Radionuclide Imaging of Tumor Angiogenesis

Dijkgraaf, Ingrid; Boerman, Otto C.

doi:10.1089/cbr.2009.0694

Cited by 44 publications

(34 citation statements)

References 111 publications

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“…The results reported here describe how these tumors models have enabled us to verify the potential of 111 In-RGD 2 as a specific antiangiogenic marker in HNSCC, a feature that, despite much clinical and preclinical research into radiolabeled RGD peptides as a tracer for integrin a v b 3 (11,18,20,25,26), was still uncertain. SPECT/CT imaging showed clear uptake of the tracer in areas corresponding with vascularized areas of the tumor.…”

Section: Discussionmentioning

confidence: 82%

See 1 more Smart Citation

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

et al. 2014

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Arginine-glycine-aspartic acid (RGD)-based imaging tracers allow specific imaging of integrin a v b 3 , a protein overexpressed during angiogenesis, leading to the possibility that it might serve as a tool to stratify patients for antiangiogenic treatment. However, these tracers have generally been characterized in xenograft models in which integrin a v b 3 was constitutively expressed by the tumor cells themselves. In the studies presented here, the use of 111 In-RGD 2 as a tracer to image only integrin a v b 3 expression on blood vessels in the tumor was determined using tumor xenografts in which tumor cells were integrin a v b 3 -negative. Methods: DOTA-E-[c(RGDfK)] 2 was radiolabeled with 111 In ( 111 In-RGD 2 ), and biodistribution studies were performed in squamous cell carcinoma of the head and neck (HNSCC) xenograft mouse models to determine the optimal peptide dose to image angiogenesis. Next, biodistribution and imaging studies were performed at the optimal peptide dose in 3 HNSCC mouse models, FaDu, SCCNij3, and SCCNij202. Immunohistochemical analysis of tumor vascular and cell surface expression of integrin a v b 3 and correlation analysis of vascular integrin a v b 3 and autoradiography were completed. Results: All 3 HNSCC xenografts expressed integrin a v b 3 on the vessels only. The optimal peptide dose of 111 In-RGD 2 was 1 mg or less for specific integrin a v b 3 -mediated uptake of the tracer. SPECT/CT imaging showed clear uptake of the tracer in the periphery of the tumors, corresponding with wellvascularized areas of the tumor. Within the tumor, 111 In-RGD 2 autoradiography coincided with vascular integrin a v b 3 expression, as determined immunohistochemically. Integrin a v b 3 -mediated uptake was also detected in nontumor tissues, which, through immunohistochemical analysis, proved positive for integrin a v b 3 . Conclusion: 111 In-RGD 2 allows the visualization of integrin a v b 3 in xenograft models in which integrin a v b 3 is expressed only on the neovasculature, such as in the HNSCC tumors. Thus, 111 In-RGD 2 allows specific visualization of angiogenesis in tumor models lacking constitutive tumoral integrin a v b 3 expression but may be less useful for this purpose in many tumors in which tumor cells express integrin a v b 3 .

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Section: Discussionmentioning

confidence: 82%

“…These include radiolabeled VEGF isoforms, antibodies against VEGF, and RGD-based peptides against integrin a v b 3 (11). RGD-based tracers have a major advantage because of their hydrophilicity and low molecular weight, enabling fast clearance via the kidneys while retaining high tumor uptake.…”

mentioning

confidence: 99%

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

et al. 2014

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“…Compounds that specifically target vascular endothelial growth factor (VEGF) and its receptors together with compounds that target integrins are the best-studied candidates to image tumor vascularization. Although several of these tracers have been tested in a preclinical and clinical setting in which they successfully visualized several types of tumors and their metastases (15,16), none of these are routinely used in the clinic and few have been used to detect antiangiogenic therapy response. In 2 studies, response to antiangiogenic therapy was successfully detected using 99m Tc-hydrazinonicotinamide-VEGF and 89 Zr-ranibizumab (17,18).…”

