MicroPET imaging of breast cancer ?-integrin expression with Cu-labeled dimeric RGD peptides

Chen, Xiaoyuan; Liu, Shuang; Hou, Yingping; Tohme, Michel; Park, Ryan; Bading, James R.; Conti, Peter S.

doi:10.1016/j.mibio.2004.06.004

Cited by 202 publications

(235 citation statements)

References 26 publications

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“…4A). The activity accumulation of 64 Cu-DOTA-EfE[c(RGDyK)] 2 g 2 (the D-Tyr analog) in U87MG tumor was slightly higher than of 64 Cu-DOTAEfE[c(RGDfK)] 2 g 2 (the D-Phe analog) (20), and no significant difference in liver and kidney uptake was observed between D-Tyr and D-Phe RGD tetramer analogs, similar to previous reports for RGD dimers (32).…”

Section: Pet Imaging Of U87mg Tumor-bearing Mice and C-neu Oncomicesupporting

confidence: 89%

64Cu-Labeled Tetrameric and Octameric RGD Peptides for Small-Animal PET of Tumor v 3 Integrin Expression

Cai

Cao

et al. 2007

Journal of Nuclear Medicine

233

227

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Integrin a v b 3 plays a critical role in tumor angiogenesis and metastasis. Suitably radiolabeled cyclic arginine-glycine-aspartic (RGD) peptides can be used for noninvasive imaging of a v b 3 expression and targeted radionuclide therapy. In this study, we developed 64 Cu-labeled multimeric RGD peptides, EfE[c(RGDyK)] 2 g 2 (RGD tetramer) and E(EfE[c(RGDyK)] 2 g 2 ) 2 (RGD octamer), for PET imaging of tumor integrin a v b 3 expression. Methods: Both RGD tetramer and RGD octamer were synthesized with glutamate as the linker. After conjugation with 1,4,7,10-tetra-azacyclododecane-N, N9,N$,N$9-tetraacetic acid (DOTA), the peptides were labeled with 64 Cu for biodistribution and small-animal PET imaging studies (U87MG human glioblastoma xenograft model and c-neu oncomouse model). A cell adhesion assay, a cell-binding assay, receptor blocking experiments, and immunohistochemistry were also performed to evaluate the a v b 3 -binding affinity/specificity of the RGD peptide-based conjugates in vitro and in vivo. Results: RGD octamer had significantly higher integrin a v b 3 -binding affinity and specificity than RGD tetramer analog (inhibitory concentration of 50% was 10 nM for octamer vs. 35 nM for tetramer). 64 Cu-DOTA-RGD octamer had higher tumor uptake and longer tumor retention than 64 Cu-DOTA-RGD tetramer in both tumor models tested. The integrin a v b 3 specificity of both tracers was confirmed by successful receptor-blocking experiments. The high uptake and slow clearance of 64 Cu-DOTA-RGD octamer in the kidneys was attributed mainly to the integrin positivity of the kidneys, significantly higher integrin a v b 3 -binding affinity, and the larger molecular size of the octamer, as compared with the other RGD analogs. Conclusion: Polyvalency has a profound effect on the receptor-binding affinity and in vivo kinetics of radiolabeled RGD multimers. The information obtained here may guide the future development of RGD peptidebased imaging and internal radiotherapeutic agents targeting integrin a v b 3 .

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Section: Pet Imaging Of U87mg Tumor-bearing Mice and C-neu Oncomicesupporting

confidence: 89%

64Cu-Labeled Tetrameric and Octameric RGD Peptides for Small-Animal PET of Tumor v 3 Integrin Expression

Cai

Cao

et al. 2007

Journal of Nuclear Medicine

233

227

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“…We recently radiolabeled DOTA-conjugated RGD monomer, dimer, and tetramer with 64 Cu and compared their tumor targeting efficacy and in vivo kinetics (33,37,46). Tetrameric RGD peptide tracer had almost twice as much tumor uptake than the corresponding dimer.…”

Section: Discussionmentioning

confidence: 99%

“…Dimeric RGD peptide, E[c(RGDyK)] 2 , was prepared according to the literature method (37). The tetrameric RGD peptide E{E[c(RGDyK)] 2 } 2 was obtained by coupling Boc-protected glutamic acid activated ester Boc-E(OSu) 2 with RGD dimer E[c(RGDyK)] 2 in the presence of diiso-propylethylamine (DIPEA) (pH = 8.5-9) followed by semipreparative HPLC purification (46).…”

