Hematological Toxicity in Mice after High Activity Injections of 177Lu-PSMA-617

Kristiansson, Amanda; Timmermand, Oskar Vilhelmsson; Altai, Mohamed; Strand, Joanna; Strand, Sven‐Erik; Åkerström, Bo; Örbom, Anders

doi:10.3390/pharmaceutics14040731

Cited by 5 publications

(8 citation statements)

References 36 publications

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“…Other research groups did not observe severe hematotoxicity in immunocompetent mice after injection of up to sixfold higher activities of [ 177 Lu]Lu-PSMA-617 [ 30 , 35 ]. It has to be critically acknowledged that the application of such high activities would most probably not be possible without causing undesired hematological effects when using albumin-binding PSMA radioligands.…”

Section: Discussionmentioning

confidence: 99%

Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

Tschan

Borgna

Busslinger

et al. 2022

Eur J Nucl Med Mol Imaging

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Abstract[177Lu]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [177Lu]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [177Lu]Lu-PSMA-617 and the previously developed [177Lu]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands’s therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [177Lu]Lu-Ibu-DAB-PSMA (~ 6.6 Gy/MBq) was more effective to inhibit tumor growth than [177Lu]Lu-PSMA-617 (~ 4.5 Gy/MBq) and only moderately less potent than [177Lu]Lu-PSMA-ALB-56 (~ 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [177Lu]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [177Lu]Lu-Ibu-DAB-PSMA or [177Lu]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [177Lu]Lu-Ibu-DAB-PSMA or 30 MBq [177Lu]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [177Lu]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant therapeutic advantage of [177Lu]Lu-Ibu-DAB-PSMA over [177Lu]Lu-PSMA-617 and a more favorable safety profile as compared to that of [177Lu]Lu-PSMA-ALB-56. Based on these results, [177Lu]Lu-Ibu-DAB-PSMA may has the potential for a clinical translation.

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Section: Discussionmentioning

confidence: 99%

Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

Tschan

Borgna

Busslinger

et al. 2022

Eur J Nucl Med Mol Imaging

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“…However, after 7 d, no significant difference was observed between the negative control and the treatment with lutetium radionanoparticles ( p > 0.05). Therefore, the observed toxicity can be attributed to a well-known and transient toxic effect of radiation on the bone marrow [ 38 , 40 ], but not to the nanoparticles themselves. That is, if the activation of DNA repair mechanisms was not sufficiently effective due to severe nanoparticle damage, the expected behavior would be, at least, like that of the positive control (colchicine), which did not occur.…”

Section: Resultsmentioning

confidence: 99%

“…The genotoxicity associated with the bone marrow irradiation was transient since a recovery in mice treated with [ 177 Lu]Lu−iFAP/iPSMA was observed after 7 d [ 38 , 40 ]. Therefore, genotoxicity was not observed as a consequence of an excess of free radicals induced from nanoparticles due to oxidative stress with a potential mutagenic effect [ 28 , 29 ], which confirmed that intravenous systemic administration is safe.…”

Section: Discussionmentioning

confidence: 99%

Toxicity Assessment of [177Lu]Lu−iFAP/iPSMA Nanoparticles Prepared under GMP-Compliant Radiopharmaceutical Processes

