Coligand effects on the solution stability, biodistribution and metabolism of the 99mTc-labeled cyclic RGDfK tetramer

Liu, Shuang; Kim, Young-Seung; Hsieh, Wen‐Yuan; Sreerama, Subramanya Gupta

doi:10.1016/j.nucmedbio.2007.08.006

Cited by 34 publications

(50 citation statements)

References 53 publications

(88 reference statements)

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“…Over the last several years, we have been using a ternary ligand system (HYNIC, tricine and TPPTS) (Figure 1 A : HYNIC = 6-hydrazinonicotinyl; TPPTS = trisodium triphenylphosphine-3,3′,3″-trisulfonate) for 99m Tc-labeling of small biomolecules (BMs), which include chemotactic peptides and LTB 4 receptor antagonists for imaging infection and inflammation, 1, 2 integrin α v β 3 receptor antagonists for tumor imaging, 3–7 and GPIIb/IIIa receptor antagonists for imaging thrombus. 8–10 This ternary ligand system forms complexes [ 99m Tc(HYNIC-BM)(tricine)(TPPTS)] (Figure 1 A : BM = peptide and non-peptide receptor ligand) with extremely high specific activity.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of ^99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and ^99mTc Chelates on Biological Properties

et al. 2012

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The main objective of this study is to explore the impact of cyclic RGD peptides and 99mTc chelates on biological properties of 99mTc radiotracers. Cyclic RGD peptide conjugates, HYNIC-K(NIC)-RGD2 (HYNIC = 6-hydrazinonicotinyl; RGD2 = E[c(RGDfK)]2 and NIC = nicotinyl) HYNIC-K(NIC)-3G-RGD2 (3G-RGD2 = Gly-Gly-Gly-E[Gly-Gly-Gly-c(RGDfK)]2), and HYNIC-K(NIC)-3P-RGD2 (3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2), were prepared. Macrocyclic 99mTc complexes [99mTc(HYNIC-K(NIC)-RGD2)(tricine)] (1), [99mTc(HYNIC-K(NIC)-3G-RGD2)(tricine)] (2) and [99mTc(HYNIC-K(NIC)-3P-RGD2)(tricine)] (3) were evaluated for their biodistribution and tumor-targeting capability in athymic nude mice bearing MDA-MB-435 human breast tumor xenografts. It was found that 1, 2 and 3 could be prepared with high specific activity (~111GBq/3mol). All three 99mTc radiotracers have two major isomers, which show almost identical uptake in tumors and normal organs. Replacing the bulky and highly charged [99mTc(HYNIC)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3′,3″-trisulfonate) with a smaller [99mTc(HYNIC-K(NIC))(tricine)] resulted in less uptake in the kidneys and lungs for 3. Surprisingly, all three 99mTc radiotracers shared a similar tumor uptake (1: 5.73 ± 0.40 %ID/g; 2: 5.24 ± 1.09 %ID/g; and 3: 4.94 ± 1.71 %ID/g) at 60 min p.i. The metabolic stability of 99mTc radiotracers depends on cyclic RGD peptides (3P-RGD2 > 3G-RGD2 ~ RGD2) and 99mTc chelates ([99mTc(HYNIC)(tricine)(TPPTS)] > [99mTc(HYNIC-K(NIC))(tricine)]). Immunohistochemical studies revealed a linear relationship between the αvβ3 expression levels and tumor uptake or tumor/muscle ratios of 3, suggesting that 3 is useful for monitoring the tumor αvβ3 expression. Complex 3 is a very attractive radiotracer for detection of integrin αvβ3 –positive tumors.

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Section: Introductionmentioning

confidence: 99%

Evaluation of ^99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and ^99mTc Chelates on Biological Properties

et al. 2012

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“…It was found that multimerization of cyclic RGD peptides enhances their integrin α v β 3 binding affinity and improves the radiotracer tumor uptake. However, the kidney and liver uptake of radiolabeled cyclic RGD peptides was also increased significantly as the peptide multiplicity increases 47,57–61…”

Section: Introductionmentioning

confidence: 99%

Improving Tumor Uptake and Excretion Kinetics of ⁹⁹^mTc-Labeled Cyclic Arginine-Glycine-Aspartic (RGD) Dimers with Triglycine Linkers

et al. 2008

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This report describes the synthesis of two new cyclic RGD (Arg-Gly-Asp) dimers, 3 (E[G 3 -c (RGDfK)] 2 ) and 4 (G 3 -E[G 3 -c(RGDfK)] 2 ), and their corresponding conjugates 5 (HYNIC-E[G 3 -c (RGDfK)] 2 : HYNIC = 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinyl) and 6 (HYNIC-G 3 -E [G 3 -c(RGDfK)] 2 ). Integrin α v β 3 binding affinities of 5 and 6 were determined by displacement of 125 I-echistatin bound to U87MG glioma cells. 99m Tc complexes 7 ([ 99m Tc(5)(tricine)(TPPTS)]: TPPTS = trisodium triphenylphosphine-3,3′,3″-trisulfonate) and 8 ([ 99m Tc(6)(tricine)(TPPTS)]) were prepared in high yield and high specific activity. Biodistribution and imaging studies were performed in athymic nude mice bearing U87MG glioma and MDA-MB-435 breast cancer xenografts. It was found that G 3 linkers are particularly useful for increasing integrin α v β 3 binding affinity of cyclic RGD dimers, and improving the tumor uptake and clearance kinetic of their 99m Tc radiotracers. Complex 8 is a very promising radiotracer for the early detection of integrin α v β 3 -positive tumors, and may have the potential for non-invasive monitoring of tumor growth or shrinkage during antiangiogenic treatment.