Section: Discussionmentioning

confidence: 99%

^99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature

et al. 2012

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Given the importance of angiogenesis for a tumor's survival and growth, several therapeutic strategies rely on the selective inhibition of angiogenesis and the destruction of existing tumor vasculature. These strategies raise the need for a noninvasive tool to evaluate tumor vasculature. We describe the radiosynthesis and evaluation of an imaging tracer that specifically binds tumor subendothelial collagen and thereby images tumor vasculature. Methods: 99m Tc-tricarbonyl was prepared and labeled with His-collagen-binding adhesion protein 35 (CNA35). After in vitro specificity testing, in vivo biodistribution and dosimetric studies were performed in healthy nude mice via planar imaging. 99m Tc-(CO) 3 His-CNA35 was evaluated for in vivo imaging of tumor vasculature in a HT29 colorectal carcinoma xenograft. Results: The labeling procedure yielded a compound with 95%-99% radiochemical purity and good in vitro stability. An in vitro binding test confirmed specificity and functionality. 99m Tc-(CO) 3 His-CNA35 rapidly cleared from the blood and predominantly accumulated in the kidneys and liver. The effective dose for a proposed single injection of 500 MBq of 99m Tc-(CO) 3 His-CNA35 is 3.70 mSv per organ or 2.01 mSv/g of tissue.Tumors were successfully visualized, and uptake correlated with ex vivo immunohistochemical staining of tumor vasculature. Conclusion: 99m Tc-(CO) 3 His-CNA35 may be a useful radioligand for the in vivo detection of tumor vasculature through subendothelial collagen binding. A noninvasive method of imaging tumor vasculature that could provide a reliable assessment of tumor vasculature would allow evaluation of the effectiveness of commonly used antiangiogenic therapies and determination of their optimal dosing and scheduling. As a tumor mass grows beyond the support capacity of the vasculature it relies on, the need for new blood vessels arises. The formation of new blood vessels is achieved through angiogenesis, a multistep process that relies on the tumor-driven production of proangiogenic factors. These resulting new blood vessels, however, are structurally and functionally deficient when compared with normal ones. They are disorganized, tortuous, and leaky, leading to heterogeneous blood flow, hypoxia, acidosis, and elevated interstitial fluid pressure, with a disturbed tumor microenvironment as a result (1). Nevertheless, this neovascularization allows the tumor to grow and plays an important role in tumor invasiveness and metastasis. Given the importance of angiogenesis, several therapeutic strategies rely on the selective inhibition of angiogenesis and destruction of tumor vasculature. In several types of cancer, antiangiogenic therapy alone or in combination with standard chemotherapeutic strategies has led to an improvement of survival (2,3). As the importance of these therapies increases, noninvasive methods are needed to provide a reliable assessment of tumor vasculature and thus a means for the management and planning of antiangiogenic therapy.A possible mechanism to target tumor vas...

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“…Nowadays, peptidebased radionuclide imaging and therapy plays a well established role in the management of patients with neuroendocrine tumors. 2 The use of somatostatin analogues for imaging and therapy of neuroendocrine tumors 3 and RGD (Arg-Gly-Asp) peptides to visualize tumorassociated angiogenesis 4 are some well known examples. Selectivity of these radionuclide loaded peptides to cancer cells, rapid penetration to the tumor tissue in combination with rapid clearance from normal tissues, designates them as very promising targeting agents.…”

Section: Introductionmentioning

confidence: 99%

In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors

Altai

Varasteh

Andersson

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody Z HER2:342 was developed for imaging of HER2 expression in tumors and a clinical study has demonstrated that the 111 In-and 68 Ga-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, significant renal accumulation of radioactivity after systemic injection of radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in murine model and in vitro using opossum derived proximal tubule cells (OK). It was found that kidney reabsorption of affibody was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody were involved in binding to OK cells. On OK cells two types of receptors for anti-HER2 affibody were found: K D1 =0.8 nM, B max1 =71,500 and K D2 =9.2 nM, B max2 =367,000. The results of the present study indicate affibody and other scaffold-based targeting proteins with relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells.

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Radionuclide Imaging of Tumor Angiogenesis

Cited by 44 publications

References 111 publications

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

^99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature

In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors

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Radionuclide Imaging of Tumor Angiogenesis

Cited by 44 publications

References 111 publications

Imaging Integrin αvβ3 on Blood Vessels with 111In-RGD2 in Head and Neck Tumor Xenografts

Imaging Integrin αvβ3 on Blood Vessels with 111In-RGD2 in Head and Neck Tumor Xenografts

99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature

In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors

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Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

^99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature