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Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α 1 -microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT., Results: We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 ( 177 Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term), 177 Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term), 177 Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment.

131I is widely used for therapy in the clinic and 125I and 131I, and increasingly 211At, are often used in experimental studies. It is important to know the biodistribution and dosimetry for these radionuclides to determine potential risk organs when using radiopharmaceuticals containing these radionuclides. The purpose of this study was to investigate the biodistribution of 125I-, 131I-, and free 211At in rats and to determine absorbed doses to various organs and tissues. Male Sprague Dawley rats were injected simultaneously with 0.1-0.3 MBq 125I- and 0.1-0.3 MBq 131I-, or 0.05-0.2 MBq 211At and sacrificed 1 hour to 7 days after injection. The activities and activity concentrations in organs and tissues were determined and mean absorbed doses were calculated. The biodistribution of 125I- was similar to that of 131I- but the biodistribution of free 211At was different compared to 125I- and 131I-. The activity concentration of radioiodine was higher compared with 211At in the thyroid and lower in all extrathyroidal tissues. The mean absorbed dose per unit injected activity was highest to the thyroid. 131I gave the highest absorbed dose to the thyroid, and 211At gave the highest absorbed dose to all other tissues studied.

Background: Radiation can be used to up-regulate the expression of the somatostatin receptor (sstr) subtype 2 in small cell lung cancer (SCLC) cells at absorbed doses of 2-8 Gy. Increased sstr expression results in increased binding of radiolabeled somatostatin analogs to the tumor cell, which enhances the efficacy of systemic radionuclide therapy. The aim of this study was to determine if lower absorbed doses could up-regulate sstr2 expression, and possibly influence other sstr subtypes., Methods: Human H69 SCLC cells were irradiated with an absorbed dose of 0.12-6.0 Gy and the sstr mRNA expression 3 days after irradiation was measured by quantitative real-time polymerase chain reaction for sstr1-5. At the same time point was the binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate to the cells measured after irradiation to an absorbed dose of 0.12-2.0 Gy and compared to the binding to nonirradiated cells., Results: mRNA expression of sstr1, sstr2, and sstr5 was increased by a factor of 1.5-2 in cells irradiated with absorbed doses≥4 Gy and the binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate was, accordingly, 2-3 times higher to irradiated cells for all absorbed doses, except 0.25 Gy., Conclusion: The binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate was increased after radiation exposure. This increase was observed at low absorbed doses in parallel with up-regulation of sstr1, sstr2, and sstr5 mRNA.

Point kernels describe the energy deposited at a certain distance from an isotropic point source and are useful for nuclear medicine dosimetry. They can be used for absorbed-dose calculations for sources of various shapes and are also a useful tool when comparing different Monte Carlo (MC) codes. The aim of this study was to compare point kernels calculated by using the mixed MC code, PENELOPE (v. 2006), with point kernels calculated by using the condensed-history MC codes, ETRAN, GEANT4 (v. 8.2), and MCNPX (v. 2.5.0). Point kernels for electrons with initial energies of 10, 100, 500, and 1 MeV were simulated with PENELOPE. Spherical shells were placed around an isotropic point source at distances from 0 to 1.2 times the continuous-slowing-down-approximation range (R(CSDA)). Detailed (event-by-event) simulations were performed for electrons with initial energies of less than 1 MeV. For 1-MeV electrons, multiple scattering was included for energy losses less than 10 keV. Energy losses greater than 10 keV were simulated in a detailed way. The point kernels generated were used to calculate cellular S-values for monoenergetic electron sources. The point kernels obtained by using PENELOPE and ETRAN were also used to calculate cellular S-values for the high-energy beta-emitter, 90Y, the medium-energy beta-emitter, 177Lu, and the low-energy electron emitter, 103mRh. These S-values were also compared with the Medical Internal Radiation Dose (MIRD) cellular S-values. The greatest differences between the point kernels (mean difference calculated for distances, <0.9 r/R(CSDA)), using PENELOPE and those from ETRAN, GEANT4, and MCNPX, were 3.6%, 6.2%, and 14%, respectively. The greatest difference between the cellular S-values for monoenergetic electrons was 1.4%, 2.5%, and 6.9% for ETRAN, GEANT4, and MCNPX, respectively, compared to PENELOPE, if omitting the S-values when the activity was distributed on the cell surface for 10-keV electrons. The largest difference between the cellular S-values for the radionuclides, between PENELOPE and ETRAN, was seen for 177Lu (1.2%). There were large differences between the MIRD cellular S-values and those obtained from PENELOPE: up to 420% for monoenergetic electrons and <22% for the radionuclides, with the largest difference for 103mRh. In conclusion, differences were found between the point kernels generated by different MC codes, but these differences decreased when cellular S-values were calculated, and decreased even further when the energy spectra of the radionuclides were taken into consideration.

