^99mTc-Galacto-RGD₂: A Novel ^99mTc-Labeled Cyclic RGD Peptide Dimer Useful for Tumor Imaging

Abstract

This study sought to evaluate [99mTc(HYNIC-Galacto-RGD2)(tricine)(TPPTS)] (99mTc-Galacto-RGD2: HYNIC = 6-hydrazinonicotinyl; Galacto-RGD2 = Glu[cyclo[Arg-Gly-Asp-D-Phe-Lys(SAA-PEG2-(1,2,3-triazole)-1-yl-4-methylamide)]]2 (SAA = 7-amino-L-glycero-L-galacto-2,6-anhydro-7-deoxy-heptanamide, and PEG2 = 3,6-dioxaoctanoic acid); and TPPTS = trisodium triphenylphosphine-3,3',3"-trisulfonate) as a new radiotracer for tumor imaging. Galacto-RGD2 was prepared via the copper (I)-catalyzed 1,3-dipolar azide–alkyne Huisgen cycloaddition. HYNIC-Galacto-RGD2 was prepared by reacting Galacto-RGD2 with sodium succinimidyl 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinate (HYNIC-OSu) in the presence of diisopropylethylamine, and was evaluated for its integrin αvβ3 binding affinity against 125I-echistatin bound to U87MG glioma cells. The IC50 value for HYNIC-Galacto-RGD2 was determined to be 20 ± 2 nM. 99mTc-Galacto-RGD2 was prepared in high specific activity (~185 GBq/µmol) and high radiochemical purity (>95%), and was evaluated in athymic nude mice bearing U87MG glioma xenografts for its tumor-targeting capability and biodistribution. The tumor uptake of 99mTc-Galacto-RGD2 was 10.30 ± 1.67, 8.37 ± 2.13, 6.86 ± 1.33 and 5.61 ± 1.52 %ID/g at 5, 30, 60 and 120 min p.i., respectively, which was in agreement with high integrin αvβ3 expression on glioma cells and neovasculature. Its lower uptake in intestines, lungs and spleen suggests that 99mTc-Galacto-RGD2 has advantages over 99mTc-3P–RGD2 ([99mTc(HYNIC-3P–RGD2)(tricine)(TPPTS)]: 3P–RGD2 = PEG4-E[PEG4-c(RGDfK)]2; PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) for imaging tumors in the chest and abdominal regions. U87MG tumors were readily detected by SPECT and the tumor uptake of 99mTc-Galacto-RGD2 was integrin αvβ3-specific. 99mTc-Galacto-RGD2 also had very high metabolic stability. On the basis of results from this study, it was concluded that 99mTc-Galacto-RGD2 is an excellent radiotracer for imaging integrin αvβ3-positive tumors and related metastases.

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

“…The most significant difference between 99m Tc-4P-RGD 3 and 99m Tc-3P-RGD 2 is their uptake values in intestines (Figure 3C) and kidneys (Figure 3D). It is important to note that the uptake of 99m Tc-4P-RGD 3 and 99m Tc-3P-RGD 2 in the U87MG glioma xenografted in BALB/c nude mice was significantly lower than that reported for 99m Tc-3P-RGD 2 in previous studies [14,21,27]. To understand this difference, we performed immunohistochemical (IHC) staining on the tumor tissues obtained from U87MG-bearing BALB/c and athymic nude mice.…”

99mTc-ixolaris targets glioblastoma-associated tissue factor: In vitro and pre-clinical applications

“…Ji et al have developed a gallate-RGD2-99m Tc radiopharmaceutical that was able to specifically identify integrin α v β 3 in U87-MG glioma xenografts [46]. However, the methodology herein employed to label ixolaris takes advantage of being a direct 99m Tc-labeling technique.…”

Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects

“…Nude mice bearing HCT116 human colonic cancer xenografts were established to estimate the biodistribution and tumor selectivity characteristics of the two types of liposomes. 30 DiR was used as the fluorescence probe and model drug. The accumulation of DiR at selected time points after iv injection (20 µg per mouse) and ig administration (40 µg per mouse) with different formations is shown in Figures 9 and 10.…”