Renal uptake and metabolism of radiopharmaceuticals derived from peptides and proteins

Akizawa, Hiromichi; Uehara, Tomoya; Arano, Yasushi

doi:10.1016/j.addr.2008.04.005

Cited by 98 publications

(96 citation statements)

References 84 publications

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“…High levels of radioactivity retention in the kidneys could be attributed to the degraded forms of the radiolabeled antibody, a result of lysosomal degradation of the antibody with long residence times within renal cells and slow clearance from the lysosome [24,25,26]. Methods to minimize this nonspecific renal retention of radiolabeled antibodies are under investigation.…”

Section: Discussionmentioning

confidence: 99%

[99mTc(CO)3]-Radiolabeled Bevacizumab: In vitro and in vivo Evaluation in a Melanoma Model

Camacho

Garcia²,

Calzada³

et al. 2013

Oncology

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Introduction: Vascular endothelial growth factor (VEGF) is one of the classic factors to tumor-induced angiogenesis in several tumor types, including melanoma. Bevacizumab, a monoclonal antibody against VEGF, could be used as an imaging tool in preclinical studies. Objective: To radiolabel bevacizumab with [^99mTc(CO)₃(OH₂)₃]⁺ and evaluate it in vivo and in vitro for melanoma imaging properties. Methods: Bevacizumab was radiolabeled with [^99mTc(CO)₃(OH₂)₃]⁺ ion in saline. The radiochemical stability of the labeled antibody was assessed. The biodistribution and scintigraphy imaging of the radiolabeled antibody were evaluated in normal C57BL/6J mice and in C57BL/6J mice bearing murine B16F1 melanoma tumors. Immunoreactivity of bevacizumab to murine tumors was determined from direct immunofluorescence and immunoblotting assays. Results: We demonstrate that ^99mTc(CO)₃-bevacizumab was stable. In vivo biodistribution studies revealed that tumor uptake of ^99mTc(CO)₃-bevacizumab was 2.64 and 2.51 %ID/g at 4 and 24 h postinjection. Scintigraphy image studies showed tumor selective uptake of ^99mTc(CO)₃-bevacizumab in the tumor-bearing mice. This affinity was confirmed by immunoassays performed on B16F10 tumor samples. Conclusions:^99mTc(CO)₃-bevacizumab could be used as an approach for tumor nuclear imaging in preclinical studies. This should be useful to provide insights into the angiogenic stimulus before and after chemotherapy, which might help improve current antitumor therapy.

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Section: Discussionmentioning

confidence: 99%

[99mTc(CO)3]-Radiolabeled Bevacizumab: In vitro and in vivo Evaluation in a Melanoma Model

Camacho

Garcia²,

Calzada³

et al. 2013

Oncology

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“…Considering that similar doses are being used in current clinical trials with 177 Luradiolabeled antibodies (www.clinicaltrials.gov), we expect that radiotoxicity would not be a barrier for translational development of scVEGF/ 177 Lu. Nevertheless, several general strategies, such as coinjection with lysine or the use of plasma expanders, are available for decreasing kidney uptake of radiopharmaceuticals (22). Another strategy might be introducing certain point mutations that could selectively decrease kidney uptake, as was reported for a VEGF-DOTA/ 64 Cu tracer based on human VEGF (19).…”

Section: Discussionmentioning

confidence: 99%

Targeted Systemic Radiotherapy with scVEGF/¹⁷⁷Lu Leads to Sustained Disruption of the Tumor Vasculature and Intratumoral Apoptosis

