Noninvasive Visualization of the Activated αvβ3 Integrin in Cancer Patients by Positron Emission Tomography and [18F]Galacto-RGD

Haubner, Roland; Weber, Wolfgang; Beer, Ambros J.; Vabuliene, Eugenija; Reim, Daniel; Sarbia, Mario; Becker, Karl‐Friedrich; Goebel, M.; Hein, Rüdiger; Wester, Hans‐Jürgen; Kessler, Horst; Schwaiger, Markus

doi:10.1371/journal.pmed.0020070

Cited by 453 publications

(449 citation statements)

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“…The RGD motif is present in many extracellular matrix components, such as fibronectin and vitronectin, and binds to integrins. Peptides containing the RGD sequence are commonly employed in tumor imaging (6,7) and tumor targeting therapy while coupled with therapeutic agents such as radionucleotides (8,9) and chemotherapeutic drugs (10,11).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro

Yang

Li²,

Wang³

et al. 2006

Oncol Rep

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Abstract. The Arg-Gly-Asp (RGD) sequence was selected by using phage-display peptides to target tumors, focusing on targeting ·(v) integrins in tumor blood vessels. Recent studies suggest that peptides containing the RGD sequence can bind to tumor cells, as well as tumor endothelial cells. To investigate whether the RGD peptide has other effects on tumor cells expressing ·(v) integrins, besides its tumor targeting capability, we designed and synthesized a 10-amino peptide that contained the RGD sequence in a cyclic conformation with a disulfide bond, which specifically bound to breast cancer cell lines MDA-MB-231 and MCF-7. We found that this RGD peptide, GCGGRGDGGC, inhibited tumor cell proliferation in a dosedependent manner, and also induced apoptosis and G1-phase cell cycle arrest in both of the cell lines that bound and internalized the peptide. Normal ovarian epithelial cells, which did not bind the RGD peptide, were unaffected. RGD peptide treatment also reduced cell invasiveness in both cell lines in vitro. This study suggests that the RGD peptide not only possesses tumor targeting capacity, but also has direct tumor cytotoxic and invasiveness inhibition effects dependent on the blockage of ·(v) integrin activity, which would make it more efficient in tumor targeting therapy. IntroductionTargeting agents specifically to tumors and their metastases is a central challenge in improving existing cancer detection and therapy. Directing therapeutic agents to tumor cells, tumor blood vessels or tumor lymphatic vasculature is likely to enhance the efficacy of anti-cancer drugs and decrease side effects (1). Different strategies have been pursued to achieve this goal, among which 'homing' peptides are promising alternatives because they bind to surface molecules specific to the tumor, and tumor endothelial and tumor lymphatic cells (2-4), but are smaller than other agents such as antibody fragments, which allow them to easily penetrate tumor tissues. A prominent example for homing peptides is an Arg-Gly-Asp (RGD) sequence that was selected by using phage-display peptides to target tumors, focusing on targeting ·(v) integrins in tumor blood vessels (5). The RGD motif is present in many extracellular matrix components, such as fibronectin and vitronectin, and binds to integrins. Peptides containing the RGD sequence are commonly employed in tumor imaging (6,7) and tumor targeting therapy while coupled with therapeutic agents such as radionucleotides (8,9) and chemotherapeutic drugs (10,11).The RGD-peptide receptor-·(v) integrins are also expressed on the surface of many kinds of tumor cells. Studies indicate that the RGD sequence can bind not only to tumor endothelial cells, but also to tumor cells in vivo (3,12). And in vitro, the RGD peptide can be internalized by tumor cells (13). It is known that ·(v) integrins can mediate adhesion and migration in some tumor cell lines (13) and regulate cell proliferation and survival (14). However, whether the RGD peptide has any direct anti-tumor effects on tumor cells expr...

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Section: Introductionmentioning

confidence: 99%

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro

Yang

Li²,

Wang³

et al. 2006

Oncol Rep

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“…Haubner et al showed that there was a correlation between the tumor uptake of 18 F-galacto-c(RGDfK) and the level of a v b 3 -integrin expression (27). We developed 111 In-DOTA-c(RGDfK), an 111 Inlabeled RGD, and demonstrated that this radiopharmaceutical showed high tumor uptake in SKOV-3, a human ovarian carcinoma model, with strong expression of a v b 3 -integrin (29).…”

Section: Discussionmentioning

confidence: 94%

“…Because a v b 3 -integrin is often expressed in various kinds of malignant tumors and endothelial cells, tumor imaging with radiolabeled RGD peptides, which are promising agents for a v b 3 -integrin imaging, has been actively investigated in animal models and cancer patients (26)(27)(28)(29). Haubner et al showed that there was a correlation between the tumor uptake of 18 F-galacto-c(RGDfK) and the level of a v b 3 -integrin expression (27).…”