et al. 2022

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The fibroblast activation protein (FAP) is heavily expressed in fibroblasts associated with the tumor microenvironment, while the prostate-specific membrane antigen (PSMA) is expressed in the neovasculature of malignant angiogenic processes. Previously, we reported that [177Lu]lutetium sesquioxide-iFAP/iPSMA nanoparticles ([177Lu]Lu−iFAP/iPSMA) inhibit HCT116 tumor progression in mice. Understanding the toxicity of [177Lu]Lu−iFAP/iPSMA in healthy tissues, as well as at the tissue and cellular level in pathological settings, is essential to demonstrate the nanosystem safety for treating patients. It is equally important to demonstrate that [177Lu]Lu−iFAP/iPSMA can be prepared under good manufacturing practices (GMP) with reproducible pharmaceutical-grade quality characteristics. This research aimed to prepare [177Lu]Lu−iFAP/iPSMA under GMP-compliant radiopharmaceutical processes and evaluate its toxicity in cell cultures and murine biological systems under pathological environments. [177Lu]Lu2O3 nanoparticles were formulated as radiocolloidal solutions with FAP and PSMA inhibitor ligands (iFAP and iPSMA), sodium citrate, and gelatin, followed by heating at 121 °C (103-kPa pressure) for 15 min. Three consecutive batches were manufactured. The final product was analyzed according to conventional pharmacopeial methods. The Lu content in the formulations was determined by X-ray fluorescence. [177Lu]Lu−iFAP/iPSMA performance in cancer cells was evaluated in vitro by immunofluorescence. Histopathological toxicity in healthy and tumor tissues was assessed in HCT116 tumor-bearing mice. Immunohistochemical assays were performed to corroborate FAP and PSMA tumor expression. Acute genotoxicity was evaluated using the micronuclei assay. The results showed that the batches manufactured under GMP conditions were reproducible. Radiocolloidal solutions were sterile and free of bacterial endotoxins, with radionuclidic and radiochemical purity greater than 99%. The lutetium content was 0.10 ± 0.02 mg/mL (0.9 GBq/mg). Significant inhibition of cell proliferation in vitro and in tumors was observed due to the accumulation of nanoparticles in the fibroblasts (FAP+) and neovasculature (PSMA+) of the tumor microenvironment. No histopathological damage was detected in healthy tissues. The data obtained in this research provide new evidence on the selective toxicity to malignant tumors and the absence of histological changes in healthy tissues after intravenous injection of [177Lu]Lu−iFAP/iPSMA in mammalian hosts. The easy preparation under GMP conditions and the toxicity features provide the added value needed for [177Lu]Lu−iFAP/iPSMA clinical translation.

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“…Radiolabeling was performed similarly to previous work 27 . Freeze-dried PSMA-617 (MedChemExpress, Monmouth Junction, NJ, USA) was dissolved in chelexed 0.2 M ammonium acetate, pH 5.5, to a final concentration of 2 µg/µL.…”

Section: Methodsmentioning

confidence: 99%

“…In order to reach absorbed doses to the kidney that causes measurable damage, we have previously established that mice can recover from hematotoxicity caused by one injection of up to 200 MBq of [ 177 Lu]Lu-PSMA-617 27 . The aim of this study was to employ a high activity therapy delivered in three cycles of [ 177 Lu]Lu-PSMA-617 in a preclinical mouse model to achieve nephrotoxicity and analyze the effect of co-injecting rA1M on kidney function and blood cell counts.…”

Section: Introductionmentioning

confidence: 99%

Hematological and renal toxicity in mice after three cycles of high activity [177Lu]Lu-PSMA-617 with or without human α1-microglobulin

Kristiansson,

Vilhelmsson Timmermand,

Altai

et al. 2024

Sci Rep

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Radioligand therapy with [177Lu]Lu-PSMA-617 can be used to prolong life and reduce tumor burden in terminally ill castration resistant prostate cancer patients. Still, accumulation in healthy tissue limits the activity that can be administered. Therefore, fractionated therapy is used to lower toxicity. However, there might be a need to reduce toxicity even further with e.g. radioprotectors. The aim of this study was to (i). establish a preclinical mouse model with fractionated high activity therapy of three consecutive doses of 200 MBq [177Lu]Lu-PSMA-617 in which we aimed to (ii). achieve measurable hematotoxicity and nephrotoxicity and to (iii). analyze the potential protective effect of co-injecting recombinant α1-microglobulin (rA1M), a human antioxidant previously shown to have radioprotective effects. In both groups, three cycles resulted in increased albuminuria for each cycle, with large individual variation. Another marker of kidney injury, serum blood urea nitrogen (BUN), was only significantly increased compared to control animals after the third cycle. The number of white and red blood cells decreased significantly and did not reach the levels of control animals during the experiment. rA1M did reduce absorbed dose to kidney but did not show significant protection here, but future studies are warranted due to the recent clinical studies showing a significant renoprotective effect in patients.

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Hematological Toxicity in Mice after High Activity Injections of 177Lu-PSMA-617

Cited by 5 publications

References 36 publications

Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

Toxicity Assessment of [177Lu]Lu−iFAP/iPSMA Nanoparticles Prepared under GMP-Compliant Radiopharmaceutical Processes

Hematological and renal toxicity in mice after three cycles of high activity [177Lu]Lu-PSMA-617 with or without human α1-microglobulin

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