The aim of this study was to compare the tumor uptake versus time and the tumor response in nude mice transplanted with a human midgut carcinoid (GOT1), when treated with either [(177)Lu-DOTA(0),Tyr(3)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate and to evaluate if plasma chromogranin A (P-CgA) was a reliable marker of tumor response. The tumor uptake and retention of activity of a single intravenous (i.v.) dose (15 MBq) of [(177)Lu-DOTA(0),Tyr(3)]-octreotate or [(177)Lu-DOTA(0),Tyr(3)]-octreotide were compared in nude mice xenografted with GOT1. The activity concentration 24 hours after injection was significantly higher in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate versus [(177)Lu-DOTA(0),Tyr(3)]-octreotide (16%+/-1.4% of injected activity per gram [%IA/g] vs. 8.1%+/-2.1% IA/g, mean +/- standard error of the mean) (p=0.00061). The mean absorbed dose was higher in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate (46+/-4.3 vs. 17 +/- 3.4 Gy). The reduction of tumor volume was accordingly more prominent in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate than in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotide (p=0.003). The mean tumor volume for animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate was reduced to 3% of its initial value. P-CgA values were strongly correlated with tumor volume. Octreotate seems to be a more suitable somatostatin analog than octreotide for receptor-mediated radiation therapy. P-CgA is a simple, accurate method for the estimation of tumor response in this animal model.

Purpose: The aim of this study was to analyze the effect therapeutic injections of (177)Lu-DOTA(0)-Tyr(3)]-octreotate (DOTATATE) had on the tumor uptake of a subsequent injection with (111)In-DOTATATE in GOT1-bearing nude mice., Methods and Materials: Nude mice, xenografted with the human midgut carcinoid, GOT1, were first intravenously injected with a curative (30 MBq) or a suboptimal (7.5 MBq) amount of (177)Lu-DOTATATE. At various intervals thereafter (4-13 days), a second injection with (111)In-DOTATATE (0.5 MBq) was given. One (1) day after the second injection, the animals were sacrificed, tumor tissues collected, the tumor (111)In and (177)Lu activity concentration determined, and tumor regression/cell density was recorded., Results: In animals given curative amounts, the uptake of (111)In was lower than in untreated animals. On the other hand, a second late injection (3-13 days) after suboptimal amounts resulted in a twofold higher tumor activity concentration versus untreated animals. When the uptake of the curative injection was corrected for tumor cell density, which decreased from 66% to 4% over 2 weeks, an enhanced uptake per tumor cell was observed. The curative and suboptimal amounts resulted in a different uptake and retention of (177)Lu in tumors. The suboptimal amount resulted in a constant activity concentration, while the curative amount resulted in an increased activity concentration over time., Conclusions: Our results, as presented in this paper, describe how the second injection in a fractionation protocol will be affected by the first therapeutic amount. This new information might be useful in the optimization of radionuclide therapy.

The radionuclide evaluation for therapy starts with preclinical studies in, for example, mice and rats, and various radionuclides have shown promising results. However, many radionuclides emit photons that will irradiate normal tissues. The risk of normal tissue toxicity in patients (e.g., bone marrow suppression) may be underestimated when relying on preclinical results. To illustrate the influence of photons in preclinical and clinical trials, the ratio between the tumor-to-normal tissue absorbed-dose rate ratio (TND) was calculated for humans, rats, and mice for 111In, 125I, 67Ga, 90Y, 131I, and 177Lu. The normal tissues were simulated by 70-kg, 300-g, and 20-g ellipsoids for humans, rats, and mice, respectively. It was assumed that the radionuclides were uniformly distributed, and that the activity concentration was 25 times higher in the tumor than in the normal tissue. There were only small differences between the TND values for the different species for 90Y and 177Lu. 131I showed similar TND values for rats and mice, whereas they were lower for humans. For 111In, 125I, and 67Ga, however, there were large differences between the different species. The influence of photons may thus be much lower in preclinical studies than in clinical situations. Therefore, translations of absorbed doses from animals to humans must be performed with caution.

