Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach
Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may impr...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-01-01
|
| Series: | Frontiers in Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2022.1051825/full |
| _version_ | 1797951476304183296 |
|---|---|
| author | Asta Juzeniene Asta Juzeniene Vilde Yuli Stenberg Vilde Yuli Stenberg Vilde Yuli Stenberg Øyvind Sverre Bruland Øyvind Sverre Bruland Mona-Elisabeth Revheim Mona-Elisabeth Revheim Roy Hartvig Larsen |
| author_facet | Asta Juzeniene Asta Juzeniene Vilde Yuli Stenberg Vilde Yuli Stenberg Vilde Yuli Stenberg Øyvind Sverre Bruland Øyvind Sverre Bruland Mona-Elisabeth Revheim Mona-Elisabeth Revheim Roy Hartvig Larsen |
| author_sort | Asta Juzeniene |
| collection | DOAJ |
| description | Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment. |
| first_indexed | 2024-04-10T22:31:10Z |
| format | Article |
| id | doaj.art-d7c8d3316aea442f97f2e4ac8628bf55 |
| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-04-10T22:31:10Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Medicine |
| spelling | doaj.art-d7c8d3316aea442f97f2e4ac8628bf552023-01-17T05:15:24ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2023-01-01910.3389/fmed.2022.10518251051825Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approachAsta Juzeniene0Asta Juzeniene1Vilde Yuli Stenberg2Vilde Yuli Stenberg3Vilde Yuli Stenberg4Øyvind Sverre Bruland5Øyvind Sverre Bruland6Mona-Elisabeth Revheim7Mona-Elisabeth Revheim8Roy Hartvig Larsen9Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, NorwayDepartment of Physics, University of Oslo, Oslo, NorwayDepartment of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, NorwayInstitute for Clinical Medicine, University of Oslo, Oslo, NorwayARTBIO AS, Oslo, NorwayInstitute for Clinical Medicine, University of Oslo, Oslo, NorwayDepartment of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, NorwayInstitute for Clinical Medicine, University of Oslo, Oslo, NorwayDivision of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, NorwayARTBIO AS, Oslo, NorwayMetastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment.https://www.frontiersin.org/articles/10.3389/fmed.2022.1051825/fullcancerlead-212radiopharmaceuticalradium-224radium-223targeted radionuclide therapy (TRT) |
| spellingShingle | Asta Juzeniene Asta Juzeniene Vilde Yuli Stenberg Vilde Yuli Stenberg Vilde Yuli Stenberg Øyvind Sverre Bruland Øyvind Sverre Bruland Mona-Elisabeth Revheim Mona-Elisabeth Revheim Roy Hartvig Larsen Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach Frontiers in Medicine cancer lead-212 radiopharmaceutical radium-224 radium-223 targeted radionuclide therapy (TRT) |
| title | Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach |
| title_full | Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach |
| title_fullStr | Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach |
| title_full_unstemmed | Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach |
| title_short | Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach |
| title_sort | dual targeting with 224ra 212pb conjugates for targeted alpha therapy of disseminated cancers a conceptual approach |
| topic | cancer lead-212 radiopharmaceutical radium-224 radium-223 targeted radionuclide therapy (TRT) |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2022.1051825/full |
| work_keys_str_mv | AT astajuzeniene dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT astajuzeniene dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT vildeyulistenberg dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT vildeyulistenberg dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT vildeyulistenberg dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT øyvindsverrebruland dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT øyvindsverrebruland dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT monaelisabethrevheim dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT monaelisabethrevheim dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach AT royhartviglarsen dualtargetingwith224ra212pbconjugatesfortargetedalphatherapyofdisseminatedcancersaconceptualapproach |