Author
Erik Vegt
Bio: Erik Vegt is an academic researcher from Radboud University Nijmegen Medical Centre. The author has contributed to research in topics: Kidney & Radionuclide therapy. The author has an hindex of 8, co-authored 10 publications receiving 670 citations.
Papers
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TL;DR: An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce neph rotoxicity are discussed.
Abstract: 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
258 citations
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TL;DR: Gelofusine is a well-known and generally used blood volume substitute that can be applied safely without the induction of toxicity, and evaluation of this compound for its potential to reduce the kidney uptake of radiolabeled peptides in patients is warranted.
Abstract: 111In-Diethylenetriaminepentaacetic acid-octreotide generally is used for the scintigraphic imaging of neuroendocrine and other somatostatin receptor–positive tumors. On the basis of the successful targeting of octreotide, radiolabeled somatostatin analogs, such as 90Y-(1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid [DOTA])0-Tyr3-octreotide and 177Lu-DOTA0-Tyr3-octreotate, were developed for peptide receptor radionuclide therapy. However, the maximum tolerated doses of these analogs are limited because of the high and persistent renal uptake that leads to relatively high radiation doses in the kidneys. Renal uptake can be reduced by coinfusion of basic amino acids or polypeptides. However, high doses of basic amino acids can induce severe side effects. It was reported that the infusion of gelatin-based plasma expanders resulted in increased low-molecular-weight proteinuria, suggesting that these plasma expanders interfere with the tubular reabsorption of peptides and proteins. In the present study, we analyzed the effects of several plasma expanders on the renal uptake of 111In-octreotide in rats and mice. Methods: Wistar rats and BALB/c mice were injected with 0.5 or 0.1 mL of plasma expander, respectively. Thereafter, the animals received 111In-octreotide intravenously. Animals were killed at 20 h after the injection of the radiopharmaceutical. Organs were dissected, and the amount of radioactivity in the organs and tissues was measured. Results: The administration of 20 mg of Gelofusine in rats or 4 mg in mice was as effective in reducing the renal uptake of 111In-octreotide as the administration of 80 or 20 mg of lysine in rats or mice, respectively, without reducing 111In-octreotide uptake in receptor-positive organs. Plasma expanders based on starch or dextran had no effect on the renal uptake of 111In-octreotide. Conclusion: The gelatin-based plasma expander Gelofusine significantly reduced the kidney uptake of 111In-octreotide as effectively as did lysine. Because Gelofusine is a well-known and generally used blood volume substitute that can be applied safely without the induction of toxicity, evaluation of this compound for its potential to reduce the kidney uptake of radiolabeled peptides in patients is warranted.
113 citations
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TL;DR: Megalin is involved in the renal reabsorption of radiolabelled octreotide, octreotate, exendin, neurotensin and minigastrin, and knowledge may help in the design of strategies to reduce this re absorption and the resulting nephrotoxicity in peptide receptor radionuclide therapy, enabling more effective therapy.
Abstract: Purpose
Radiolabelled peptides used for peptide receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells. The resulting high renal radiation dose can cause nephrotoxicity, limiting the maximum activity dose and the effectiveness of peptide receptor radionuclide therapy. The mechanisms of kidney reabsorption of these peptides are incompletely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of 111In-octreotide. In this study, the role of megalin in the renal reabsorption of various relevant radiolabelled peptides was investigated.
110 citations
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TL;DR: It is observed that gelatin-based plasma expanders induced tubular low-molecular-weight proteinuria in healthy volunteers, suggesting that components in these solutions can interfere with the tubular reabsorption of proteins and peptides.
Abstract: Peptide receptor–mediated radiotherapy of neuroendocrine and other somatostatin receptor–positive tumors with radiolabeled somatostatin analogs has been applied in several experimental settings. The kidneys are the organs responsible for dose-limiting toxicity attributable to the retention of radiolabeled octreotide in the renal cortex, leading to a relatively high radiation dose that may result in irreversible loss of kidney function. The administration of basic amino acids reduces renal uptake but does have significant side effects. We observed that gelatin-based plasma expanders induced tubular low-molecular-weight proteinuria in healthy volunteers, suggesting that components in these solutions can interfere with the tubular reabsorption of proteins and peptides. Here, we studied the effects of infusion of low doses of the plasma expander succinylated gelatin (GELO) on the renal uptake of 111In-labeled octreotide (111In-OCT). Methods: Five healthy volunteers were given 111In-OCT, first in combination with normal saline and 2 wk later in combination with GELO. Scintigraphic images of the kidneys as well as blood and urine samples were analyzed. To exclude a nonspecific hemodynamic effect of the plasma expander, the procedure was repeated with 5 other volunteers who received the carbohydrate-based plasma expander hydroxyethyl starch (HES). Results: Low doses of GELO were able to effectively reduce the kidney retention of 111In-OCT. The renal radiation dose was significantly reduced by 45% ± 10% (mean ± SD) (P = 0.006), whereas HES showed no significant effect (0% ± 12%). The infusion of GELO did not cause any side effects. Conclusion: GELO effectively reduces the renal uptake of 111In-OCT. In contrast to currently used mixtures of amino acids, GELO does not cause any side effects.