Unlabelled: Free 211At has been proposed for therapy of anaplastic thyroid carcinoma (ATC). However, no extensive biodistribution study comparing tumor-bearing and nontumor-bearing mice has previously been performed. The aim of this study was to perform a complete evaluation of the biodistribution of 211At, both for normal and ATC-bearing mice. For comparison, the biodistribution of 125I- was simultaneously studied. Dosimetric evaluations were performed to investigate if (211)At can be used for therapy of ATC., Methods: Athymic nude mice were subcutaneously injected with either of two human ATC cell lines, HTh83 and KAT-4. Tumor-bearing and nontumor-bearing mice were injected intravenously with 0.3 MBq 211At and 0.3 MBq 125I- simultaneously. The mice were sacrificed 4-24 hours after injection, and the activity concentrations in tissues were determined., Results: Except for the thyroid, the concentration of 211At was higher than that of 125I- in the tissues. The uptake of 211At was primarily high in NIS-expressing organs. Furthermore, the absorbed doses to these organs were higher than both tumor types., Conclusions: The biodistribution of 211At and 125I- differed in this animal model. The higher mean absorbed dose from 211At in several organs than in tumor tissue restricts the possibility of using free 211At for therapy of ATC.

Objective: This study evaluates a novel photon radiation detector system for in vitro biokinetic measurements., Methods: A cell-culture well can be considered to consist of two different compartments: the cells and the medium. By placing the well on a lead-collimated scintillation (NaI(T1)) detector, changes in activity distribution between the compartments will result in changes in count rates owing to the efficiency ratio (ER) between the cells and the medium. The ER depends on differences in detection solid angles for the compartments and differences in attenuation of photons emitted from the compartments. Evaluation of the optimal measuring geometries for the detector system was done by Monte Carlo (MC) simulations. The detector system was tested in two different in vitro situations., Results: The MC simulations showed that the most optimal detector system was obtained by using a lead-collimated well crystal. Both the MC simulations and the experiments have proven the usability of the system., Conclusions: The detector system was demonstrated to be of value for biokinetic studies. The cellular binding of radiolabeled substances can be determined with high precision, and real-time measurements can be performed on a cell culture without harvesting the cells.

Aim: (177)Lu-DOTA-Tyr(3)-octreotate is a candidate radiopharmaceutical for the therapy of somatostatin receptor (sstr)-positive small cell lung cancer (SCLC). Scintigraphy of lung tumors is made with 2 alternative somatostatin analogs, (111)In-DTPA-octreotide or (99m)Tc-depreotide. The aim of this study was to compare the biodistribution of these 3 radiopharmaceuticals in SCLC xenografted to nude mice., Methods: Nude mice, bearing tumors from the human SCLC cell line NCI-H69, were intravenously injected with 10 MBq (2.4 microg) (99m)Tc-depreotide and 2 MBq (0.5 microg) (111)In-DTPA-octreotide simultaneously. The activity concentration (%IA/g) was measured in tumor and normal tissue at 2, 4, and 24 hours postinjection (hpi). The results were compared with earlier published biodistribution data of 3 MBq (0.7 microg) (177)Lu-DOTA-Tyr(3)-octreotate in the same animal model., Results: The activity concentration of (111)In-DTPAoctreotide in tumor was higher than the activity concentration of (99m)Tc-depreotide at 2-24 hpi, p < 0.05. The highest tumor uptake at 24 hpi was, however, found for (177)Lu-DOTA-Tyr(3)-octreotate. The activity concentration of (99m)Tc-depreotide was significantly higher in the heart, lungs, liver, the salivary glands, spleen, and bone marrow than for (111)In-DTPA-octreotide at 2-24 hpi. Saturation of the somatostatin receptors may have influenced the uptake in tumor and sstr-positive normal tissues., Conclusion: The low tumor-to-lung and tumor-to-liver activity concentration ratios for (99m)Tc-depreotide could result in a lower detection rate of SCLC with this compound versus (111)In-DTPA-octreotide. (177)Lu-DOTA-Tyr(3)-octreotate gave the highest tumor-activity concentration, and has, thus, the best properties for therapy.