Search

Molecular radiotherapy using 177Lu-DOTATATE is a most effective treatment for somatostatin receptor-expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after 177Lu-DOTATATE therapy using SPECT imaging with 111In-anti-γH2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with β-emitting therapeutic radiopharmaceuticals. Methods: Six cell lines were exposed to external-beam radiotherapy (EBRT) or 177Lu-DOTATATE, after which the number of γH2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor-positive tumor xenografts were treated with 177Lu-DOTATATE or sham-treated and coinjected with 111In-anti-γH2AX-TAT, 111In-IgG-TAT control, or vehicle. Results: Clonogenic survival after external-beam radiotherapy was cell-line-specific, indicating varying levels of intrinsic radiosensitivity. Regarding in vitro cell lines treated with 177Lu-DOTATATE, clonogenic survival decreased and γH2AX foci increased for cells expressing high levels of somatostatin receptor subtype 2. Ex vivo measurements revealed a partial correlation between 177Lu-DOTATATE uptake and γH2AX focus induction between different regions of CA20948 xenograft tumors, suggesting that different parts of the tumor may react differentially to 177Lu-DOTATATE irradiation. Conclusion:111In-anti-γH2AX-TAT allows monitoring of DNA damage after 177Lu-DOTATATE therapy and reveals heterogeneous damage responses.

The gastrin releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The gallium-68 labeled GRPr antagonist SB3 (68Ga-SB3) has shown excellent results in (pre)clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate 68Ga-SB3 PET/CT-imaging of primary PCa tumors and assess safety. More aims included biodistribution, dosimetry, comparison with pathology and GRPr expression. MATERIALS AND METHODS: Ten therapy-naive, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-hour extensive PET/CT-imaging protocol was performed, within 2 weeks prior to prostatectomy. Prostate tissue was evaluated for tumor localization, Gleason Score and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 months prior to the study were matched. For dosimetry residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose 2.1 model. RESULTS: Administration of 68Ga-SB3 (187.4 ± 40.0 MBq, 40±5 μg) was well tolerated, no significant changes in vital signs or laboratory results were observed. 68Ga-SB3 PET/CT showed lesions in 8 out of 10 patients. Pathological analysis revealed a total of 16 tumor lesions of which PET/CT showed 14, resulting in a sensitivity of 88%. 68Ga-SB3 PET/CT-imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor of PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, level of GRPr expression showed significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other 68Ga labeled radiopeptides. Highest absorbed dose was detected in the physiological GRPr-expressing pancreas (0.198 mGy/MBq), followed by bladder wall and kidneys. CONCLUSION: 68Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.

Affibody molecules are small proteins engineered using a nonantibody scaffold. Radiolabeled Affibody molecules are excellent imaging probes, but their application to radionuclide therapy has been prevented by high renal reabsorption. The aim of this study was to test the hypothesis that Affibody-based peptide nucleic acid (PNA)-mediated pretargeted therapy of human epidermal growth factor receptor 2 (HER2)-expressing cancer extends survival without accompanying renal toxicity. Methods: A HER2-targeting Affibody molecule ligated with an AGTCGTGATGTAGTC PNA hybridization probe (ZHER2:342-SR-HP1) was used as the primary pretargeting agent. A complementary AGTCGTGATGTAGTC PNA conjugated to the chelator DOTA and labeled with the radionuclide 177Lu (177Lu-HP2) was used as the secondary agent. The influence of different factors on pretargeting was investigated. Experimental radionuclide therapy in mice bearing SKOV-3 xenografts was performed in 6 cycles separated by 7 d. Results: Optimal tumor targeting was achieved when 16 MBq/3.5 μg (0.65 nmol) of 177Lu-HP2 was injected 16 h after injection of 100 μg (7.7 nmol) of ZHER2:342-SR-HP1. The calculated absorbed dose to tumors was 1,075 mGy/MBq, whereas the absorbed dose to kidneys was 206 mGy/MBq and the absorbed dose to blood (surrogate of bone marrow) was 4 mGy/MBq. Survival of mice was significantly longer (P < 0.05) in the treatment group (66 d) than in the control groups treated with the same amount of ZHER2:342-SR-HP1 only (37 d), the same amount and activity of 177Lu-HP2 only (32 d), or phosphate-buffered saline (37 d). Conclusion: The studied pretargeting system can deliver an absorbed dose to tumors appreciably exceeding absorbed doses to critical organs, making Affibody-based PNA-mediated pretargeted radionuclide therapy highly attractive.

