Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Mar 24;10(1):12.
doi: 10.1186/s41181-025-00333-y.

Hematological toxicity of [225Ac]Ac-PSMA-617 and [177Lu]Lu-PSMA-617 in RM1-PGLS syngeneic mouse model

Meryl Maria Vilangattil  1 , Abir Swaidan  2 , Jonathan Godinez  2 , Marco F Taddio  2 , Johannes Czernin  2   3 , Christine E Mona  2   3 , Giuseppe Carlucci  4   5
Affiliations

Hematological toxicity of [225Ac]Ac-PSMA-617 and [177Lu]Lu-PSMA-617 in RM1-PGLS syngeneic mouse model

Meryl Maria Vilangattil et al. EJNMMI Radiopharm Chem. .

Abstract

Background: Prostate cancer (PC) has a 34% 5-year survival rate after progressing to metastatic castration-resistant prostate cancer (mCRPC), which occurs in 20-30% of cases. Treatments like chemotherapy, immunotherapy, and PSMA-targeted radioligand therapy (RLT) show promise, but challenges remain with tumor resistance, side effects, and dose-limiting toxicity in kidneys and bone marrow. This study investigated the hematotoxicity, treatment efficacy, and recovery after [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 treatment in a syngeneic PC mouse model.

Method: Twenty-five male C57BL/6 mice were inoculated with RM1-PGLS cells and monitored using [68Ga]Ga-PSMA-11 PET/CT. The mice were divided into five groups as follows: (1) [225Ac]Ac-PSMA-617 treatment with tumors, (2) [177Lu]Lu-PSMA-617 treatment with tumors, (3) control group with tumors, (4) [225Ac]Ac-PSMA-617 treatment without tumors, and (5) [177Lu]Lu-PSMA-617 treatment without tumors. Tumor volume was measured weekly, and animals were sacrificed when tumors reached 1.5 cm³. Endpoint criteria included tumor size, survival, and body mass. Blood samples were collected at different time points to assess blood cell counts and liver and kidney function.

Results: Both treatments significantly slowed tumor progression and extended survival. [225Ac]Ac-PSMA-617-treated mice had a median survival of 70 days, compared to 58 days for [177Lu]Lu-PSMA-617-treated mice and 30 days for the control group. Tumor volumes were significantly reduced in both treatment groups (P < 0.05). Hematological analysis showed that both treatments reduced WBCs, RBCs, and platelets, but values normalized within 35-42 days. Liver and kidney functions remained unaffected, and no significant renal or hepatic toxicity was observed.

Conclusion: Both [225Ac]Ac-PSMA-617 and [177Lu]Lu-PSMA-617 caused transient hematotoxicity without prolonged effects. The data do not explicitly support the necessity of immunocompetent models for studying therapeutic outcomes in this context. Future studies incorporating immune profiling are warranted to investigate immune system interactions in radioligand therapy further.

Keywords: Actinium-225; Hematotoxicity; Luetitium-177; PC; PSMA-617; RLT.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethical approval: All animal studies were approved by the UCLA Institutional Animal Care and Use Committee, known as the Chancellor’s Animal Research Committee (ARC; # 2005-090). The institutional guidelines for the care and use of animals were strictly followed. Twenty-five mice were housed under pathogen-free conditions. Water and food were provided ad libitum. Male C57BL/6 mice were injected subcutaneously with into the shoulder region. Tumor growth was monitored by caliper. Animals were sacrificed upon reaching any of the termination criteria specified in the ARC protocol, including but not limited to apathy, ulceration, severe weight loss, or other signs of deteriorating condition. The study was carried out in compliance with the ARRIVE guidelines. This article does not contain any studies with human participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests related to this work.

