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The receptors neuropilin-1 (NRP-1) and integrin α v β 3 are overexpressed in breast cancer and associated with neovascularization. We synthesized a heterodimeric tracer, 68 Ga-DOTA-RGD-ATWLPPR, which simultaneously targets integrin α v β 3 and NRP-1 in breast cancer. In this study, we evaluated the diagnostic efficacy of 68 Ga-DOTA-RGD-ATWLPPR during micropositron emission tomography (microPET)/X-ray computed tomography (CT) imaging and gamma counting. We evaluated the receptor-binding characteristics and tumor-targeting efficacy of the tracer in vitro and in vivo . Static microPET/CT imaging and gamma counting studies showed that 68 Ga-DOTA-RGD-ATWLPPR uptake in MCF-7 tumors is higher than that of monomeric tracers. 68 Ga-DOTA-RGD-ATWLPPR uptake could be blocked with excess unlabeled RGD or ATWLPPR, demonstrating the sensitivity and specificity of the tracer. We did not observe bone tracer uptake in vivo , but the data indicated that 68 Ga-DOTA-RGD-ATWLPPR is metabolized in the kidneys and the liver uptake is low. In conclusion, 68 Ga-DOTA-RGD-ATWLPPR has improved binding affinity, targeting efficiency, and tumor retention time when compared to monomeric tracers, suggesting that it has potential as an imaging probe for breast cancer detection.

Purpose: Tumor Necrosis Factor Receptor 1 (TNFR1) and integrin αvβ3 receptor are overexpressed in breast cancer. We hypothesized that a peptide ligand recognizing both receptors in a single receptor-binding probe would be advantageous. Here, we developed a novel 18F-labeled fusion peptide probe [18F]-NOTA-Gly3- E(2PEG4-RGD-WH701) targeting dual receptors (TNFR1 and αvβ3) and evaluated the diagnostic efficacy of this radioactive probe in both MDA-MB-231 and MCF-7 xenograft models in mice., Methods: The NOTA-conjugated RGD-WH701 analog was radiolabeled with 18F using NOTA-AlF chelation method. We used two PEG4 molecules and Glutamic acid (Glu) to covalently link c(RGDyK) with WH701. Gly3 was also added to further improve the water solubility and pharmacokinetic properties of the probe. The expression of TNFR1 and Integrin αvβ3 in MCF-7 and MDA-MB-231 cells was detected by western blot analysis and immunofluorescence staining. The tumor-targeting characteristics of [18F]-NOTA-Gly3-E(2PEG4-RGDWH701) were assessed in nude mice bearing MDA-MB-231 and MCF-7 xenografts., Results: HPLC analysis of the product NOTA-G3-E (2P4-RGD-WH701) revealed a purity >95%. The yield after attenuation correction was approximately 33.5%±2.8% (n=5), and the radiochemical purity was above 95%. The MDA-MB-231 tumor uptake of [18F]-NOTA-Gly3-E(2PEG4-RGD-WH701) was 1.14±0.14%ID/g, as measured by PET at 40min postinjection (p.i.). In comparison, the tumor uptake of [18F]-NOTA-RGD and [18F]- NOTA-WH701 in MDA-MB-231 xenografts was 0.96±0.13%ID/g and 0.93±0.28%ID/g, respectively. The MCF-7 tumor uptake of [18F]-NOTA-Gly3-E(2PEG4-RGD-WH701) was 1.22±0.11%ID/g, as measured by PET at 40min postinjection (p.i.). In comparison, the tumor uptake of [18F]-NOTA-RGD and [18F]-NOTA-WH701 in MCF-7 xenografts was 0.99±0.18%ID/g and 0.57±0.08%ID/g, respectively., Conclusion: [18F]AlF-NOTA-Gly3-E(2PEG4-RGD-WH701) was successfully synthesized and labeled with 18F. The results from the microPET/CT and biodistribution studies of [18F]AlF-NOTA-Gly3-E(2PEG4-RGDWH701) showed that the tracer could specifically target TNFR1 and integrin αvβ3 receptors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)