Improved Tumor Targeting of Radiolabeled RGD Peptides Using Rapid Dose Fractionation

Janssen, Marcel; Frielink, Cathelijne; Dijkgraaf, Ingrid; Oyen, Wim J.G.; Edwards, David S.; Liu, Shuang; Rajopadhye, Milind; Massuger, Leon F.A.G.; Corstens, F.H.M.; Boerman, Otto C.

doi:10.1089/cbr.2004.19.399

Cited by 68 publications

(73 citation statements)

References 13 publications

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“…av-integrins on endothelial cells recognize an exposed Arg-Gly-Asp (RGD) sequence within a variety of ECM proteins, including vitronectin, fibrinogen, thrombospondin, proteolysed collagen, von Willenbrand factor and osteopontin (Hynes, 1992;Stupack and Cheresh, 2002;Ru¨egg et al, 2004). Several agents such as blocking antibodies or synthetic RGD-containing peptides directed against av-integrins have been generated and shown to inhibit in vitro endothelial tube formation or microvessel formation (Janssen et al, 2002;Buerkle et al, 2002). To this regard, we reported that specific a v b 3 antagonists decreased the viability and growth of MCF-7 cells forced to overexpress CYR61, an angiogenic regulator that is differentially expressed in invasive human breast cancer cells (Tsai et al, 2000;Menendez et al, 2004).…”

Section: Hrg Regulates a V B 3 Expression In Breast Cancer Cellsmentioning

confidence: 99%

“…a v b 3 integrin plays an important role in a number of physiological and pathological processes such as bone resorption, wound healing, angiogenesis, tumor invasion and metastasis (Jin and Varner, 2004;Pereira et al, 2004). To the same extent, it has been shown that a v b 3 expression in breast and ovarian cancer, in addition to melanoma and glioma, is related to tumor progression (Janssen et al, 2002;Rolli et al, 2003). Likewise, forced expression of the a v or the b 3 integrin subunit in a melanoma cell line increases metastatic potential (Hood and Cheresh, 2002).…”

Section: Introductionmentioning

confidence: 99%

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αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer

2005

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Section: Hrg Regulates a V B 3 Expression In Breast Cancer Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer

2005

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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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“…Compounds containing the RGD peptide sequence are currently used as either antiangiogenic drugs (14)(15)(16)(17) or carriers for radioisotopes (8,12,13) to target a variety of integrins. The improved binding affinity of cyclic peptides to integrins has inspired numerous research efforts toward their use in biomedical research (28)(29)(30).…”

Section: Resultsmentioning

confidence: 99%

Synergistic effects of light-emitting probes and peptides for targeting and monitoring integrin expression

Achilefu

Bloch²,

Markiewicz³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

119

113

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mouse ͉ optical imaging ͉ RGD peptides ͉ tumor ͉ near-infrared A ngiogenesis, the formation of new blood vessels, is the cardinal feature of virtually all malignant tumors (1). Because of this commonality, probing tumor-induced angiogenesis and associated proteins is a viable approach to detect and treat a wide range of cancers. Angiogenesis is stimulated by integrins, a large family of transmembrane proteins that mediate dynamic linkages between extracellular adhesion molecules and the intracellular actin skeleton. Integrins are composed of two different subunits, ␣ and ␤, which are noncovalently bound into ␣␤ complexes (2-4). Particularly, the expression of ␣ v ␤ 3 integrin (ABI) in tumor cells undergoing angiogenesis and on the epithelium of tumor-induced neovasculature alters the interaction of cells with the extracellular matrix, thereby increasing tumorigenicity and invasiveness of cancers (5-9).Numerous studies have shown that ABI and more than seven other heterodimeric integrins recognize proteins and low molecular weight ligands containing RGD (arginine-glycineaspartic acid) motifs in proteins and small peptides (10). Based on structural and bioactivity considerations, cyclic RGD peptide ligands are preferentially used as delivery vehicles for molecular probes for imaging (8,(11)(12)(13) and treating (14-17) ABI-positive tumors and proliferating blood vessels. Until recently, most of the in vivo imaging studies were performed with radiopharmaceuticals because of the high sensitivity and clinical utility of nuclear imaging methods. Particularly, the use of small monoatomic radioisotopes does not generally interfere with the biodistribution and bioactivity of ligands. Despite these advantages, nuclear imaging is currently only performed in specialized centers because of regulatory, production, and handling issues associated with radiopharmaceuticals. Optical imaging is an alternative but complementary method to interrogate molecular processes in vivo and in vitro.Optical imaging for biomedical applications typically relies on activating chromophore systems with low energy radiation between 400 -and 1,500-nm wavelengths and monitoring the propagation of light in deep tissues with a charge-coupled device camera or other point source detectors (18). Molecular optical imaging of diseases with molecular probes is attractive because of the flexibility of altering the detectable spectral properties of the probes, especially in the fluorescence detection mode. The probes can be designed to target cellular and molecular processes at functional physiological concentrations. For deep-tissue imaging, molecular probes that are photoactive in the near-infrared (NIR) instead of visible wavelengths are preferred to minimize background tissue autof luorescence and light attenuation caused by absorption by intrinsic chromophores (19). In contrast to radioisotopes, the NIR antennas are usually large heteroatomic molecules that could impact the biodistribution and activity of conjugated bioactive ligands. However, previous s...

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Improved Tumor Targeting of Radiolabeled RGD Peptides Using Rapid Dose Fractionation

Abstract: Arginine-glycine-aspartic acid (RGD) peptides preferentially bind to

Cited by 68 publications

References 13 publications

αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer

αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer

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

Synergistic effects of light-emitting probes and peptides for targeting and monitoring integrin expression

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