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• W3125640807 abstract "289 Objectives: 212/203Pb-based radiopharmaceuticals have emerged as a promising theranostic pair for peptide receptor-targeted radionuclide therapy (PRRT). This approach employs 203Pb-based SPECT to provide dosimetry information for 212Pb alpha (α)-PRRT. In this preclinical study, we performed dosimetry and toxicity analysis for 212Pb α-PRRT therapy, using [203/212Pb]VMT01, a click-cyclized octapeptide, as an example. Comprehensive toxicity analysis was performed with a focus on urine biomarkers for acute kidney injury, changes in kidney function, and kidney morphology. Methods: Biodistribution analysis of [203Pb]VMT01 was performed in CD1-ELITE mice from 1.5 to 24 hours post-injection. Organs of interest included blood, heart, liver, lung, kidney, pancreas, spleen, stomach, adrenal glands, intestines, testes, muscle, skin, bone, brain and eyes. The absorbed dose (α+β) from [212Pb]VMT01 was estimated by DigiMouse voxel-based phantom model, based on the time-activity curves of [203Pb]VMT01. A study of dosimetry using OLINDA 2.1 is underway to confirm the renal dose estimation and further comprehensive dose assessment. CD1-ELITE mice were injected 0, 0.93, 2.9 and 6.6 MBq [212Pb]VMT01 (n=6). Toxicity parameters were monitored until the conclusion of the study at 30 weeks. Cardiac function was monitored by echocardiogram. Complete blood count (CBC) was measured at 2, 3, 30 weeks post-injection. Acute kidney injury was monitored by urine neutrophil gelatinase-associated lipocalin (NGAL), tissue inhibitor of metalloproteinases 2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7) during acute (1-3 days), transient (53 days) and late (30 weeks) phase. Serum blood urea nitrogen (BUN) and creatinine were also determined throughout the study to assess kidney function. At the conclusion of the study, tubular injury, glomerular changes, histological fibrosis, and inflammation were scored using stained kidney sections. Results: The escalated doses (0, 0.93, 2.9 and 6.6 MBq [212Pb]VMT01) resulted in 0, 3.7, 11.7, and 24.6 Gy in kidney. No significant weight loss was observed after [212Pb]VMT01 dosing. Echocardiogram displayed no noticeable change in cardiac functions. CBC analysis showed no significant hematotoxicity, except for mild decrease of red blood cells and hemoglobin at 30 weeks in animals that received 6.6 MBq [212Pb]VMT01. Increase of urine NGAL was found in both acute (1-3 days) and late (30 weeks) stage in dose-dependent manner, but not during transient period in between. On day 1, 34.72 ng/mL, 301.4 ng/mL, 663 ng/mL, 1179 ng/mL of urine NGAL were observed in animals injected with 0, 0.93, 2.9 and 6.6 MBq [212Pb]VMT01. At the end of study, the urine NGAL were 41.9 ng/mL, 35.81 ng/mL, 1918 ng/mL and 3267 ng/mL in same animals. However, no increase in NGAL was observed during the transient period. On the other hand, increased BUN and creatinine (by factor of 2 and 4.5 vs control, respectively) were only identified at the end of study. Histopathological scoring revealed localized injury in tubules. In animals that received 6.6 MBq [212Pb]VMT01, the tubular injury score were 1 (1of 5), 2 (2 of 5) and 4(2 of 5) whereas the glomerular injury score were 0 (1of 5), 1 (2of 5), 2(1of 5), 3(1of 5). 10% trichrome-positive staining was observed in kidney sections from animals dosed with 2.9 and 6.6 MBq [212Pb]VMT01. Conclusions: In this study, we conducted 203Pb-based dosimetry for 212Pb-based α-radiotherapy and dose-dependent renal toxicity in CD1-ELITE mice that received [212Pb]VMT01 therapy. Injuries from [212Pb]VMT01 appeared to be localized to tubules compared with glomeruli. At early timepoints (day 1 to day 3), analysis of urine biomarkers (e.g., NGAL ) is a promising approach to monitoring acute renal tubular injury where BUN and creatinine fall short." @default.
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• W3125640807 date "2020-05-01" @default.
• W3125640807 modified "2023-09-30" @default.
• W3125640807 title "Preclinical evaluation of 203/212Pb-based theranostics-dosimetry and renal toxicity." @default.
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