18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of αvβ3 integrin expression

Wu, Zhanhong; Li, Zibo; Cai, Weibo; He, Lina; Chin, Frederick T.; Li, Fang; Chen, Xiaoyuan

doi:10.1007/s00259-007-0427-0

Cited by 118 publications

(164 citation statements)

References 30 publications

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“…A similar tumor uptake of 6 %ID/g was seen in the renal cell carcinoma SK-RC-52 model, in which, as in the ovarian carcinoma tumors, integrin a v b 3 is also expressed constitutively on the tumor cells (15,19). Uptake of other radiolabeled dimeric RGD tracers also averaged around 5-10 %ID/g in the SK-RC-52, OVCAR-3, and glioma tumor models (17,(30)(31)(32)(33). The average uptake of 111 In-RGD 2 in the HNSCC tumors approximates 1.3 %ID/g, suggesting that only vascular integrin a v b 3 expression has any influence on the tumor uptake of 111 In-RGD 2 and that therefore total tumor uptake is lower than in tumor models in which integrin a v b 3 is expressed constitutively.…”

Section: Discussionmentioning

confidence: 54%

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: 54%

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

et al. 2014

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“…We also observed a low 18 F-labeling yield for RGD homodimer and homotetramer in which 18 F-SFB was reacted with the glutamate amine group, presumably due to the steric hindrance and relatively low reactivity of the glutamate a-amino group. A mini-PEG (polyethylene glycol) spacer has been successfully used to reduce the spatial hindrance and improve the labeling yield for the multimeric RGD peptides (21,23). A similar strategy may also be applied here.…”

Section: Discussionmentioning

confidence: 99%

“…At 1 h after injection, the mouse was sacrificed, the blood, urine, liver, kidneys, and tumor were collected, and metabolite analysis was performed as reported previously (23). In brief, the blood sample was immediately centrifuged for 5 min at 13,200 rpm.…”

Section: Metabolic Stability Of 18 F-fb-bbn-rgdmentioning

confidence: 99%

¹⁸F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

Li¹,

Wu²,

Chen³

et al. 2008

J Nucl Med

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133

138

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“…PEGylation can alter pharmacokinetics by increasing the size of the molecule, increasing hydrophilicity, masking charges, and decreasing antigenicity. Insertion of 2-to 4-kDa PEG groups was reported to reduce the renal uptake and increase the tumor-to-kidney ratio of 125 I-and 18 F-labeled RGD peptides (52,54). Addition of larger PEG groups or albumin binding sequences can reduce glomerular filtration and increase the circulatory half-life of peptides (53,55).…”

Section: Reduction Of Renal Uptakementioning

confidence: 99%

Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention

Vegt¹,

Jong²,

Wetzels³

et al. 2010

J Nucl Med

257

251

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Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.

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18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of αvβ3 integrin expression

Cited by 118 publications

References 30 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

¹⁸F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention

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18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of αvβ3 integrin expression

Cited by 118 publications

References 30 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

18F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention

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Product

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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

¹⁸F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging