Design, Synthesis, and Evaluation of Radiolabeled Integrin α_vβ₃ Receptor Antagonists for Tumor Imaging and Radiotherapy

Abstract

The goal of this research is the development of tumor imaging and radiotherapeutic agents based on targeting of the integrin alpha(v)beta(3) (vitronectin receptor). Macrocyclic chelator DOTA has been conjugated to peptidomimetic vitronectin receptor antagonist SH066 to give TA138. TA138 and (89)Y-TA138 retain antagonist properties and high affinity for integrin alpha(v)beta(3) (IC(50) = 12 and 18 nM, respectively), and good selectivity versus integrin alpha(IIb)beta(3) (IC(50) > 10,000 nM). TA138 forms stable complexes with (111)In and (90)Y in > 95% RCP. (111)In-TA138 demonstrates high tumor uptake in the c-neu Oncomouse (Charles River Laboratories [Charles River, Canada]) mammary adenocarcinoma model (9.39% ID/g at 2 hours PI) and low background activity. Blood clearance is rapid and excretion is renal. Tumors are visible as early as 0.5 hours PI. Radiotherapy studies in the c-neu Oncomouse model demonstrated a slowing of tumor growth at a dose of 15 mCi/m(2), and a regression of tumors at a dose of 90 mCi/m(2).

Endothelial α ν β 3 Integrin–Targeted Fumagillin Nanoparticles Inhibit Angiogenesis in Atherosclerosis

“…11 In general, the emulsions comprised 20% (vol/vol) perfluorooctylbromide (PFO) (Minnesota Manufacturing and Mining), 2% (wt/vol) of a surfactant comixture, 1.7% (wt/vol) glycerin, and water for the balance. The surfactant comixture included 68 mole% lecithin (Avanti Polar Lipids Inc), 0.1 mole% peptidomimetic vitronectin antagonist (US Patent 6,322,770) [17][18][19] conjugated to polyethylene glycol (PEG) 2000 phosphatidylethanolamine (Avanti Polar Lipids Inc), 1.8 mole% phosphatidylethanolamine (Avanti Polar Lipids Inc), and 30 mole% gadolinium diethylene-triamine-pentaacetic acid-bis-oleate (Gateway Chemical Technologies) in chloroform:methanol (3:1), which was dried to a lipid film under vacuum. Therapeutic nanoparticle formulations included 0.2 mole% fumagillin (a gift from the National Cancer Institute), which was added to the surfactant mixture at the proportionate expense of lecithin.…”

Impact of PKM Linkers on Biodistribution Characteristics of the 99mTc-Labeled Cyclic RGDfK Dimer

“…For example, a sugar moiety was used to increase T/B ratios of the 125 I-and 18 F-labeled cyclic RGD peptides (15)(16)(17)(18)(19)(20). Small peptides sequences, such as di(cysteic acid), Asp 3 and Ser 3 , have been used to improve blood clearance and to minimize liver accumulation of radiolabeled nonpeptide integrin α v β 3 antagonists (21,22) and 18 Flabeled c(RGDfK) (23,24). The hexaethylene glycol (HEG) linker has been used in the 18 Flabeled RGDfE dimer and tetramer (11,12,23,24).…”

Synergistic effects of light-emitting probes and peptides for targeting and monitoring integrin expression

“…Compounds containing the RGD peptide sequence are currently used as either antiangiogenic drugs (14)(15)(16)(17) or carriers for radioisotopes (8,12,13) to target a variety of integrins. The improved binding affinity of cyclic peptides to integrins has inspired numerous research efforts toward their use in biomedical research (28)(29)(30).…”

“…Based on structural and bioactivity considerations, cyclic RGD peptide ligands are preferentially used as delivery vehicles for molecular probes for imaging (8,(11)(12)(13) and treating (14-17) ABI-positive tumors and proliferating blood vessels. Until recently, most of the in vivo imaging studies were performed with radiopharmaceuticals because of the high sensitivity and clinical utility of nuclear imaging methods.…”