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One-step (18)F labeling of non-peptidic bivalent integrin ?v?3 antagonist for cancer imaging.

ABSTRACT: A rapid one-step (18)F labeling reaction with fluoridealuminum complex, which is based on chelation chemistry, has received a surge of interest for (18)F radiolabeling of peptides. In this study, a non-peptidic bivalent integrin ?v?3 antagonist (bivalent-IA) was conjugated with 1,4,7-triazacyclononane-1,4-diiacetic acid (NODA). A novel (18)F labeled radiotracer, (18)F-bivalent-IA, was developed via one step (18)F-AlF/NODA chelation reaction in aqueous phase with high radiochemical yield (65-75%, decay corrected) and good specific activity (750-850 mCi/?mol). The tumor integrin targeting efficiency and in vivo pharmacokinetic profile of (18)F-bivalent-IA were evaluated in U-87 MG (integrin positive) and MDA-MB-231 (integrin negative) models by small-animal PET/CT scan followed by a biodistribution study. The PET/CT and ROI results showed high tumor uptake of (18)F-bivalent-IA in U-87 MG tumor-bearing mice from 5 to 120 min p.i. with good contrast, and the U-87 MG tumor uptake values (6.35 ± 0.67%ID/g, at 1 h p.i.) were 6 times higher than those of MDA-MB-231 tumor (1.05 ± 0.12%ID/g, at 1 h p.i.) (P < 0.0001) which correlated with the integrin ?v?3 expression in tumor tissues confirmed by immunohistochemistry. Co-injection of the (18)F-bivalent-IA with 6 nmol (6 ?g) of nonradioactive bivalent-IA effectively blocked tumor uptake demonstrating the integrin ?v?3-specificity. In conclusion, the first (18)F labeled non-peptidic bivalent integrin ?v?3 targeting radiotracer, (18)F-bivalent-IA, was developed and proved to be a highly potent and specific PET radiopharmaceutical for noninvasive imaging of integrin ?v?3, which plays a critical role in tumor angiogenesis and metastasis.

SUBMITTER: Wang W

PROVIDER: S-EPMC4334273 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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One-step (18)F labeling of non-peptidic bivalent integrin αvβ3 antagonist for cancer imaging.

Wang Weiwei W Liu Zhiyi Z Li Zheng Z

Bioconjugate chemistry 20150112 1

A rapid one-step (18)F labeling reaction with fluoridealuminum complex, which is based on chelation chemistry, has received a surge of interest for (18)F radiolabeling of peptides. In this study, a non-peptidic bivalent integrin αvβ3 antagonist (bivalent-IA) was conjugated with 1,4,7-triazacyclononane-1,4-diiacetic acid (NODA). A novel (18)F labeled radiotracer, (18)F-bivalent-IA, was developed via one step (18)F-AlF/NODA chelation reaction in aqueous phase with high radiochemical yield (65-75%, ...[more]

PMID: 25551189

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Project description:Background & aimsThe vitronectin receptor integrin αvβ3 drives fibrogenic activation of hepatic stellate cells (HSCs). Molecular imaging targeting the integrin αvβ3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvβ3 on activated HSCs (aHSCs) in the injured liver. In this study, we sought to compare differences in the uptake of [18F]-Alfatide between normal and injured liver to evaluate its utility for assessment of hepatic fibrogenesis.MethodsPET with [18F]-Alfatide, non-enhanced CT, histopathology, immunofluorescence staining, immunoblotting and gene analysis were performed to evaluate and quantify hepatic integrin αvβ3 levels and liver fibrosis progression in mouse models of fibrosis (carbon tetrachloride [CCl4] and bile duct ligation [BDL]). The liver AUC divided by the blood AUC over 30 min was used as an integrin αvβ3-PET index to quantify fibrosis progression. Ex vivo analysis of frozen liver tissue from patients with fibrosis and cirrhosis verified the animal findings.ResultsFibrotic mouse livers showed enhanced [18F]-Alfatide uptake and retention compared to control livers. The radiotracer was demonstrated to bind specifically with integrin αvβ3, which is mainly expressed on aHSCs. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA and protein level of integrin αvβ3 and its signaling complex were higher in CCl4 and BDL models than controls. The results obtained from analyses on human fibrotic liver sections supported the animal findings.ConclusionsImaging hepatic integrin αvβ3 with PET and [18F]-Alfatide offers a potential non-invasive method for monitoring the progression of liver fibrosis.Lay summaryIntegrin αvβ3 expression on activated hepatic stellate cells (aHSCs) is associated with HSC proliferation during hepatic fibrogenesis. Herein, we show that a radioactive tracer, [18F]-Alfatide, binds to integrin αvβ3 with high affinity and specificity. [18F]-Alfatide could thus be used as a non-invasive imaging biomarker to track hepatic fibrosis progression.

Dataset Information

One-step (18)F labeling of non-peptidic bivalent integrin ?v?3 antagonist for cancer imaging.

Publications

One-step (18)F labeling of non-peptidic bivalent integrin αvβ3 antagonist for cancer imaging.

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