Section: Discussionmentioning

confidence: 99%

“…Radiolabeled Arg-Gly-Asp (RGD) peptides are widely used as a v b 3 -integrin imaging agents (26)(27)(28). In a previous study, 111 In-1,4,7,10-tetraazacylododecane-N,N9,N$,N999-tetraacetic acid-cyclo-(Arg-Gly-Asp-D-Phe-Lys) [ 111 In-DOTAc(RGDfK)] showed high uptake in tumors with strong expression of a v b 3 -integrin, low uptake in normal pancreas, and extremely rapid clearance from the blood (29).…”

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confidence: 99%

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In Vivo SPECT Imaging with ¹¹¹In-DOTA-c(RGDfK) to Detect Early Pancreatic Cancer in a Hamster Pancreatic Carcinogenesis Model

Yoshimoto¹,

Hayakawa²,

Mutoh³

et al. 2012

J Nucl Med

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Early detection of pancreatic cancer is key to overcoming its poor prognosis. a v b 3 -integrin is often overexpressed in pancreatic tumor cells, whereas it is scarcely expressed in normal pancreatic cells. In this study, we investigated the usefulness of SPECT imaging with 111 In-1,4,7,10-tetraazacylododecane-N,N9,N$,N999-tetraacetic acidcyclo-(Arg-Gly-Asp-D-Phe-Lys) [ 111 In-DOTA-c(RGDfK)], an imaging probe of a v b 3 -integrin, for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. Methods: Hamsters were subcutaneously injected with the pancreatic duct carcinogen N-nitrosobis(2-oxopropyl)amine to induce pancreatic cancer. N-nitrosobis(2-oxopropyl)amine-treated hamsters underwent in vivo SPECT with 111 In-DOTA-c(RGDfK). After imaging, the tumorto-normal pancreatic tissue radioactivity ratios in excised pancreatic samples were measured with autoradiography (ARG) and compared with the immunopathologic findings for a v b 3 -integrin. In a mouse model in which inflammation was induced with turpentine, the uptake of 111 In-DOTA-c(RGDfK) in inflammatory regions was evaluated with ARG and compared with that of 18 F-FDG. Results: 111 In-DOTA-c(RGDfK) was clearly visualized in pancreatic cancer lesions as small as 3 mm in diameter. ARG analysis revealed high tumor-to-normal pancreatic tissue radioactivity ratios (4.6 6 1.0 [mean 6 SD] in adenocarcinoma and 3.3 6 1.4 in atypical hyperplasia). The uptake of 111 In-DOTA-c(RGDfK) strongly correlated with a v b 3 -integrin expression. In the inflammatory model, inflammation-to-muscle ratios for In-DOTA-c(RGDfK) were 8.37 6 4.37 and 1.98 6 0.60, respectively. These results imply that 111 In-DOTA-c(RGDfK) has a lower rate of false-positive tumor detection than 18 F-FDG. Conclusion: Our findings suggest that SPECT with 111 In-DOTA-c(RGDfK) has great potential for the early and accurate detection of pancreatic cancer.

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“…[13][14][15][16][17] Most molecular targets are expressed at nanomolar concentrations in the tumor tissue, which presents a challenge for the development of ligands. Many potential probes not only bind with high affinity to their targets but also demonstrate considerable nonspecific binding and/or unfavorable pharmacokinetic properties for in vivo imaging.…”

Section: Imaging Of Target Expressionmentioning

confidence: 99%

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

et al. 2008

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SUMMARYTargeted drugs hold great promise for the treatment of malignant tumors; however, there are several challenges for efficient evaluation of these drugs in preclinical and clinical studies. These challenges include identifying the 'correct', biologically active concentration and dose schedule, selecting the patients likely to benefit from treatment, monitoring inhibition of the target protein or pathway, and assessing the response of the tumor to therapy. Although anatomic imaging will remain important, molecular imaging provides several new opportunities to make the process of drug development more efficient. Various techniques for molecular imaging that enable noninvasive and quantitative imaging are now available in the preclinical and clinical settings, to aid development and evaluation of new drugs for the treatment of cancer. In this Review, we discuss the integration of molecular imaging into the process of drug development and how molecular imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs. Examples include imaging of the expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response.

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Noninvasive Visualization of the Activated αvβ3 Integrin in Cancer Patients by Positron Emission Tomography and [18F]Galacto-RGD

Cited by 453 publications

References 44 publications

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro

In Vivo SPECT Imaging with ¹¹¹In-DOTA-c(RGDfK) to Detect Early Pancreatic Cancer in a Hamster Pancreatic Carcinogenesis Model

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

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Noninvasive Visualization of the Activated αvβ3 Integrin in Cancer Patients by Positron Emission Tomography and [18F]Galacto-RGD

Cited by 453 publications

References 44 publications

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro

In Vivo SPECT Imaging with 111In-DOTA-c(RGDfK) to Detect Early Pancreatic Cancer in a Hamster Pancreatic Carcinogenesis Model

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

Contact Info

Product

Resources

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In Vivo SPECT Imaging with ¹¹¹In-DOTA-c(RGDfK) to Detect Early Pancreatic Cancer in a Hamster Pancreatic Carcinogenesis Model