Renal uptake of radiolabeled octreotide in human subjects is efficiently inhibited by succinylated gelatin.

UNLABELLED: 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.

Residualizing iodine markedly improved tumor targeting using bispecific antibody-based pretargeting.

UNLABELLED: Previous studies have shown that pretargeting allows rapid visualization of renal cell carcinomas (RCC) with an (111)In-labeled bivalent peptide. For radioimmunotherapy, a beta-emitting radionuclide labeled to a bivalent peptide is required. Therapeutic efficacy of these radionuclides depends on the E(max), physical half-life, and residence time of the radiolabel in the tumor. The (131)I radiolabel generally clears rapidly from the tumor after internalization and subsequent degradation of the bivalent l-amino acid peptide (l-a.a. peptide) in the tumor cells. To improve the residence time of the iodine label in the tumor, a new bivalent peptide was synthesized that is peptidase resistant and consists of 4 d-amino acids (d-a.a. peptide). Here we investigated the characteristics of the residualizing iodine label in SK-RC-52 RCC tumors. METHODS: The d-a.a. peptide was manually synthesized according to standard solid-phase Fmoc/HBTU (2-[1H-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate) chemistry. The uptake and retention in the tumor of (111)In-/(125)I-labeled bivalent peptides (l-a.a. peptide and d-a.a. peptide) were studied in female BALB/c athymic mice with subcutaneous SK-RC-52 RCC tumors. Tumors were pretargeted with the bispecific monoclonal antibody (bs-mAb) G250xDTIn-1 and, 72 h later, mice were injected intravenously with one of both radiolabeled peptides. The effect of bs-mAb-diDTPA-bs-mAb (DTPA is diethylenetriaminepentaacetic acid) bridging at the tumor cell surface on the internalization of the bs-mAb-diDTPA complex was investigated in SK-RC-52 tumor-bearing mice. RESULTS: The maximum uptake and retention of (125)I-labeled l-a.a. peptide in the tumor were significantly lower compared with that of the (111)In-labeled l-a.a. peptide. In contrast, the tumor uptake and retention of the (125)I-labeled d-a.a. peptide) were similar to that of the (111)In-labeled l-a.a. peptide but were superior at later time points. The biodistribution of the radioiodinated d-a.a. peptide was highly similar to that of the (111)In-labeled d-a.a. peptide, and both radiolabeled peptides were retained significantly better in the tumor than the (111)In-labeled l-a.a. peptide. bs-mAb-diDTPA-bs-mAb bridge formation did not affect internalization of the bs-mAb-diDTPA complex. CONCLUSION: Uptake and retention in the tumor of the iodinated peptide after pretargeting with a bs-mAb can be significantly improved using d-a.a. peptides. Accordingly, the radiation dose to the tumor, correlating with the therapeutic efficacy of pretargeted RCC, can be enhanced substantially.

Biodistribution and imaging of FDG in rats with LS174T carcinoma xenografts and focal Escherichia coli infection.

OBJECTIVE: The aim of this study was to compare the dynamic distribution of fluorodeoxyglucose (FDG) in malignant and in infectious lesions. METHODS: The dynamic distribution of FDG was studied in Rowett nude (RNU) rats with a LS174T carcinoma xenograft in the left front leg and an Escherichia coli-induced focal infection in the right front leg. In 5 rats, dynamic FDG-PET was performed (27 frames of 6-15 minutes) up to 4 hours after injection of 11 MBq 18FDG. The mean FDG uptake (SUV) was calculated and plotted by using a region of interest (ROI) centered over both lesions. In groups of 6 rats, the biodistribution of FDG was determined by counting dissected tissues at 1, 2, 3, and 4 hours after an injection of 11 MBq FDG. Means +/- the standard error of the mean (SEM) were calculated. RESULTS: Dynamic positron emission tomography (PET) visualized both the tumor and the infection. The ROI analysis showed that FDG uptake in the infections was faster and higher, as compared to the tumor lesions. FDG uptake in the tumor reached a standardized uptake value (SUV) of 0.8 +/- 0.3 at 60 minutes and in the infectious lesions a SUV of 1.6 +/- 0.2 at 45 minutes, both remaining constant until 4 hours postinjection (p.i.). In the biodistribution study with ex vivo tissue counting, FDG had accumulated up to 1.1 +/- 0.1 %ID/g and 0.8 +/- 0.1 %ID/g at 1 hour in the tumor and infection, respectively, and remained constant until 4 hours for both lesions without significantly different wash-out from the 2 lesions. The tumor/blood and abscess/ blood ratios increased with time to 57 +/- 17 and 48 +/- 14, respectively. CONCLUSION: Although in this model differences in absolute FDG uptake and initial kinetics between tumor and infection were observed, the wash-out rate of FDG from the lesions was similar over time. The retention of FDG in the inflammatory lesion indicated that dual time-point imaging does not necessarily resolve diagnostic pitfalls for FDG-PET in oncology in order to discriminate between malignant tumorous and benign infectious lesions.