98 citations
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TL;DR: Renal uptake of 111In-octreotide and other radiolabeled peptides in rats can be effectively reduced by administration of albumin fragments, as well as the effect of lysine, succinylated gelatin solution, albumin, and FRALB on the kidney uptake.
Abstract: In most types of peptide receptor radionuclide therapy, the maximum activity dose that can be administered is limited by high and persistent renal retention of the radiolabeled peptides, which is, at least partly, mediated by the megalin receptor. Several agents that interfere with renal reabsorption of radiolabeled peptides have been identified (e.g., lysine, arginine, succinylated gelatin solution), but none of these inhibit renal reabsorption completely. Albumin, a naturally abundant megalin ligand, might be a safe and potent alternative. In this study, we analyzed the effects of albumin and fragments of albumin (FRALB) on the renal reabsorption of (111)In-diethylenetriaminepentaacetic acid (DTPA)-d-Phe(1)-octreotide ((111)In-octreotide), [Lys(40)(aminohexoic acid-DTPA-(111)In)NH(2)]-exendin-4 ((111)In-exendin), and (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-Glu(1)-minigastrin ((111)In-minigastrin). METHODS: The effects of albumin and FRALB on megalin-associated binding of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of (111)In-albumin and (111)In-FRALB in the kidneys of Wistar rats were determined, as well as the effect of lysine, succinylated gelatin solution, albumin, and FRALB on the kidney uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin. RESULTS: FRALB significantly reduced binding and uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin by BN16 cells. In rats, renal uptake of (111)In-labeled FRALB was significantly higher than that of (111)In-labeled intact albumin (P<0.001). FRALB administration effectively reduced renal uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin. Administration of 1-2 mg of FRALB reduced renal uptake of (111)In-octreotide as efficiently as 80 mg of lysine. CONCLUSION: Renal uptake of (111)In-octreotide and other radiolabeled peptides in rats can be effectively reduced by administration of albumin fragments. Additional studies to identify the albumin fragments responsible for inhibition of renal peptide uptake are warranted.
80 citations
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TL;DR: Identified risk factors provide a limited (<30 %) risk estimate even with target tissue dosimetry, and strongly suggest the existence of unidentified individual susceptibilities to radiation-associated disease.
Abstract: Peptide receptor radionuclide therapy (PRRT) with 90Y and 177Lu provides objective responses in neuroendocrine tumours, and is well tolerated with moderate toxicity. We aimed to identify clinical parameters predictive of long-term renal and haematological toxicity (myelodysplastic syndrome and acute leukaemia). Of 807 patients studied at IEO-Milan (1997–2013), 793 (98 %) received 177Lu (278, 34.4 %), 90Y (358, 44.4 %) or 177Lu and 90Y combined (157. 19.5 %), and 14 (2 %) received combinations of PRRT and other agents. Follow-up was 30 months (1–180 months). The parameters evaluated included renal risk factors, bone marrow toxicity and PRRT features. Data analysis included multiple regression, random forest feature selection, and recursive partitioning and regression trees. Treatment with 90Y and 90Y + 177Lu was more likely to result in nephrotoxicity than treatment with 177Lu alone (33.6 %, 25.5 % and 13.4 % of patients, respectively; p < 0.0001). Nephrotoxicity (any grade), transient and persistent, occurred in 279 patients (34.6 %) and was severe (grade 3 + 4) in 12 (1.5 %). In only 20–27 % of any nephrotoxicity was the disease modelled by risk factors and codependent associations (p < 0.0001). Hypertension and haemoglobin toxicity were the most relevant factors. Persistent toxicity occurred in 197 patients (24.3 %). In only 22–34 % of affected patients was the disease modelled by the clinical data (p < 0.0001). Hypertension (regression coefficient 0.14, p < 0.0001) and haemoglobin toxicity (regression coefficient 0.21, p < 0.0001) were pertinent factors. Persistent toxicity was associated with shorter PRRT duration from the first to the last cycle (mean 387 vs. 658 days, p < 0.004). Myelodysplastic syndrome occurred in 2.35 % of patients (modelled by the clinical data in 30 %, p < 0.0001). Platelet toxicity grade (2.05 ± 1.2 vs. 0.58 ± 0.8, p < 0.0001) and longer PRRT duration (22.6 ± 24 vs. 15.5 ± 9 months, p = 0.01) were relevant. Acute leukaemia occurred in 1.1 % of patients (modelled by the clinical data in 18 %, p < 0.0001). Identified risk factors provide a limited (<30 %) risk estimate even with target tissue dosimetry. These data strongly suggest the existence of unidentified individual susceptibilities to radiation-associated disease.
