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177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging

1
Section for Infection Medicine, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden
2
Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, 221 84 Lund, Sweden
3
Division of Oncology, Department of Clinical Sciences Lund, Lund University, 221 00 Lund, Sweden
4
Lund University Bioimaging Center, Lund University, 221 84 Lund, Sweden
5
Pediatrics, Department of Clinical Sciences Lund, Lund University, 221 84 Lund, Sweden
6
Division of Medical Radiation Physics, Department of Clinical Sciences Lund, Lund University, 221 00 Lund, Sweden
*
Author to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Academic Editor: Theodoros Eleftheriadis
Biomolecules 2021, 11(2), 263; https://doi.org/10.3390/biom11020263
Received: 13 January 2021 / Revised: 5 February 2021 / Accepted: 6 February 2021 / Published: 10 February 2021
Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α1-microglobulin (A1M) together with 177-Lutetium (177Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [177Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3–4 days and 3–4 weeks after injections). In a parallel set of experiments, mice were given [177Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [177Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [99mTc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [177Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [99mTc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [177Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy. View Full-Text
Keywords: radioligand therapy; α1-microglobulin; [99mTc]Tc-MAG3 imaging; [177Lu]Lu-PSMA-617; prostate cancer; mouse model; kidney damage; dosimetry radioligand therapy; α1-microglobulin; [99mTc]Tc-MAG3 imaging; [177Lu]Lu-PSMA-617; prostate cancer; mouse model; kidney damage; dosimetry
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MDPI and ACS Style

Kristiansson, A.; Örbom, A.; Ahlstedt, J.; Karlsson, H.; Zedan, W.; Gram, M.; Åkerström, B.; Strand, S.-E.; Altai, M.; Strand, J.; Vilhelmsson Timmermand, O. 177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging. Biomolecules 2021, 11, 263. https://doi.org/10.3390/biom11020263

AMA Style

Kristiansson A, Örbom A, Ahlstedt J, Karlsson H, Zedan W, Gram M, Åkerström B, Strand S-E, Altai M, Strand J, Vilhelmsson Timmermand O. 177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging. Biomolecules. 2021; 11(2):263. https://doi.org/10.3390/biom11020263

Chicago/Turabian Style

Kristiansson, Amanda; Örbom, Anders; Ahlstedt, Jonas; Karlsson, Helena; Zedan, Wahed; Gram, Magnus; Åkerström, Bo; Strand, Sven-Erik; Altai, Mohamed; Strand, Joanna; Vilhelmsson Timmermand, Oskar. 2021. "177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging" Biomolecules 11, no. 2: 263. https://doi.org/10.3390/biom11020263

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