Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

Abstract

Angiogenesis is a requirement for tumor growth and metastasis. The angiogenic process depends on vascular endothelial cell migration and invasion, and is regulated by various cell adhesion receptors. Integrins are such a family of receptors that facilitate the cellular adhesion to and migration on extracellular matrix proteins in the intercellular spaces and basement membranes. Among 24 members of the integrin family, αvβ3 is studied most extensively for its role in tumor angiogenesis and metastasis. The αvβ3 is expressed at relatively low levels on epithelial cells and mature endothelial cells, but it is highly expressed on the activated endothelial cells of tumor neovasculature and some tumor cells. This restricted expression makes αvβ3 an excellent target to develop antiangiogenic drugs and diagnostic molecular imaging probes. Since αvβ3 is a receptor for extracellular matrix proteins with one or more RGD tripeptide sequence, many radiolabeled cyclic RGD peptides have been evaluated as “αvβ3–targeted” radiotracers for tumor imaging over the last decade. This article will use the dimeric and tetrameric cyclic RGD peptides developed in our laboratories as examples to illustrate basic principles for development of αvβ3–targeted radiotracers. It will focus on different approaches to maximize the radiotracer tumor uptake and tumor/background ratios. This article will also discuss some important assays for pre-clinical evaluations of integrin–targeted radiotracers. In general, multimerization of cyclic RGD peptides increases their integrin binding affinity and the tumor uptake and retention times of their radiotracers. Regardless of their multiplicity, the capability of cyclic RGD peptides to bind other integrins (namely αvβ5, α5β1, α6β4, α4β1 and αvβ6) is expected to enhance the radiotracer tumor uptake due to the increased integrin population. The result from preclinical and clinical studies clearly show that radiolabeled cyclic RGD peptides (such as 99mTc-3P-RGD2, 18F-Alfatide-I and 18F-Alfatide-II) are useful as the molecular imaging probes for early cancer detection and noninvasive monitoring of the tumor response to antiangiogenic therapy.

Liposomes derivatized with multimeric copies of KCCYSL peptide as targeting agents for HER-2-overexpressing tumor cells

“…Several papers have reported the capacity of peptides synthesized in their branched form to enhance resistance toward proteases and to increase linear peptide biological activity through multivalent binding. [16][17][18] Recently, some evidence that these properties are also maintained when the peptide is bounded on the external liposomal surface have been demonstrated. 19,20 Liposomes were chosen as the vector since they can accommodate large quantities of relevant therapeutic drugs in their lumen.…”

Comparison of biological properties of 99m Tc-labeled cyclic RGD Peptide trimer and dimer useful as SPECT radiotracers for tumor imaging

“…The α v β 3 is generally expressed at low levels on epithelial cells and mature endothelial cells, but it is overexpressed on the tumor cells and activated endothelial cells of neovasculature. Because of the role of α v β 3 in tumor angiogenesis and metastasis, cyclic RGD peptides are often used as α v β 3 antagonists for tumor therapy, and radiolabeled cyclic RGD peptides are utilized as “α v β 3 –targeted” radiotracers for tumor imaging [1–10]. Over the last several years, we have been interested in radiolabeled multimeric cyclic RGD peptides as radiotracers for imaging α v β 3 -positive tumors and related metastasis [11–29].…”

Molecular imaging of integrins in oncology

“…Achieving sufficiently low background, it was possible to use the radioiodinated liver-specific probe PET radiopharmaceuticals for imaging integrin expression were extensively reviewed by Haubner and Liu. 12,19 First clinical studies described in the second part of this review already show very promising results. A strategy to improve tracer kinetics is the utilization of homodimeric or -trimeric RGD-based compounds, thereby enhancing the local RGD concentration and hence the target affinity.…”

“…12,[18][19][20] This review focuses on recent advances of integrin molecular imaging for cancer diagnosis. First, clinical applications are highlighted, and experimental approaches in preclinical research and multimodal setups are also discussed.…”