Blankenberg¹,

Levashova

Goris

et al. 2011

J Nucl Med

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Tumor vessels abundantly express receptors for vascular endothelial growth factor (VEGF), despite treatment with conventional or antiangiogenic drugs. We wished to determine whether the high levels of VEGF receptor (VEGFR) within the tumor vasculature could be leveraged for intracellular delivery of therapeutically significant doses of scVEGF/ 177 Lu, a novel radiopharmaceutical based on a recombinant single-chain (sc) derivative of VEGF, in orthotopic breast cancer models. Methods: scVEGF-PEG (polyethylene gycol)-DOTA conjugates containing 2.0-, 3.4-, or 5.0-kDa PEG linkers site-specifically conjugated to a cysteinecontaining tag (Cys-tag) in scVEGF were radiolabeled with 177 Lu (scVEGF/ 177 Lu) for in vivo studies. Human MDA231luc and mouse 4T1luc cell lines were injected orthotopically to establish breast carcinoma tumors in immunodeficient and immunocompetent hosts, respectively. The effects of scVEGF/ 177 Lu were defined by analysis of changes in tumor growth and immunohistochemical staining for the endothelial markers CD31 and VEGFR-2 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining for intratumoral apoptosis. Results: Biodistribution assays and dosimetric calculations established that scVEGF/ 177 Lu with a 3.4-kDa PEG linker delivered the highest dose of radiation to tumors (69.9 cGy/MBq/g of tissue) and the lowest dose to the kidneys (33.3 cGy/MBq/ organ). Total doses below 40 MBq/mouse of scVEGF/ 177 Lu did not affect renal function, and 3 divided doses of 6.3 MBq/mouse or a bolus dose of 18.9 MBq/mouse induced only transient lymphopenia and weight loss (,10% baseline weight). In mice with orthotopic mammary breast carcinoma, intravenous injections of well-tolerated bolus and fractionated doses of scVEGF/ 177 Lu in the range from 6.3 to 18.9 MBq/mouse (25-76 MBq/m 2 ) resulted in dose-dependent tumor growth inhibition. Immunohistochemical analysis of tumors at 4-5 wk after single injections of scVEGF/ 177 Lu indicated dose-dependent regression of tumor vasculature and widespread intratumoral apoptosis. A single dose of 7.4 MBq/mouse of scVEGF/ 177 Lu given before a course of bevacizumab or sunitinib treatment enhanced the antiangiogenic effects of both drugs. Conclusion: Selective targeting of VEGFR in tumor vasculature with well-tolerated doses of scVEGF/ 177 Lu is effective in orthotopic breast cancer models. As high levels of VEGFR expression in the tumor vasculature are a common feature in a variety of cancers, targeting tumor angiogenesis with scVEGF/ 177 Lu warrants further exploration.

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“…The reabsorption is mainly mediated by endocytosis and results in subsequent cleavage of the peptides. Thus, high radioactivity accumulation in the kidney is often caused by a long residence time of radiolabeled metabolites generated by intracellular degradation (1,2). The uptake of the radiolabeled compound into cells of the proximal tubules is subject to different mechanisms depending on the total charge, distribution of charge, and structural size (3,4).…”

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confidence: 99%

Pharmacokinetic Properties of Peptidic Radiopharmaceuticals: Reduced Uptake of (EH)₃-Conjugates in Important Organs

et al. 2013

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Renal uptake and metabolism of radiopharmaceuticals derived from peptides and proteins

Cited by 98 publications

References 84 publications

[<sup>99m</sup>Tc(CO)<sub>3</sub>]-Radiolabeled Bevacizumab: In vitro and in vivo Evaluation in a Melanoma Model

[<sup>99m</sup>Tc(CO)<sub>3</sub>]-Radiolabeled Bevacizumab: In vitro and in vivo Evaluation in a Melanoma Model

Targeted Systemic Radiotherapy with scVEGF/¹⁷⁷Lu Leads to Sustained Disruption of the Tumor Vasculature and Intratumoral Apoptosis

Pharmacokinetic Properties of Peptidic Radiopharmaceuticals: Reduced Uptake of (EH)₃-Conjugates in Important Organs

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Renal uptake and metabolism of radiopharmaceuticals derived from peptides and proteins

Cited by 98 publications

References 84 publications

[<sup>99m</sup>Tc(CO)<sub>3</sub>]-Radiolabeled Bevacizumab: In vitro and in vivo Evaluation in a Melanoma Model

[<sup>99m</sup>Tc(CO)<sub>3</sub>]-Radiolabeled Bevacizumab: In vitro and in vivo Evaluation in a Melanoma Model

Targeted Systemic Radiotherapy with scVEGF/177Lu Leads to Sustained Disruption of the Tumor Vasculature and Intratumoral Apoptosis

Pharmacokinetic Properties of Peptidic Radiopharmaceuticals: Reduced Uptake of (EH)3-Conjugates in Important Organs

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Targeted Systemic Radiotherapy with scVEGF/¹⁷⁷Lu Leads to Sustained Disruption of the Tumor Vasculature and Intratumoral Apoptosis

Pharmacokinetic Properties of Peptidic Radiopharmaceuticals: Reduced Uptake of (EH)₃-Conjugates in Important Organs