Figures

Fig. 1
Fig. 1
Progression of the tumor by measuring tumor volume from day 6 (before the start of treatment) until the end of the study for all 3 tumor groups
Fig. 2
Fig. 2
WBC count (A) throughout the study for all 5 groups. (B) Control with tumor, (C) [225Ac]Ac-PSMA-617 treated with tumor, (D) [225Ac]Ac-PSMA-617 treated without tumor, (E) [177Lu]Lu-PSMA-617 treated with tumor, (F)[177Lu]Lu-PSMA-617 treated without tumor show one-way ANOVA test corrected for multiple comparisons (Dunnett’s multiple comparison test), comparing each time point to the first time point (before start of treatment). (B) represents WBC analysis for the control group that did not receive treatment, (C) and (D) for the group that was treated with [225Ac]Ac-PSMA-617 with and without tumor, respectively, (E) and (F) for the group that was treated with [177Lu]Lu-PSMA-617with and without tumor respectively
Fig. 3
Fig. 3
Lymphocyte count (A) throughout the study for all 5 groups. (B) Control with tumor, (C) [225Ac]Ac-PSMA-617 treated with tumor, (D)[225Ac]Ac-PSMA-617 treated without tumor, (E) [177Lu]Lu-PSMA-617 treated with tumor, (F)[177Lu]Lu-PSMA-617 treated without tumor show one-way ANOVA test corrected for multiple comparisons (Dunnett’s multiple comparison test), comparing each time point to the first time point (before start of treatment). (B) represents lymphocyte analysis for the control group that did not receive treatment, (C) and (D) for the group that was treated with [225Ac]Ac-PSMA-617 with and without tumor, respectively, (E) and (F) for the group that was treated with [177Lu]Lu-PSMA-617with and without tumor respectively
Fig. 4
Fig. 4
Monocyte count (A) and Neutrophil count (B) for all five groups over the course of the study
Fig. 5
Fig. 5
RBC count (A) throughout the study for all 5 groups. (B) Control with tumor, (C)[225Ac]Ac-PSMA-617 treated with tumor, (D)[225Ac]Ac-PSMA-617 treated without tumor, (E)[177Lu]Lu-PSMA-617 treated with tumor, (F)[177Lu]Lu-PSMA-617 treated without tumor show one-way ANOVA test corrected for multiple comparisons (Dunnett’s multiple comparison test), comparing each time point to the first time point (before start of treatment). (B) represents RBC analysis for the control group that did not receive treatment, (C) and (D) for the group that was treated with [225Ac]Ac-PSMA-617with and without tumor, respectively, (E) and (F) for the group that was treated with [177Lu]Lu-PSMA-617with and without tumor respectively
Fig. 6
Fig. 6
Hemoglobin levels (A) for the study for all 5 groups. (B) Control with tumor, (C)[225Ac]Ac-PSMA-617 treated with tumor, (D)[225Ac]Ac-PSMA-617 treated without tumor, (E)[177Lu]Lu-PSMA-617 treated with tumor, (F)[177Lu]Lu-PSMA-617 treated without tumor show one-way ANOVA test corrected for multiple comparisons (Dunnett’s multiple comparison test), comparing each time point to the first time point (before start of treatment). (B) represents hemoglobin levels for the control group that did not receive treatment, (C) and (D) for the group that was treated with [225Ac]Ac-PSMA-617 with and without tumor, respectively, (E) and (F) for the group that was treated with [177Lu]Lu-PSMA-617 with and without tumor respectively
Fig. 7
Fig. 7
Platelet count (A) for the study for all 5 groups. (B) Control with tumor, (C)[225Ac]Ac-PSMA-617 treated with tumor, (D)[225Ac]Ac-PSMA-617 treated without tumor, (E)[177Lu]Lu-PSMA-617 treated with tumor, (F)[177Lu]Lu-PSMA-617 treated without tumor show one-way ANOVA test corrected for multiple comparisons (Dunnett’s multiple comparison test), comparing each time point to the first time point (before start of treatment). (B) represents platelet count analysis for the control group that did not receive treatment, (C) and (D) for the group that was treated with [225Ac]Ac-PSMA-617 with and without tumor, respectively, (E) and (F) for the group that was treated with [177Lu]Lu-PSMA-617 with and without tumor respectively
Fig. 8
Fig. 8
Mean platelet volume (A) for the study for all 5 groups. (B)Control with tumor, (C)[225Ac]Ac-PSMA-617 treated with tumor, (D)[225Ac]Ac-PSMA-617 treated without tumor, (E)[177Lu]Lu-PSMA-617 treated with tumor, (F)[177Lu]Lu-PSMA-617 treated without tumor show one-way ANOVA test corrected for multiple comparisons (Dunnett’s multiple comparison test), comparing each time point to the first time point (before start of treatment). (B) represents MPV analysis for the control group that did not receive treatment, (C) and (D) for the group that was treated with [225Ac]Ac-PSMA-617 with and without tumor, respectively, (E) and (F) for the group that was treated with [177Lu]Lu-PSMA-617 with and without tumor respectively
Fig. 9
Fig. 9
Platelet distribution width (A) For the study for all 5 groups. (B)Control with tumor, (C)[225Ac]Ac-PSMA-617 treated with tumor, (D)[225Ac]Ac-PSMA-617 treated without tumor, (E)[177Lu]Lu-PSMA-617 treated with tumor, (F)[177Lu]Lu-PSMA-617 treated without tumor show one-way ANOVA test corrected for multiple comparisons (Dunnett’s multiple comparison test), comparing each time point to the first time point (before start of treatment). (B) represents PDW analysis for the control group that did not receive treatment, (C) and (D) for the group that was treated with [225Ac]Ac-PSMA-617 with and without tumor, respectively, (E) and (F) for the group that was treated with [177Lu]Lu-PSMA-617 with and without tumor respectively
Fig. 10
Fig. 10
Results of kidney function test and liver function test performed at the end of the study for all groups include the following parameters: (A) Creatinine, (B) Blood Urea Nitrogen, (C) Total Bilirubin, (D) Alanine Transaminase, (E) Alkaline Phosphatase, (F) Aspartate Aminotransferase, (G) Globulin, (H) Albumin, (I) Total Protein
See this image and copyright information in PMC

References

    1. Alam MR, et al. A review of 177Lutetium-PSMA and 225Actinium-PSMA as emerging theranostic agents in prostate Cancer. Cureus. 2022;14(9):e29369. - PMC - PubMed
    1. Arbuznikova D, et al. Towards improving the efficacy of PSMA-Targeting radionuclide therapy for Late-Stage prostate Cancer-Combination strategies. Curr Oncol Rep. 2023a;25(11):1363–74. - PMC - PubMed
    1. Arbuznikova D, et al. Towards improving the efficacy of PSMA-Targeting radionuclide therapy for Late-Stage prostate Cancer-Combination strategies. Current Oncology Reports; 2023b. - PMC - PubMed
    1. Babich JW, et al. Therapeutic efficacy of PSMA-Targeted radioligands in prostate Cancer xenograft models. Eur J Nucl Med Mol Imaging. 2020;47(5):1175–84. 10.1007/s00259-019-04556-7.
    1. Beer TM, et al. Enzalutamide in men with Chemotherapy-naive metastatic Castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71(2):151–4. - PMC - PubMed

LinkOut - more resources