Rationale: The aim of this study is to build a simulation framework to evaluate the number of DNA double strand breaks (DSBs) induced by in vitro targeted radionuclide therapy (TRT). This work represents the first step towards exploring underlying biological mechanisms and influence of physical/chemical parameters to enable a better response prediction in patients. We used this tool to characterize early DSB induction by [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE), a commonly used TRT for neuroendocrine tumors. Methods: A multiscale approach is implemented to simulate the number of DSBs produced over 4 h by the cumulated decays of 177Lu distributed according the somatostatin receptor-binding. The approach involves 2 sequential simulations performed with Geant4/Geant4-DNA. The radioactive source is sampled according to uptake experiments on the distribution of activities within the medium and the planar cellular cluster, assuming instant and permanent internalization. A phase space (PHSP) is scored around the nucleus of the central cell. Then, the PHSP is used to generate particles entering the nucleus containing a multi-scale description of the DNA in order to score the number of DSBs per particle source. The final DSB computations are compared to experimental data, measured by immunofluorescent detection of 53BP1 foci. Results: The probability of electrons reaching the nucleus was significantly influenced by the shape of the cell compartment, causing large variance in the induction pattern of DSBs. A significant difference was found in the DSBs induced by activity distributions in cell and medium, which is explained by the specific energy (z) distributions. The average number of simulated DSBs is 14 DSBs/cell (range: 7-24 DSBs/cell) compared to 13 DSBs/cell (2-30) experimentally determined. We found a linear correlation between the mean absorbed dose to the nucleus and the number of DSBs/cell: 0.014 DSBs/cell mGy-1 for internalization in the Golgi apparatus and 0.017 DSBs/cell mGy-1 for internalization in the cytoplasm. Conclusion: This simulation tool can lead to more reliable absorbed dose to DNA correlation and help in prediction of biological response.

Because overexpression of the gastrin-releasing peptide receptor (GRPR) has been reported on various cancer types, for example, prostate cancer and breast cancer, targeting this receptor with radioligands might have a significant impact on staging and treatment of GRPR-expressing tumors. NeoBOMB1 is a novel DOTAcoupled GRPR antagonist with high affinity for GRPR and excellent in vivo stability. The purpose of this preclinical study was to further explore the use of NeoBOMB1 for theranostic application by determining the biodistribution of 68Ga-NeoBOMB1 and 177Lu- NeoBOMB1. Methods: PC-3 tumor–xenografted BALB/c nu/nu mice were injected with either approximately 13 MBq/250 pmol 68Ga- NeoBOMB1 or a low (;1MBq/200pmol) versus high (;1MBq/10 pmol) peptide amount of 177Lu-NeoBOMB1, after which biodistribution and imaging studies were performed. At 6 time points (15, 30, 60, 120, 240, and 360 min for 68Ga-NeoBOMB1 and 1, 4, 24, 48, 96, and 168 h for 177Lu-NeoBOMB1) postinjection tumor and organ uptake was determined. To assess receptor specificity, additional groups of animals were coinjected with an excess of unlabeled NeoBOMB1. Results of the biodistribution studies were used to determine pharmacokinetics and dosimetry. Furthermore, PET/CT and SPECT/MRI were performed. Results: Injection of approximately 250 pmol 68Ga-NeoBOMB1 resulted in a tumor and pancreas uptake of 12.4 6 2.3 and 22.7 6 3.3 percentage injected dose per gram (%ID/g) of tissue, respectively, at 120 min after injection. 177Lu-NeoBOMB1 biodistribution studies revealed a higher tumor uptake (17.9 6 3.3 vs. 11.6 6 1.3 %ID/g of tissue at 240 min after injection) and a lower pancreatic uptake (19.8 6 6.9 vs. 105 6 13 %ID/g of tissue at 240 min after injection) with the higher peptide amount injected, leading to a significant increase in the absorbed dose to the tumor versus the pancreas (200 pmol, 570 vs. 265 mGy/ MBq; 10 pmol, 435 vs. 1393 mGy/MBq). Using these data to predict patient dosimetry, we found a kidney, pancreas, and liver exposure of 0.10, 0.65, and 0.06mGy/MBq, respectively. Imaging studies resulted in good visualization of the tumor with both 68Ga-NeoBOMB1 and 177Lu-NeoBOMB1. Conclusion: Our findings indicate that 68Ga- or 177Lu-labeled NeoBOMB1 is a promising radiotracer with excellent tumor uptake and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors.

Contains fulltext : 89547.pdf (Publisher’s version ) (Closed access) We determined the renal radiation dose of a series of (111)In-labeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed. METHODS: Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention after injection of 40-50 MBq of (111)In-diethylenetriaminepentaacetic acid-labeled peptides (octreotide, exendin, octreotate, neurotensin, and minigastrin analogs), and the absorbed kidney radiation doses were estimated. Body weight, renal function parameters, and renal histology were determined at 16-20 wk after the first scan and compared with those in naive animals. RESULTS: Because of high renal retention, (111)In-diethylenetriaminepentaacetic acid-exendin-4 scans resulted in a 70-Gy kidney radiation dose in wild-type mice. Megalin-deficient kidneys received 20-40 Gy. The other peptides resulted in much lower renal doses. Kidney function monitoring indicated renal damage in imaged animals. CONCLUSION: Micro-SPECT enables longitudinal studies in 1 animal. However, long-term nephrotoxic effects may be induced after high renal radiation doses, even with (111)In-labeled radiotracers. 01 juni 2010

Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose–response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. Methods: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. Results: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and 166Ho-phosphonate clinical investigations. Conclusion: Radionuclide therapy dose–response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.

TO THE EDITOR: We read with great interest the paper by Ulrich et al. ([1][1]) reporting on the predictive value of 99mTc-macroaggregated albumin (99mTc-MAA) uptake in patients with colorectal liver metastasis scheduled for selective internal radiation therapy (SIRT) with 90Y-loaded resin