(99m)Tc-3PRGD(2) can be readily available using the kit formulation. This tracer is safe and well tolerated, and no adverse events occurred in non-human primates. Further clinical testing and translation of (99m)Tc-3PRGD(2) for noninvasive imaging of integrin α(v)β(3) in humans are warranted.
Integrin a v b 3 has been proposed as a potential imaging target for radiolabeled RGD peptides and a molecular marker for the estimation of tumor angiogenesis, yet it has not been applied in differentiated thyroid cancer (DTC) patients with radioactive iodine-refractory (RAIR) lesions. The current study was conducted to assess the potential of integrin a v b 3 imaging in the detection of RAIR DTC lesions using 99m Tc-PEG 4 -E [PEG 4 -c(RGDfK)] 2 ( 99m Tc-3PRGD2), thus providing a feasible antiangiogenetic therapeutic target. Methods: Ten DTC patients (2 men, 8 women; mean age 6 SD, 56.4 6 9.8 y; age range, 42-73 y) with multiple RAIR metastases were recruited; all patients had both elevated thyroglobulin levels (thyroglobulin-positive) and negative 131 I whole-body scan (WBS) results. Clinical data were collected including history, 131 I WBS, contemporary CT, ultrasonography, thyroid-stimulating hormone, thyroglobulin, and antithyroglobulin. One or 2 target lesions were selected on the contemporary CT images using Response Evaluation Criteria in Solid Tumors 1.0 for all patients, 7 of whom were chosen for the calculation of the rates of lesion growth within the 3 mo before the study. WBS at 30 min and regional SPECT for lesions at 1 h were performed after the intravenous injection of 99m Tc-3PRGD2. Two experienced nuclear medicine physicians read the images in a masked fashion. The tumor-to-background ratios were calculated for further analysis. Results: All the target RAIR metastatic lesions were identified as positive on 99m Tc-3PRGD2 SPECT images. There was a significant correlation between the mean tumor-to-background ratios and mean growth rates of target lesions (r 5 0.878, P 5 0.009). Conclusion: The RAIR ( 131 I WBS-negative/thyroglobulin-positive) metastatic lesions can be traced using 99m Tc-3PRGD2 imaging, meaning these lesions are highly neovascularized. 99m Tc-3PRGD2 angiogenesis imaging can be used for the localization and growth evaluation of RAIR lesions, providing a new therapeutic target and a novel imaging modality to monitor the efficacy of certain antiangiogenetic therapy.
Integrin αvβ3 has been well-documented as one of the key players in the process of tumor angiogenesis. Radiolabeled RGD (Arg-Gly-Asp) peptides that specifically target integrin αvβ3 have great potential for tumor early detection and noninvasively monitoring the status of tumor angiogenesis. We developed a cyclic RGD dimeric probe (99m)Tc-HYNIC-Gly3-E[PEG4-c(RGDfK)]2 ((99m)Tc-G3-2P4-RGD2) (using tricine and TPPTS as the coligands, TPPTS = trisodium triphenylphosphine-3,3',3''-trisulfonate), and investigated whether it could be used to noninvasively visualize and quantify integrin αvβ3 expression in vivo. HYNIC-Gly3-E[PEG4-c(RGDfK)]2 was synthesized and labeled with (99m)Tc. The biodistribution and planar γ-imaging studies of (99m)Tc-G3-2P4-RGD2 were performed in both U87MG (human integrin αvβ3 positive/murine integrin αvβ3 positive) and HT-29 (human integrin αvβ3 negligible /murine integrin αvβ3 positive) tumor-bearing nude mouse models. The correlation of (99m)Tc-G3-2P4-RGD2 tumor uptake values (measured by ex vivo biodistribution) with expression levels of human integrin αvβ3 or murine integrin αvβ3 (measured by Western blot) were determined in U87MG and HT-29 tumor models, respectively. (99m)Tc-G3-2P4-RGD2 exhibited increased receptor binding affinity and in vivo tumor uptake as compared with previously reported RGD dimeric tracer (99m)Tc-RGD2 (without Gly3 and PEG4 spacers). The tumor uptake of (99m)Tc-G3-2P4-RGD2 was related to the expression levels of both human integrin αvβ3 (expressed on tumor cells) and murine integrin αvβ3 (expressed on newborn tumor vasculature). Our results demonstrate that (99m)Tc-G3-2P4-RGD2 is a useful agent for integrin αvβ3 imaging. The relationship between (99m)Tc-G3-2P4-RGD2 uptake and integrin αvβ3 expression level as determined by this study would provide useful information for clinical translation of RGD probes.
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