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First in-human radiation dosimetry of 68Ga-NODAGA-RGDyK.

ABSTRACT: BACKGROUND:Integrin-targeting radiopharmaceuticals have potential broad applications, spanning from cancer theranostics to cardiovascular diseases. We have previously reported preclinical dosimetry results of 68Ga-NODAGA-RGDyK in mice. This study presents the first human dosimetry of 68Ga-NODAGA-RGDyK in the five consecutive patients included in a clinical imaging protocol of carotid atherosclerotic plaques. Five male patients underwent whole-body time-of-flight (TOF) PET/CT scans 10, 60 and 120 min after tracer injection (200 MBq). Quantification of 68Ga activity concentration was first validated by a phantom study. To be used as input in OLINDA/EXM, time-activity curves were derived from manually drawn regions of interest over the following organs: brain, thyroid, lungs, heart, liver, spleen, stomach, kidneys, red marrow, pancreas, small intestine, colon, urinary bladder and whole body. A separate dosimetric analysis was performed for the choroid plexuses. Female dosimetry was extrapolated from male data. Effective doses (EDs) were estimated according to both ICRP60 and ICRP103 assuming 30-min and 1-h voiding cycles. RESULTS:The body regions receiving the highest dose were urinary bladder, kidneys and choroid plexuses. For a 30-min voiding cycle, the EDs were 15.7 and 16.5 ?Sv/MBq according to ICRP60 and ICRP103, respectively. The extrapolation to female dosimetry resulted in organ absorbed doses 17% higher than those of male patients, on average. The 1-h voiding cycle extrapolation resulted in EDs of 19.3 and 19.8 ?Sv/MBq according to ICRP60 and ICRP103, respectively. A comparison is made with previous mouse dosimetry and with other human studies employing different RGD-based radiopharmaceuticals. CONCLUSIONS:According to ICRP60/ICRP103 recommendations, an injection of 200 MBq 68Ga-NODAGA-RGDyK leads to an ED in man of 3.86/3.92 mSv. For future therapeutic applications, specific attention should be directed to delivered dose to kidneys and potentially also to the choroid plexuses. TRIAL REGISTRATION:Clinical trial.gov, NCT01608516.

SUBMITTER: Gnesin S

PROVIDER: S-EPMC5436995 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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First in-human radiation dosimetry of <sup>68</sup>Ga-NODAGA-RGDyK.

Gnesin Silvano S Mitsakis Periklis P Cicone Francesco F Deshayes Emmanuel E Dunet Vincent V Gallino Augusto F AF Kosinski Marek M Baechler Sébastien S Buchegger Franz F Viertl David D Prior John O JO

EJNMMI research 20170518 1

<h4>Background</h4>Integrin-targeting radiopharmaceuticals have potential broad applications, spanning from cancer theranostics to cardiovascular diseases. We have previously reported preclinical dosimetry results of <sup>68</sup>Ga-NODAGA-RGDyK in mice. This study presents the first human dosimetry of <sup>68</sup>Ga-NODAGA-RGDyK in the five consecutive patients included in a clinical imaging protocol of carotid atherosclerotic plaques. Five male patients underwent whole-body time-of-flight (TO ...[more]

PMID: 28523582

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Project description:BackgroundGastrin-releasing peptide receptor antagonists have promise in theranostics of several highly incident tumours, including prostate and breast. This study presents the first human dosimetry of 68Ga-NODAGA-MJ9 in the first five consecutive patients with recurrent prostate cancer included in a dual-tracer positron emission tomography (PET) protocol. Five male patients with biochemical relapse of prostate adenocarcinoma underwent four whole-body time-of-flight PET/CT scans within 2 h after tracer injection. To be used as input in OLINDA/EXM 2.0, time-integrated activity coefficients were derived from manually drawn regions of interest over the following body regions: brain, thyroid, lungs, heart, liver, gallbladder, spleen, stomach, kidneys, adrenals, red marrow, pancreas, intestines, urinary bladder and whole body. Organ absorbed doses and effective dose (ED) were calculated with OLINDA/EXM 2.0 using the NURBS voxelized phantoms adjusted to the ICRP-89 organ masses and ICRP103 tissue-weighting factors. Additional absorbed dose estimations were performed with OLINDA/EXM 1.1 to be comparable with similar previous publications.ResultsThe body regions receiving the highest absorbed doses were the pancreas, the urinary bladder wall, the small intestine and the kidneys (260, 69.8, 38.8 and 34.8 μGy/MBq respectively). The ED considering a 30-min urinary voiding cycle was 17.6 μSv/MBq in male patients. The increment of voiding time interval produced a significant increase of absorbed doses in bladder, prostate and testes, as well as an increase of ED. ED also increased if calculated with OLINDA/EXM 1.1. These results have been discussed in view of similar publications on bombesin analogues or on other commonly used theranostic peptides.ConclusionsThe pancreas is the most irradiated organ after the injection of 68Ga-NODAGA-MJ9, followed by the urinary bladder wall, the small intestine and the kidneys. ED is in the same range of other common 68Ga-labelled peptides. Differences with similarly published studies on bombesin analogues exist, and are mainly dependent on the methodology used for absorbed dose calculations.Trial registrationClinicaltrial.Gov identifier: NCT02111954 , posted on 11/042014.

