Washington University in St. Louis
Structually diverse Cu-64-labeled RGD peptide conjugates for PET imaging of αvβ3 expression
Abstract
dc:description.abstractRadiolabeled receptor-binding peptides have emerged as an important class of radiopharmaceuticals for diagnostic imaging and cancer therapy. Following radionuclide labeling, the specific receptor-binding properties of the ligand can be exploited to guide the radioactivity to tissues expressing a particular receptor. This dissertation reports on the development of integrin α<sub>v</sub>β<sub>3</sub>-targeting radiopharmaceuticals for medical imaging applications from the perspective of both the radiometal-labeled chelator as well as the targeting peptide. Several macrocyclic copper(II) chelators have been studied with the goal of improving kinetic and in vivo stability. Structurally diverse bifunctional RGD: arginine-glycine-aspartic acid) peptides were investigated for α<sub>v</sub>β<sub>3</sub> integrin affinity <italic>in vitro</italic> and <italic>in vivo</italic>. The goal of accomplishing higher binding affinity through multivalency has been pursued by evaluating the binding affinity of nanoparticles presenting multiple peptides on their surface. Copper radionuclides have been the subject of considerable research effort because they offer a varying range of half-lives and positron energies, making them useful for diagnostic imaging and/or targeted radiotherapy. Ensuring the stability of metal complexes <italic>in vivo</italic> remains a challenge in the development of radiometal-based radiopharmaceuticals. Reported here are data on the <italic>in vitro</italic> and <italic>in vivo</italic> evaluation of three macrocyclic chelators, C3B-DO2A, CB-TR2A, and NOTA. These studies were performed to improve Cu(II) complexation kinetics while retaining the high <italic>in vivo</italic> stability of our lead chelating agent, CB-TE2A. Optimal radiolabeling conditions were established for the <super>64</super>Cu-labeled radiometal chelators and their <italic>in vivo</italic> biodistribution and excretion were studied in normal rats. Integrin α<sub>v</sub>β<sub>3</sub> is upregulated in tumor vasculature, osteoclasts, and areas of collateral circulation following ischemic injury. A series of structurally diverse bifunctional RGD: arginine-glycine-aspartic acid) peptides were investigated for α<sub>v</sub>β<sub>3</sub> affinity <italic>in vitro</italic> and <italic>in vivo</italic>. The RGD-peptide analogs were screened for affinity to the α<sub>v</sub>β<sub>3</sub> integrin and specificity compared to α<sub>v</sub>β<sub>5</sub> and α<sub>IIb</sub>β<sub>3</sub>. Extent of internalization of these peptides by an α<sub>v</sub>β<sub>3</sub> expressing cell line, U87MG human glioblastoma cells, was determined. The compounds were screened via biodistribution studies and microPET imaging of a murine U87MG tumor model. Polyvalence has known to have a profound effect on receptor-binding affinity and <italic>in vivo<italic> kinetics of radiolabeled multimers. The goal of accomplishing higher binding affinity through multivalency has been pursued by evaluating the binding affinity of shell cross-linked: SCK) nanoparticles presenting multiple RGD peptides on their surface. Difficulties encountered in obtaining nanoparticles with high levels of bioavailable targeting peptide on the surface led to a systematic study of methods of shell functionalization and particle purification with chemical, physical, and biological evaluation of each compound. The development of radiometal-labeled peptides is a relatively slow process, thus in this research, optimization of various aspects was studied in parallel. Each chapter presents a small contribution, but the knowledge gained from these studies can be taken together to produce radiopharmaceuticals with optimal properties--high <italic>in vivo<italic> stability, high uptake in tumors, low uptake in non-target tissues, and rapid blood clearance, preferably through renal excretion.
Degree
thesis:*- Name thesis:degree_name
- Doctor of Philosophy (PhD)
- Level thesis:degree_level
- Dissertation
- Discipline thesis:degree_discipline
- Chemistry
- Year dc:date.available
- 2009
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Fiamengo, Ashley
- Contributors dc:contributor
-
- Carolyn Anderson
Subjects
dc:subject × 12Rights
- Language dc:language
- English (en)
Identifiers
dc:identifier.*- OAI identifier oai:identifier
- oai:openscholarship.wustl.edu:etd-1406