title: Evaluation of a (99m)Tc-labeled cyclic RGD tetramer for noninvasive imaging integrin alpha(v)beta3-positive breast cancer.
abstract: Integrin alphavbeta3 plays a critical role in tumor angiogenesis and metastasis. Radiolabeled RGD peptides that are integrin alphavbeta3-specific are very useful for noninvasive imaging of integrin expression in rapidly growing and metastatic tumors. In this study, we determined the binding affinity of E{E[c(RGDfK)]2}2 (tetramer) and its 6-hydrazinonicotinamide conjugate (HYNIC-tetramer) against the binding of 125I-echistatin to the integrin alphavbeta3-positive MDA-MB-435 breast cancer cells. The athymic nude mice bearing MDA-MB-435 xenografts were used to evaluate the potential of ternary ligand complex [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3',3' '-trisulfonate) as a new radiotracer for imaging breast cancer integrin alphavbeta3 expression by single photon emission computed tomography (SPECT). It was found that the binding affinity of tetramer (IC50 = 51 +/- 11 nM) was slightly higher than that of its dimeric analogue (IC50 = 78 +/- 27 nM) and is comparable to that of the HYNIC-tetramer conjugate (IC50 = 55 +/- 11 nM) within the experimental error. Biodistribution data showed that [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] had a rapid blood clearance (4.61 +/- 0.81 %ID/g at 5 min postinjection (p.i.) and 0.56 +/- 0.12 %ID/g at 120 min p.i.) and was excreted mainly via the renal route. [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] had high tumor uptake with a long tumor retention (5.60 +/- 0.87 %ID/g and 7.30 +/- 1.32 %ID/g at 5 and 120 min p.i., respectively). The integrin alphavbeta3-specificity was demonstrated by co-injection of excess E[c(RGDfK)]2, which resulted in a significant reduction in tumor uptake of the radiotracer. The metabolic stability of [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] was determined by analyzing urine and feces samples from the tumor-bearing mice at 120 min p.i. In the urine, about 20% of [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] remained intact while only approximately 15% metabolized species was detected in feces. SPECT images displayed significant radiotracer localization in tumor with good contrast as early as 1 h p.i. The high tumor uptake and fast renal excretion make [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] a promising radiotracer for noninvasive imaging of the integrin alphavbeta3-positive tumors by SPECT.
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana 47907-2051, USA. lius@pharmacy.purdue.edu
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Hsieh
authors.forename: Young
authors.initials: Y
authors.lastname: Jiang
authors.forename: Young-Seung
authors.initials: YS
authors.lastname: Kim
authors.forename: Subramanya G
authors.initials: SG
authors.lastname: Sreerama
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D039302:Integrin alphaVbeta3; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; C507169:cyclic arginine-glycine-aspartic acid peptide