Project description:Arginine-Glycine-Aspartate (RGD)-recognizing cell surface integrins are involved in tumor growth, invasiveness/metastases, and angiogenesis, and are therefore an attractive treatment target in cancers. The subtype integrin αvβ3 is upregulated on endothelial cells during angiogenesis and on tumor cells. In vivo assessment of integrin αvβ3 is possible with positron emission tomography (PET). Preclinical data on radiochemical properties, tumor uptake and radiation exposure identified [68Ga]Ga-NODAGA-E[c(RGDyK)]2 as a promising candidate for clinical translation. In this first-in-human phase I study, we evaluate [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET in patients with neuroendocrine neoplasms (NEN) and breast cancer (BC). The aim was to investigate safety, biodistribution and dosimetry as well as tracer uptake in tumor lesions. A total of 10 patients (5 breast cancer, 5 neuroendocrine neoplasm) received a single intravenous dose of approximately 200 MBq [68Ga]Ga-NODAGA-E[c(RGDyK)]2. Biodistribution profile and dosimetry were assessed by whole-body PET/CT performed at 10 min, 1 h and 2 h after injection. Safety assessment with vital parameters, electrocardiograms and blood tests were performed before and after injection. In vivo stability of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 was determined by analysis of blood and urine. PET images were analyzed for tracer uptake in tumors and background organs. No adverse events or pharmacologic effects were observed in the 10 patients. [68Ga]Ga-NODAGA-E[c(RGDyK)]2 exhibited good in vivo stability and fast clearance, primarily by renal excretion. The effective dose was 0.022 mSv/MBq, equaling a radiation exposure of 4.4 mSv at an injected activity of 200 MBq. The tracer demonstrated stable tumor retention and good image contrast. In conclusion, this first-in-human phase I trial demonstrated safe use of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 for integrin αvβ3 imaging in cancer patients, low radiation exposure and favorable uptake in tumors. Further studies are warranted to establish whether [68Ga]Ga-NODAGA-E[c(RGDyK)]2 may become a tool for early identification of patients eligible for treatments targeting integrin αvβ3 and for risk stratification of patients.

Project description:68Ga-NODAGA-exendin-4 is a promising tracer for β-cell imaging using PET/CT. Possible applications include preoperative visualization of insulinomas and discrimination between focal and diffuse forms of congenital hyperinsulinism. There is also a significant role for this tracer in extending our knowledge on the role of β-cell mass in the pathophysiology of type 1 and type 2 diabetes by enabling noninvasive quantification of tracer uptake as a measure for β-cell mass. Calculating radiation doses from this tracer is important to assess its safety for use in patients (including young children) with benign diseases and healthy individuals. Methods: Six patients with hyperinsulinemic hypoglycemia were included. After intravenous injection of 100 MBq of the tracer, 4 successive PET/CT scans were obtained at 30, 60, 120, and 240 min after injection. Tracer activity in the pancreas, kidneys, duodenum, and remainder of the body were determined, and time-integrated activity coefficients for the measured organs were calculated. OLINDA/EXM software, version 1.1, was applied to calculate radiation doses using the reference adult male and female models and to estimate radiation doses to children. Results: The mean total effective dose for adults was very low (0.71 ± 0.07 mSv for a standard injected dose of 100 MBq). The organ with the highest absorbed dose was the kidney (47.3 ± 10.2 mGy/100 MBq). The estimated effective dose was 2.32 ± 0.32 mSv for an injected dose of 20 MBq in newborns. This dose decreased to 0.77 ± 0.11 mSv/20 MBq for 1-y-old children and 0.59 ± 0.05 mSv for an injected dose of 30 MBq in 5-y-old children. Conclusion: Our human PET/CT-based dosimetric calculations show that the effective radiation doses from the novel tracer 68Ga-NODAGA-exendin-4 are very low for adults and children. The doses are lower than reported for other polypeptide tracers such as somatostatin analogs (2.1-2.6 mSv/100 MBq) and are beneficial for application as a research tool, especially when repeated examinations are needed.

Project description:Tracers triggering ?v?3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18F-fluorodeoxyglucose (18F-FDG) with that of 68Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma.Nude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of 68Ga-NODAGA-RGD and of 18F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for 68Ga-NODAGA-RGD.Both tracers showed a primary renal route of clearance, although with faster clearance for 68Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from 68Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of 68Ga-NODAGA-RGD decreased progressively with time, contrary to that of 18F-FDG, although 68Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to 18F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high 68Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and ?v integrin expression, irrespective of cell density.68Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2nd hour following injection in order to provide sufficiently high integrin specificity.

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First in-human radiation dosimetry of 68Ga-NODAGA-RGDyK.

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First in-human radiation dosimetry of <sup>68</sup>Ga-NODAGA-RGDyK.

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