Comparison of biological properties of (111)In-labeled dimeric cyclic RGD peptides.

Abstract

INTRODUCTION:

In this study two (111)In-labeled dimeric cyclic RGD peptides, (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2), were evaluated as radiotracers for breast tumor imaging. The objective was to evaluate the impact of SAA, PEG2 and 1,2,3-triazole linkers as compare to PEG4 on the tumor uptake and excretion kinetics of (111)In radiotracers.

METHODS:

DOTA-Galacto-RGD2 was prepared by conjugation of Galacto-RGD2 with DOTA-OSu in the presence of diisopropylethylamine. Its integrin αvβ3 binding affinity was determined using a whole-cell displacement assay against (125)I-echistatin bound to U87MG glioma cells, and was compared with those of c(RGDfK), DOTA-3P-RGD2 and DOTA-3P-RGK2 (a nonsense peptide conjugate with "scrambled" RGK sequences). (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2) were prepared and evaluated for their tumor-targeting capability and biodistribution properties in athymic nude mice bearing MDA-MB-435 breast tumor xenografts. Planar imaging studies were performed to demonstrate the utility of (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2) for breast tumor imaging.

RESULTS:

IC50 values of DOTA-Galacto-RGD2, DOTA-3P-RGD2, and DOTA-3P-RGK2 were calculated to be 27±2, 29±4, 596±48nM, respectively. The tumor uptake values of (111)In(DOTA-Galacto-RGD2) (6.79±0.98, 6.56±0.56, 4.17±0.61 and 1.09±0.13 %ID/g at 1, 4, 24 and 72hours p.i., respectively) were almost identical to those of (111)In(DOTA-3P-RGD2) (6.17±1.65, 5.94±0.84, 3.40±0.50 and 0.99±0.20 %ID/g, respectively). (111)In(DOTA-Galacto-RGD2) had a faster clearance from blood and muscle than (111)In(DOTA-3P-RGD2), leading to higher tumor/blood and tumor/muscle ratios. (111)In(DOTA-3P-RGD2) had lower liver uptake and better tumor/liver ratios than (111)In(DOTA-Galacto-RGD2). The tumor uptake of (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2) was both integrin αvβ3 and RGD-specific. Imaging data suggest that (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2) are useful as radiotracers for imaging integrin αvβ3-positive breast tumors.

CONCLUSION:

The results from this study suggest that replacing PEG4 linkers between two RGD moieties with a pair of SAA, PEG2 and 1,2,3-triazole groups has little impact on integrin αvβ3 binding affinity and tumor uptake of (111)In-labeled dimeric cyclic RGD peptides. Despite the subtle differences in their excretion kinetics from noncancerous tissues, (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2) are useful radiotracers for imaging integrin αvβ3-positive breast tumors.

• Authors: Yumin Zheng, Shundong Ji, Elena Tomaselli, Yong Yang, Shuang Liu
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 42 Issue 2 Pg. 137-45 (Feb 2015) ISSN: 1872-9614 [Electronic] United States
• PMID: 25459111 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Heterocyclic Compounds, 1-Ring
• Indium Radioisotopes
• Integrin alphaVbeta3
• Peptides, Cyclic
• cyclic arginine-glycine-aspartic acid peptide
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Dimerization
• Female
• Heterocyclic Compounds, 1-Ring (chemistry)
• Humans
• Indium Radioisotopes
• Integrin alphaVbeta3 (metabolism)
• Mice
• Molecular Imaging
• Peptides, Cyclic (chemistry, metabolism, pharmacokinetics)
• Radiochemistry
• Tissue Distribution