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“…Tricine/trisodium triphenylphosphine-3,39,3$-trisulfonate was used as a coligand and reductant in the radiolabeling protocol. The whole procedure was rapid and efficient, with a high labeling yield, consistent with the convenient formulation of a labeling kit (31). Moreover, 99m Tc-HYNIC-H6F exhibited excellent in vitro stability in saline for 6 h (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 57%

SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe ^99mTc-HYNIC-H6F in Breast Cancer Mouse Models

Wang

et al. 2017

J Nucl Med

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Overexpression of human epidermal growth factor receptor 2 (HER2) plays important roles in tumorigenesis and tumor progression in breast cancer. Nuclear imaging of HER2 expression in tumors might detect all HER2-positive tumors throughout the body and guide HER2-targeted therapies for patients. We therefore aimed to develop a HER2-targeted peptide probe for breast cancer imaging. A novel SPECT imaging probe, 99m Tc-HYNIC-H6F, was prepared and then evaluated in breast cancer animal models. Methods: The HER2-targeted peptide H6F (YLFFVFER) was conjugated with the bifunctional chelator hydrazinonicotinamide (HYNIC). 99m Tc-HYNIC-H6F was prepared, and the in vivo characteristics of 99m Tc-HYNIC-H6F were investigated in MDA-MB-453 (HER2-positive) and MDA-MB-231 (HER2-negative) models using small-animal SPECT/CT. Moreover, to investigate the specificity of the H6F peptide toward HER2 and the potential applications in monitoring therapies involving trastuzumab, unlabeled H6F and trastuzumab were used as blocking agents in cell competition studies and SPECT imaging. Results: A standard tricine/trisodium triphenylphosphine-3,39,3$-trisulfonate labeling procedure demonstrated that the radiochemical purity was greater than 95%. 99m Tc-HYNIC-H6F displayed excellent HER2-binding specificity both in vitro and in vivo. SPECT/ CT imaging revealed that the MDA-MB-453 tumors were clearly visualized (percentage injected dose per gram, 3.58 6 0.01 at 30 min after injection), whereas the signals in HER2-negative MDA-MB-231 tumors were much lower (0.73 6 0.22 at 30 min after injection). Tumor uptake of MDA-MB-453 was blocked by the coinjection of excess H6F but not by excess trastuzumab. Conclusion: The 99m Tc-HYNIC-H6F peptide probe specifically accumulates in HER2-positive tumors and is therefore promising for the diagnosis of HER2-positive cancers. Because 99m Tc-HYNIC-H6F and trastuzumab target different regions of the HER2 receptor, this radiotracer also has great potential for monitoring the therapeutic efficacy of trastuzumab by rechecking the expression level of HER2 without blocking effect during therapy. Br east cancer is the most frequent cancer and the second leading cause of cancer death among women worldwide. The great progress in breast cancer screening and early diagnosis in recent decades has significantly increased life expectancy and patient quality of life (1,2). The best-studied tumor-associated antigen in breast cancer is human epidermal growth factor receptor 2 (HER2), which is positive in approximately 20%-30% of all breast cancers (3-5). Moreover, overexpression of HER2 is also characterized as a major negative prognostic factor that is associated with higher mortality in early-stage disease, increased incidence of metastasis, and reduced time to relapse (6-8). Trastuzumab (Herceptin; Genentech), the first approved HER2-targeted humanized monoclonal antibody, is the standard-of-care treatment for patients with HER2-positive breast cancer. In several trials, trastuzumab has proven effective in combination with...

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Coligand effects on the solution stability, biodistribution and metabolism of the 99mTc-labeled cyclic RGDfK tetramer

Cited by 34 publications

References 53 publications

Evaluation of ^99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and ^99mTc Chelates on Biological Properties

Evaluation of ^99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and ^99mTc Chelates on Biological Properties

Improving Tumor Uptake and Excretion Kinetics of ⁹⁹^mTc-Labeled Cyclic Arginine-Glycine-Aspartic (RGD) Dimers with Triglycine Linkers

SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe ^99mTc-HYNIC-H6F in Breast Cancer Mouse Models

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Coligand effects on the solution stability, biodistribution and metabolism of the 99mTc-labeled cyclic RGDfK tetramer

Cited by 34 publications

References 53 publications

Evaluation of 99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and 99mTc Chelates on Biological Properties

Evaluation of 99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and 99mTc Chelates on Biological Properties

Improving Tumor Uptake and Excretion Kinetics of 99mTc-Labeled Cyclic Arginine-Glycine-Aspartic (RGD) Dimers with Triglycine Linkers

SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe 99mTc-HYNIC-H6F in Breast Cancer Mouse Models

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Evaluation of ^99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and ^99mTc Chelates on Biological Properties

Evaluation of ^99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and ^99mTc Chelates on Biological Properties

Improving Tumor Uptake and Excretion Kinetics of ⁹⁹^mTc-Labeled Cyclic Arginine-Glycine-Aspartic (RGD) Dimers with Triglycine Linkers

SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe ^99mTc-HYNIC-H6F in Breast Cancer Mouse Models