Comparison of a Monomeric and Dimeric Radiolabeled RGD-Peptide for Tumor Targeting

Abstract

The alpha v beta 3 integrin, a transmembrane heterodimeric protein expressed on sprouting endothelial cells, binds to the arginine-glycine-aspartic acid (RGD) amino acid sequence of extracellular matrix proteins such as vitronectin. Growing malignant tumors continuously require angiogenesis. As a result, alpha v beta 3 is preferentially expressed in growing tumors and is a potential target for radiolabeled RGD-peptides. In this study we compared the tumor targeting characteristics of a monomeric radiolabeled RGD-peptide with those of a dimeric analogue. Both peptides were radiolabeled with 99mTc via the hydrazinoni-cotinamid (= HYNIC) moiety to form 99mTc-HYNIC-c(RGDfK) and 99mTc-HYNIC-E-[c(RGDfK)]2. In vitro, the IC50 showed a 10-fold higher affinity of the dimer for the alpha v beta 3 integrin as compared to the monomer (0.1 vs. 1.0 nM). In athymic female BALB/c mice with subcutaneously growing OVCAR-3 ovarian carcinoma xenografts, tumor uptake peaked at 5.8 +/- 0.7% ID/g and 5.2 +/- 0.6% ID/g for the dimer and the monomer, respectively. At 1, 2, and 4 h postinjection (p.i.) uptake of the dimer in the tumor was significantly higher than that of the monomeric analogue. Tumor-to-blood ratios were highest at 24 h p.i. at a value of 63 for both compounds. At all timepoints kidney retention of the dimer was significantly higher as compared to kidney retention of the monomer. In conclusion, in this mouse model the dimeric RGD-peptide showed better retention in the tumor than the monomeric analogue, most likely due to the bivalent interaction with the target cell. Furthermore, kidney retention of the dimeric peptide was higher than that of the monomeric peptide.

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

“…Extensive metabolic degradation has been observed for the 99m Tc-labeled c(RGDfK) (39), [ 99m Tc(HYNIC-SU016)(tricine)(TPPTS)] (2), and the 64 Cu-labeled c(RGDfK) tetramer (9). In this study, we found that all three radiotracers have a different degree of metabolism.…”

“…For the last several years, we and others have been using multimeric cyclic RGD peptides, such as E[c(RGDfK)] 2 (SU016), to develop integrin α v β 3 -targeted radiotracers for imaging rapidly growing and metastatic tumors (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The RGD peptide serves as "vehicles" to carry radionuclide ( 99m Tc, 18 F and 64 Cu) to the integrin α v β 3 overexpressed on tumor cells and activated endothelial cells of the tumor neovasculature.…”

αvβ3 Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide

“…It has been reported that T/K ratios of 99m Tc-HYNIC-c(RGDfK) were higher than that of 99m Tc-HYNIC-E-[c(RGDfK)] 2 . 12 The enhanced renal clearance of monomeric RGD peptides may improve the delineation of abdominal tumors.…”

“…11 However, this also leads to the enhancement of radioactive accumulation in nontargeted organs such as kidney and liver. 12 Compared with antibody or multimeric RGD peptides, monomeric RGD peptides have a lower molecular mass. Therefore, monomeric RGD peptides labeled with 90 Y are thought to be promising radiopharmaceuticals for tumor therapy causing low radioactive exposure to normal tissues such as kidney and liver.…”

Coligand effects on the solution stability, biodistribution and metabolism of the 99mTc-labeled cyclic RGDfK tetramer

“…We and others have been using multimeric cyclic RGD peptides to develop the integrin α v β 3 -targeted radiotracers to image rapidly growing and metastatic tumors in several tumor-bearing animal models [27][28][29][30][31][32][33][34][35][36][37][38][39]. The RGD peptides serve as the targeting biomolecules to carry radionuclide (e.g.…”