334 citations
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TL;DR: This review will present the current situation with respect to gelatin usage as a packaging source material and the challenges that remain in order to move the manufacture of gelatin-based films nearer to commercial reality.
299 citations
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TL;DR: Recent developments in the field of small peptides, and their applications in the diagnosis and treatment of cancer are presented.
Abstract: Human cancer cells overexpress many peptide receptors as molecular targets. Radiolabeled peptides that bind with high affinity and specificity to the receptors on tumor cells hold great potential for both diagnostic imaging and targeted radionuclide therapy. The advantage of solid-phase peptide synthesis, the availability of different chelating agents and prosthetic groups and bioconjugation techniques permit the facile preparation of a wide variety of peptide-based targeting molecules with diverse biological and tumor targeting properties. Some of these peptides, including somatostatin, bombesin, vasoactive intestinal peptide, gastrin, neurotensin, exendin and RGD are currently under investigation. It is anticipated that in the near future many of these peptides may find applications in nuclear oncology. This article presents recent developments in the field of small peptides, and their applications in the diagnosis and treatment of cancer.
271 citations
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TL;DR: An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce neph rotoxicity are discussed.
Abstract: 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
258 citations
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TL;DR: Polyvalency has a profound effect on the receptor-binding affinity and in vivo kinetics of radiolabeled RGD multimers, as compared with the other RGD analogs.
Abstract: Integrin αvβ3 plays a critical role in tumor angiogenesis and metastasis. Suitably radiolabeled cyclic arginine-glycine-aspartic (RGD) peptides can be used for noninvasive imaging of αvβ3 expression and targeted radionuclide therapy. In this study, we developed 64Cu-labeled multimeric RGD peptides, E{E[c(RGDyK)]2}2 (RGD tetramer) and E(E{E[c(RGDyK)]2}2)2 (RGD octamer), for PET imaging of tumor integrin αvβ3 expression. Methods: Both RGD tetramer and RGD octamer were synthesized with glutamate as the linker. After conjugation with 1,4,7,10-tetra-azacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA), the peptides were labeled with 64Cu for biodistribution and small-animal PET imaging studies (U87MG human glioblastoma xenograft model and c-neu oncomouse model). A cell adhesion assay, a cell-binding assay, receptor blocking experiments, and immunohistochemistry were also performed to evaluate the αvβ3-binding affinity/specificity of the RGD peptide-based conjugates in vitro and in vivo. Results: RGD octamer had significantly higher integrin αvβ3-binding affinity and specificity than RGD tetramer analog (inhibitory concentration of 50% was 10 nM for octamer vs. 35 nM for tetramer). 64Cu-DOTA-RGD octamer had higher tumor uptake and longer tumor retention than 64Cu-DOTA-RGD tetramer in both tumor models tested. The integrin αvβ3 specificity of both tracers was confirmed by successful receptor-blocking experiments. The high uptake and slow clearance of 64Cu-DOTA-RGD octamer in the kidneys was attributed mainly to the integrin positivity of the kidneys, significantly higher integrin αvβ3-binding affinity, and the larger molecular size of the octamer, as compared with the other RGD analogs. Conclusion: Polyvalency has a profound effect on the receptor-binding affinity and in vivo kinetics of radiolabeled RGD multimers. The information obtained here may guide the future development of RGD peptide-based imaging and internal radiotherapeutic agents targeting integrin αvβ3.
257 citations