Radionuclide and Fluorescence Imaging of Clear Cell Renal Cell Carcinoma Using Dual Labeled Anti-Carbonic Anhydrase IX Antibody G250

Muselaers, Stijn; Rijpkema, Mark; Bos, Desirée L.; Langenhuijsen, Johan F.; Oyen, Wim J.G.; Mulders, Peter F.A.; Oosterwijk, Egbert; Boerman, Otto C.

doi:10.1016/j.juro.2015.02.041

Cited by 22 publications

(18 citation statements)

References 19 publications

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“…28–30 With this dual-modality approach, the tumor could be assessed preoperatively, with subsequent intraoperative guidance for surgical removal of the tumor lesions based on the fluorescent component of the dual-label agent. 29,31,32 In oncology, molecular imaging is mainly dependent on the availability of a specific target on tumor cells or within the tumor stroma or vasculature, and the quality of the designed labeled probe, which depends on its biodistribution, metabolism, affinity, and specificity for the target. Among the targets, NTR1 is one of the very promising targeting receptors.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Evaluation of ⁶⁴Cu-DOTA-NT-Cy5.5 as a Dual-Modality PET/Fluorescence Probe to Image Neurotensin Receptor-Positive Tumor

Deng

Wang

et al. 2015

Mol. Pharmaceutics

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Overexpression of neurotensin receptors (NTRs) has been suggested to play important roles in the growth and survival of a variety of tumor types. The aim of this study is to develop a dual-modality probe (64Cu -DOTA-NT-Cy5.5) for imaging NTR1 expression in vivo with both positron emission tomography (PET) and fluorescence. In this approach, the thiol group and N terminal amino group of neurotensin analogue (Cys-NT) were chemically modified with Cy5.5 dye and DOTA chelator, respectively. After radiolabeling with 64Cu, the resulting probe (64Cu-DOTA-NT-Cy5.5) was evaluated in NTR1 positive HT-29 tumor model. Small animal PET quantification analysis demonstrated that the tumor uptake was 1.91 ± 0.22 and 1.79 ± 0.16%ID/g at 1 and 4 h postinjection (p.i.), respectively. The tumor-to-muscle ratio was 17.44 ± 3.25 at 4 h p.i. based on biodistribution. Receptor specificity was confirmed by the successful blocking experiment at 4 h p.i. (0.42 ± 0.05%ID/g). In parallel with PET experiment, fluorescence imaging was also performed, which demonstrated prominent tumor uptake in HT-29 model. As a proof of concept, an imaging guided surgery was performed to the fluorescent moiety of this probe and could provide potential surgery guidance for NTR positive patients. In summary, our results clearly indicated that the dual-modality probe, 64Cu-DOTA-NT-Cy5.5, could serve as a promising agent to image NTR positive tumors in vivo.

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Section: Discussionmentioning

confidence: 99%

Synthesis and Evaluation of ⁶⁴Cu-DOTA-NT-Cy5.5 as a Dual-Modality PET/Fluorescence Probe to Image Neurotensin Receptor-Positive Tumor

Deng

Wang

et al. 2015

Mol. Pharmaceutics

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“…When compared against several other CA IX-imaging agents, the accumulation within the tumor of this 99m Tc-chelated conjugate is somewhat lower. For example, CA IX conjugates with the best BioD had uptake of 10%-20% ID/g in the tumor (34,53,54) at 4 hours. Other conjugates exhibited approximately 1%-5% ID/g (51) and a few poorly localized to the tumor with <1% ID/g (38,39).…”

Section: Synthesis and Cell Binding Of Ca IX 99m Tc Conjugatesmentioning

confidence: 99%

“…Because of CA IX's cancer-enriched expression pattern, considerable effort has been expended to identify CA IX-specific ligands for use in tumor targeting. In fact, multiple CA IX ligands have been identified and conjugated to fluorophores (26)(27)(28)(29)(30)(31)(32)(33)(34)(35), SPECT probes (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48), and PET (49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59) agents with the goal of imaging hypoxic tumors. While therapeutic applications of some of these ligands have been explored in the literature, on the whole, less attention has been devoted to the important goal of eliminating malignant masses.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Nonpeptidic Ligand Conjugates for the Treatment of Hypoxic and Carbonic Anhydrase IX–Expressing Cancers