Section: Peptide Synthesismentioning

confidence: 99%

Near-Infrared Fluorescent RGD Peptides for Optical Imaging of Integrin α_vβ₃ Expression in Living Mice

et al. 2005

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Near-infrared fluorescence optical imaging is a powerful technique for studying diseases at the molecular level in preclinical models. We recently reported that monomeric RGD peptide c(RGDyK) conjugated to the NIR fluorescent dye specifically targets integrin receptor both in cell culture and in living subjects. In this report, Cy5.5-conjugated mono-, di-, and tetrameric RGD peptides were evaluated in a subcutaneous U87MG glioblastoma xenograft model in order to investigate the effect of multimerization of RGD peptide on integrin avidity and tumor targeting efficacy. The binding affinities of Cy5.5-conjugated RGD monomer, dimer, and tetramer for α v β 3 integrin expressed on U87MG cell surface were determined to be 42.9 ± 1.2, 27.5 ± 1.2, and 12.1 ± 1.3 nmol/L, respectively. All three peptide-dye conjugates had integrin specific uptake both in vitro and in vivo. The subcutaneous U87MG tumor can be clearly visualized with each of these three fluorescent probes. Among them, tetramer displayed highest tumor uptake and tumor-tonormal tissue ratio from 0.5 to 4 h postinjection. Tumor-to-normal tissue ratio for Cy5.5-conjugated RGD monomer, dimer, and tetramer were found to be 3.18 ± 0.16, 2.98 ± 0.05, and 3.63 ± 0.09, respectively, at 4 h postinjection. These results suggest that Cy5.5-conjugated monomeric, dimeric, and tetrameric RGD peptides are all suitable for integrin expression imaging. The multmerization of RGD peptide results in moderate improvement of imaging characteristics of the tetramer, compared to that of the monomer and dimeric counterparts.

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“…For the last several years, we and others have been using multimeric cyclic RGD peptides, such as E[c(RGDfK)] 2 (SU016), to develop integrin α v β 3 -targeted radiotracers for imaging rapidly growing and metastatic tumors (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The RGD peptide serves as "vehicles" to carry radionuclide ( 99m Tc, 18 F and 64 Cu) to the integrin α v β 3 overexpressed on tumor cells and activated endothelial cells of the tumor neovasculature.…”

Section: Introductionmentioning

confidence: 99%

Impact of PKM Linkers on Biodistribution Characteristics of the ^99mTc-Labeled Cyclic RGDfK Dimer

Liu

Hsieh

et al. 2006

Bioconjugate Chem.

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This report describes synthesis of three new cyclic RGDfK peptide conjugates, HYNIC-PKM-SU016 (PKM = E, K and PEG4), and in vivo evaluation of the impact of PKM linkers on biodistribution characteristics of their ternary ligand complexes [ 99m Tc(HYNIC-PKM-SU016)(tricine)(TPPTS)] in athymic nude mice bearing the MDA-MB-435 human breast cancer xenografts. Results from biodistribution studies show that PKM linkers have minimal impact on the integrin α v β 3 binding capability of radiotracers. Even though they have different charges under physiological conditions, all three linkers (E, K and PEG4) are able to reduce the uptake of 99m Tc-labeled E[c(RGDfK)] 2 in blood, kidneys, liver and lungs, and increase target-to-background (T/B) ratios at >30 min postinjection. E and K may have advantages over PEG4 due to a combination of relatively low liver uptake, high tumor/liver and tumor/lung ratios of ternary ligand complexes [ 99m Tc(HYNIC-PKM-SU016)(tricine)(TPPTS)] (PKM = E and K).

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MicroPET imaging of breast cancer ?-integrin expression with Cu-labeled dimeric RGD peptides

Cited by 202 publications

References 26 publications

64Cu-Labeled Tetrameric and Octameric RGD Peptides for Small-Animal PET of Tumor v 3 Integrin Expression

64Cu-Labeled Tetrameric and Octameric RGD Peptides for Small-Animal PET of Tumor v 3 Integrin Expression

Near-Infrared Fluorescent RGD Peptides for Optical Imaging of Integrin α_vβ₃ Expression in Living Mice

Impact of PKM Linkers on Biodistribution Characteristics of the ^99mTc-Labeled Cyclic RGDfK Dimer

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MicroPET imaging of breast cancer ?-integrin expression with Cu-labeled dimeric RGD peptides

Cited by 202 publications

References 26 publications

64Cu-Labeled Tetrameric and Octameric RGD Peptides for Small-Animal PET of Tumor v 3 Integrin Expression

64Cu-Labeled Tetrameric and Octameric RGD Peptides for Small-Animal PET of Tumor v 3 Integrin Expression

Near-Infrared Fluorescent RGD Peptides for Optical Imaging of Integrin αvβ3 Expression in Living Mice

Impact of PKM Linkers on Biodistribution Characteristics of the 99mTc-Labeled Cyclic RGDfK Dimer

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Product

Resources

About

Near-Infrared Fluorescent RGD Peptides for Optical Imaging of Integrin α_vβ₃ Expression in Living Mice

Impact of PKM Linkers on Biodistribution Characteristics of the ^99mTc-Labeled Cyclic RGDfK Dimer