title: Comparison of biological properties of (111)In-labeled dimeric cyclic RGD peptides.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Nuclear Medicine, China-Japan Friendship Hospital, Beijing, 100029, China; School of Health Sciences, Purdue University, IN 47907, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: School of Health Sciences, Purdue University, IN 47907, USA.
authors.forename: Shundong
authors.initials: S
authors.lastname: Ji
authors.affiliation: School of Health Sciences, Purdue University, IN 47907, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Tomaselli
authors.affiliation: School of Health Sciences, Purdue University, IN 47907, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Health Sciences, Purdue University, IN 47907, USA. Electronic address: liu100@purdue.edu.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019281:Dimerization; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D057054:Molecular Imaging; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011854:Radiochemistry; D014018:Tissue Distribution
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
keywords: (111)In-labeled cyclic RGD peptides; Breast tumor imaging; Integrin α(v)β(3); Radiotracers