Roy

Putt

2017

Molecular Cancer Therapeutics

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The majority of tumors contain regions of hypoxia, which cause marked phenotypic changes to resident cells. This altered gene expression often leads to increased resistance to anticancer treatments. Therefore, elimination of these resistant hypoxic cells is crucial to prevent disease recurrence. Herein, we describe the selective delivery of imaging and chemotherapeutic agents to cells expressing carbonic anhydrase IX (CA IX), a highly upregulated hypoxia receptor. These agents were conjugated to a potent divalent CA IX ligand through a hydrophilic PEG linker. These conjugates are shown to bind CA IX-expressing cells in a receptor-dependent manner with mid-nanomolar affinities and with good tumor selectivity. In a mouse xenograft tumor model using HT-29 cells, a cytotoxic tubulysin B conjugate completely inhibited tumor growth. Overall, the targeting of a hypoxia marker, such as CA IX, to selectively deliver imaging or chemotherapeutic agents may lead to better treatment options for solid, hypoxic tumors. In addition, the combination of standard chemotherapeutics that are most potent in normoxic dividing cells and drugs specifically designed to eliminate hypoxic nondividing cells may elicit a superior clinical outcome. .

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“…For example, CA IX-specific peptide and small molecule ligands have been used to image moue xenograft models of colon 47–52 , renal 53 and cervical cancers 51 . CA IX-specific antibodies have also been exploited to image mouse cancer xenograft models of the kidney 54–57 , head & neck 58 , colon 59,60 and cervix 61 in addition to human patients with clear cell renal carcinomas 62–66 . However, small molecule conjugates have primarily used only PET 49,50 or fluorescence 51–53 imaging modalities to visualize hypoxic tumors.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Nonpeptidic Ligand Conjugates for SPECT Imaging of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers

Putt

2016

Bioconjugate Chem.

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As tumors grow, vasculature is often deficient or malformed, resulting in many localized areas of hypoxia. Cells located in these hypoxic regions exhibit an altered gene expression pattern that can significantly alter resistance to conventional anti-cancer treatments such as ionizing radiation and chemotherapeutic drugs. A priori knowledge of the level of hypoxia within a tumor may better guide clinical care. In an effort to create a hypoxia specific imaging agent, a ligand for the tissue hypoxia marker, carbonic anhydrase IX (CA IX), was synthesized and used as a targeting ligand to deliver an attached 99tmTc-chelating agent. Binding of the resulting conjugates to hypoxic cancer cells was first characterized in vitro. Whole animal imaging and biodistribution studies then were performed to determine tumor specificity in vivo. Several conjugates were found to bind selectively to CA IX expressing tumors in a receptor-dependent manner. We suggest that such conjugates could prove useful in identifying hypoxic cancers and/or quantitating the level of hypoxia within a tumor.

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Radionuclide and Fluorescence Imaging of Clear Cell Renal Cell Carcinoma Using Dual Labeled Anti-Carbonic Anhydrase IX Antibody G250

Cited by 22 publications

References 19 publications

Synthesis and Evaluation of ⁶⁴Cu-DOTA-NT-Cy5.5 as a Dual-Modality PET/Fluorescence Probe to Image Neurotensin Receptor-Positive Tumor

Synthesis and Evaluation of ⁶⁴Cu-DOTA-NT-Cy5.5 as a Dual-Modality PET/Fluorescence Probe to Image Neurotensin Receptor-Positive Tumor

Evaluation of Nonpeptidic Ligand Conjugates for the Treatment of Hypoxic and Carbonic Anhydrase IX–Expressing Cancers

Evaluation of Nonpeptidic Ligand Conjugates for SPECT Imaging of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers

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Radionuclide and Fluorescence Imaging of Clear Cell Renal Cell Carcinoma Using Dual Labeled Anti-Carbonic Anhydrase IX Antibody G250

Cited by 22 publications

References 19 publications

Synthesis and Evaluation of 64Cu-DOTA-NT-Cy5.5 as a Dual-Modality PET/Fluorescence Probe to Image Neurotensin Receptor-Positive Tumor

Synthesis and Evaluation of 64Cu-DOTA-NT-Cy5.5 as a Dual-Modality PET/Fluorescence Probe to Image Neurotensin Receptor-Positive Tumor

Evaluation of Nonpeptidic Ligand Conjugates for the Treatment of Hypoxic and Carbonic Anhydrase IX–Expressing Cancers

Evaluation of Nonpeptidic Ligand Conjugates for SPECT Imaging of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers

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Synthesis and Evaluation of ⁶⁴Cu-DOTA-NT-Cy5.5 as a Dual-Modality PET/Fluorescence Probe to Image Neurotensin Receptor-Positive Tumor

Synthesis and Evaluation of ⁶⁴Cu-DOTA-NT-Cy5.5 as a Dual-Modality PET/Fluorescence Probe to Image Neurotensin Receptor-Positive Tumor