Evaluation of <sup>99m</sup>Tc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and <sup>99m</sup>Tc Chelates on Biological Properties

Zhou, Yang; Kim, Young-Seung; Lü, Xin; Liu, Shuang

doi:10.1021/bc200631g

Cited by 30 publications

(50 citation statements)

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“…46,47 It was found that replacing the highly charged and bulky [ 99m Tc(HYNIC)(tricine)(TPPTS)] (MW ~ 970 Daltons) with a smaller [ 99m Tc(HYNIC-K(NIC))(tricine)] (MW ~ 650 Daltons) or [ 99m Tc(K(HYNIC) 2 )(tricine)] (MW ~ 670 Daltons) had little impact on the tumor uptake, 46,47 suggesting that changing the 99m Tc chelates had no adverse effect on their tumor-targeting capability. However, the change in 99m Tc chelates resulted in significant uptake differences in normal organs, (e.g.…”

Section: Maximizing Binding Affinity Via Multimerizationmentioning

confidence: 99%

“…intestines, kidneys, lungs and spleen). 46,47 Since [ 99m Tc(HYNIC-K(NIC))(tricine)] is structurally similar to [ 99m Tc(K(HYNIC) 2 )(tricine)] (Figure 10), it was not surprising that 99m Tc-3P-RGD 2 -A and 99m Tc-3P-RGD 2 -B shared almost identical biodistribution properties. 47 A major advantage of using K(HYNIC) 2 and HYNIC-K(NIC) as BFCs is the use of SnCl 2 as a reducing agent during 99m Tc-labeling because TPPTS can easily reduce the S-S disulfide bond, which is often important for small biomolecules to maintain their biological activity and tumor-targeting capability.…”

Section: Maximizing Binding Affinity Via Multimerizationmentioning

confidence: 99%

“…The disadvantage of K(HYNIC) 2 and HYNIC-K(NIC) is that there are more than two isomers in [ 99m Tc(HYNIC-K(NIC))(tricine)] and [ 99m Tc(K(HYNIC) 2 )(tricine)]. 46,47 …”

Section: Maximizing Binding Affinity Via Multimerizationmentioning

confidence: 99%

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Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

Liu

2015

Bioconjugate Chem.

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Angiogenesis is a requirement for tumor growth and metastasis. The angiogenic process depends on vascular endothelial cell migration and invasion, and is regulated by various cell adhesion receptors. Integrins are such a family of receptors that facilitate the cellular adhesion to and migration on extracellular matrix proteins in the intercellular spaces and basement membranes. Among 24 members of the integrin family, αvβ3 is studied most extensively for its role in tumor angiogenesis and metastasis. The αvβ3 is expressed at relatively low levels on epithelial cells and mature endothelial cells, but it is highly expressed on the activated endothelial cells of tumor neovasculature and some tumor cells. This restricted expression makes αvβ3 an excellent target to develop antiangiogenic drugs and diagnostic molecular imaging probes. Since αvβ3 is a receptor for extracellular matrix proteins with one or more RGD tripeptide sequence, many radiolabeled cyclic RGD peptides have been evaluated as “αvβ3–targeted” radiotracers for tumor imaging over the last decade. This article will use the dimeric and tetrameric cyclic RGD peptides developed in our laboratories as examples to illustrate basic principles for development of αvβ3–targeted radiotracers. It will focus on different approaches to maximize the radiotracer tumor uptake and tumor/background ratios. This article will also discuss some important assays for pre-clinical evaluations of integrin–targeted radiotracers. In general, multimerization of cyclic RGD peptides increases their integrin binding affinity and the tumor uptake and retention times of their radiotracers. Regardless of their multiplicity, the capability of cyclic RGD peptides to bind other integrins (namely αvβ5, α5β1, α6β4, α4β1 and αvβ6) is expected to enhance the radiotracer tumor uptake due to the increased integrin population. The result from preclinical and clinical studies clearly show that radiolabeled cyclic RGD peptides (such as 99mTc-3P-RGD2, 18F-Alfatide-I and 18F-Alfatide-II) are useful as the molecular imaging probes for early cancer detection and noninvasive monitoring of the tumor response to antiangiogenic therapy.

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Section: Maximizing Binding Affinity Via Multimerizationmentioning

confidence: 99%

Section: Maximizing Binding Affinity Via Multimerizationmentioning

confidence: 99%

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Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

Liu

2015

Bioconjugate Chem.

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“…RGD and RGD containing conjugates are effective antithrombotics. RGD, RGD variants, and RGD mimics have proven to be successful antithrombotics both in vitro and in vivo [11][12][13][14][15]. Molecular dynamics (MD) simulations are particularly valuable for studying structures, interactions and conformations in aqueous system [16,17].…”

Section: Introductionmentioning

confidence: 99%

Studies on the Conformations and Hydrogen-Bonding Interactions of RGD Tri-peptide in Aqueous Solutions by Molecular Dynamics Simulations and 2D-NOESY Spectroscopy

et al. 2015

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Molecular dynamic simulations and 1 H-1 H NOESY spectroscopy have been used to study the conformations and hydrogen bond interactions of RGD tri-peptide in aqueous solution. The properties are characterized by intramolecular distances, radius of gyration, root-mean-square deviation, and solvent-accessible surface. The RGD molecule is highly flexible in aqueous solutions and the conformations can shift between extended and folded states. Most of the time, RGD exists in the extended state in aqueous solution. The results in the MD simulations and 2D-NMR experiments are in good agreement.

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“…6 The 99m Tc-3P-RGD 2 tracer, which is characterized by rapid blood clearance and urinary system excretion, 9 has been demonstrated to be more effective than 99m Tc-RGD 2 , 99m Tc-P-RGD 2 , 99m Tc-2P-RGD 2 , or 99m Tc-3G-RGD 2 . [10][11][12] Besides its diagnostic role, RGD is an important agent in cancer treatment. In recent years, the use of anti-angiogenesis therapy, anti-integrin a v b 3 therapy, RGD-related chemotherapy, and gene therapy has rapidly developed.…”

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confidence: 99%

^99mTc-3P-RGD₂ Micro-Single-Photon Emission Computed Tomography/Computed Tomography Provides a Rational Basis for Integrin α_vβ₃-Targeted Therapy

Qiu

et al. 2014

Cancer Biotherapy and Radiopharmaceuticals

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Purpose: This study was to demonstrate the utility of 99m Tc-3P-RGD 2 micro-single-photon emission computed tomography/computed tomography (SPECT/CT) for the integrin a v b 3 expression quantification in NCI-H446 and A549 lung cancer xenografts. Materials and Methods: 99m Tc-3P-RGD 2 was prepared with high radiochemical purity (97% -2%) and showing high in vitro stability. The in vitro affinities of 99m Tc-3P-RGD 2 to NCI-H446 and A549 tumor cells were analyzed with c-counter, while the in vivo uptakes in NCI-H446 and A549 xenografts were evaluated with micro-SPECT/CT. The region of interest was drawn over the tumor site and contralateral muscle on the SPECT/ CT image, and the tumor to nontumor (T/NT) ratio was calculated to estimate a v b 3 expression and tumor uptake. The expressions of integrin a v b 3 in vitro and in vivo were analyzed using a flow cytometer and immunofluorescence. Results: Micro-SPECT/CT demonstrated focal uptake in the tumors. T/NT ratio in NCI-H446 xenografts was significantly higher compared with the A549 tumor model, as 5.92 -0.82 and 3.62 -0.91, respectively, with p < 0.05. In addition, integrin a v b 3 expression in NCI-H446 cells was significantly higher compared with the A549 cells, which was consistent with the imaging data. A linear relationship was observed between 99m Tc-3P-RGD 2 uptake and a v b 3 expression (R 2 = 0.7667, p < 0.001). Conclusion:99m Tc-3P-RGD 2 SPECT/CT could be used to quantify integrin a v b 3 expression within tumors, providing a rational basis for integrin a v b 3 -targeted cancer therapy.

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

Cited by 30 publications

References 33 publications

Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

Studies on the Conformations and Hydrogen-Bonding Interactions of RGD Tri-peptide in Aqueous Solutions by Molecular Dynamics Simulations and 2D-NOESY Spectroscopy

^99mTc-3P-RGD₂ Micro-Single-Photon Emission Computed Tomography/Computed Tomography Provides a Rational Basis for Integrin α_vβ₃-Targeted Therapy

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

Cited by 30 publications

References 33 publications

Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

Studies on the Conformations and Hydrogen-Bonding Interactions of RGD Tri-peptide in Aqueous Solutions by Molecular Dynamics Simulations and 2D-NOESY Spectroscopy

99mTc-3P-RGD2 Micro-Single-Photon Emission Computed Tomography/Computed Tomography Provides a Rational Basis for Integrin αvβ3-Targeted Therapy

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

^99mTc-3P-RGD₂ Micro-Single-Photon Emission Computed Tomography/Computed Tomography Provides a Rational Basis for Integrin α_vβ₃-Targeted Therapy