying cell-targeting peptides. First, we will take advantage of a multivalent BFCS for multimeric peptide presentation. Second, we will generate a series of multimeric peptides that can be conjugated to a monovalent BFCS. Finally, we will combine the multivalent BFC scaffolds with the multivalent peptides to create higher order peptide structures that can be used for PET imaging. The valency will vary from 1-8 peptide branches per molecule. To develop this probe design, we will use a peptide isolated in our laboratory which binds with high affinity and specificity to the restrictively expressed integrin ?v?6. This integrin is a biomarker for a number of epithelial derived cancers and lung fibrosis, diseases in which molecular imaging probes would have wide clinical applicability.
Aim 1 will identify the optimal valency while aim 2 focuses on chemically modifying the peptide to achieve optimal biodistribution.
In aim 3, we will utilize the optimized probe to image ?v?6 in other cancers as well as in a model of idiopathic pulmonary fibrosis. The imaging agent is anticipated to have a wide impact on molecular imaging of ?v?6 in solid tumors and fibrotic diseases. These experiments will lay the foundation for moving into preclinical and Phase I clinical trials.
Molecular imaging has the potential to aid in diagnosis by detecting disease specific markers without the need for invasive biopsies. We will develop and optimize a PET-molecular imaging agent that binds to a marker (?v?6) found in many tumors and fibrotic diseases. This probe is anticipated to have a wide impact on the diagnosis of these serious diseases.
|Gray, Bethany Powell; Brown, Kathlynn C (2014) Combinatorial peptide libraries: mining for cell-binding peptides. Chem Rev 114:1020-81|
|Singh, Ajay N; McGuire, Michael J; Li, Shunzi et al. (2014) Dimerization of a phage-display selected peptide for imaging of ?v?6- integrin: two approaches to the multivalent effect. Theranostics 4:745-60|