177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry
IntroductionProstate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlie...
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| Format: | Article |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1221103/full |
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| author | Ayman Abouzayed Kamila Seitova Kamila Seitova Fanny Lundmark Vitalina Bodenko Vitalina Bodenko Maryam Oroujeni Maryam Oroujeni Vladimir Tolmachev Vladimir Tolmachev Ulrika Rosenström Anna Orlova Anna Orlova |
| author_facet | Ayman Abouzayed Kamila Seitova Kamila Seitova Fanny Lundmark Vitalina Bodenko Vitalina Bodenko Maryam Oroujeni Maryam Oroujeni Vladimir Tolmachev Vladimir Tolmachev Ulrika Rosenström Anna Orlova Anna Orlova |
| author_sort | Ayman Abouzayed |
| collection | DOAJ |
| description | IntroductionProstate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that 177Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy. MethodsBQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [177Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [177Lu]Lu-PSMA-617 was simultaneously evaluated for comparison.ResultsBQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [177Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities KD1 = 3.8 nM and KD2 = 25 nM. The half-maximal inhibitory concentration for natLu-BQ7876 was 59 nM that is equal to 61 nM for natLu-PSMA-617. Cellular processing of [177Lu]Lu-BQ7876 was accompanied by slow internalization. [177Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3%ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.DiscussionBiodistribution studies in mice demonstrated that targeting properties of [177Lu]Lu-BQ7876 are not inferior to properties of [177Lu]Lu-PSMA-617, but do not offer any decisive advantages. |
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| language | English |
| last_indexed | 2024-03-11T21:21:24Z |
| publishDate | 2023-09-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-f29b75a246594fe3adfa12541146a8882023-09-28T05:54:18ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-09-011310.3389/fonc.2023.12211031221103177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetryAyman Abouzayed0Kamila Seitova1Kamila Seitova2Fanny Lundmark3Vitalina Bodenko4Vitalina Bodenko5Maryam Oroujeni6Maryam Oroujeni7Vladimir Tolmachev8Vladimir Tolmachev9Ulrika Rosenström10Anna Orlova11Anna Orlova12Department of Medicinal Chemistry, Uppsala University, Uppsala, SwedenScientific and Research Laboratory of Chemical and Pharmaceutical Research, Siberian State Medical University, Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk, RussiaDepartment of Medicinal Chemistry, Uppsala University, Uppsala, SwedenScientific and Research Laboratory of Chemical and Pharmaceutical Research, Siberian State Medical University, Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk, RussiaDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenAffibody AB, Solna, SwedenResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk, RussiaDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Uppsala University, Uppsala, SwedenIntroductionProstate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that 177Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy. MethodsBQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [177Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [177Lu]Lu-PSMA-617 was simultaneously evaluated for comparison.ResultsBQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [177Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities KD1 = 3.8 nM and KD2 = 25 nM. The half-maximal inhibitory concentration for natLu-BQ7876 was 59 nM that is equal to 61 nM for natLu-PSMA-617. Cellular processing of [177Lu]Lu-BQ7876 was accompanied by slow internalization. [177Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3%ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.DiscussionBiodistribution studies in mice demonstrated that targeting properties of [177Lu]Lu-BQ7876 are not inferior to properties of [177Lu]Lu-PSMA-617, but do not offer any decisive advantages.https://www.frontiersin.org/articles/10.3389/fonc.2023.1221103/fullprostate cancerPSMAlutetium-177PC3-pip cellsdosimetry |
| spellingShingle | Ayman Abouzayed Kamila Seitova Kamila Seitova Fanny Lundmark Vitalina Bodenko Vitalina Bodenko Maryam Oroujeni Maryam Oroujeni Vladimir Tolmachev Vladimir Tolmachev Ulrika Rosenström Anna Orlova Anna Orlova 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry Frontiers in Oncology prostate cancer PSMA lutetium-177 PC3-pip cells dosimetry |
| title | 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry |
| title_full | 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry |
| title_fullStr | 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry |
| title_full_unstemmed | 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry |
| title_short | 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry |
| title_sort | 177lu labeled psma targeting therapeutic with optimized linker for treatment of disseminated prostate cancer evaluation of biodistribution and dosimetry |
| topic | prostate cancer PSMA lutetium-177 PC3-pip cells dosimetry |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1221103/full |
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