Radiolabeled Integrin α_vβ₃ Antagonists as Radiopharmaceuticals for Tumor Radiotherapy

Abstract

Integrins are a family of proteins that facilitate cellular adhesion to and migration on the extracellular matrix proteins found in intercellular spaces and basement membranes. integrin α_vβ₃ is a receptor for a variety of extracellular matrix proteins with the exposed RGD tripeptide sequence. These include vitronectin, fibronectin, fibrinogen, lamin, collagen, Von Willibrand’s factor, osteoponin and adenovirus particles. Integrin α_vβ₃ is generally expressed at low levels on epithelial cells and mature endothelial cells, but it is highly expressed on the surface of both endothelial cells in tumor neovasculature and some tumor cells, including osteosarcomas, neuroblastomas, glioblastomas, melanomas, and carcinomas of the lung, the breast, the prostate, and the bladder. The expression of integrin α_vβ₃ correlates with the tumor progression in melanoma, glioma, and ovarian and breast cancers. The highly restricted expression of integrin α_vβ₃ during tumor invasion and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. This chapter will discuss some important aspects associated with the radiolabeling of diethylenetriaminepentaacetic acid conjugated and 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid conjugated integrin α_vβ₃ antagonists, and the use of ⁹⁰Y-labeled integrin α_vβ₃ receptor antagonists as potential therapeutic radiopharmaceuticals for the treatment of solid tumors. It will focus on radiopharmaceutical design, selection of the radionuclide, the bifunctional chelator, and targeting biomolecules, as well as modification of the pharmacokinetics.