Factors Influencing the Therapeutic Efficacy of the PSMA Targeting Radioligand 212Pb-NG001

Stenberg, Vilde Yuli; Tornes, Anna Julie Kjøl; Nilsen, Hogne Røed; Revheim, Mona‐Elisabeth; Bruland, Øyvind S.; Larsen, Roy H.; Juzeniene, Asta

doi:10.3390/cancers14112784

Cited by 9 publications

(7 citation statements)

References 84 publications

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“…Additionally, up to 80% free 212 Bi can also be conjugated (41). Similar binding and uptake abilities of the 212 Pb-labeled PSMA-targeting ligand NG001 in 224 Ra-solution or in 212 Pb-solution were observed in vitro and in vivo (41,56,57). Biodistribution studies of 224 Ra with free 212 Pb, 212 Pb-NG001, and 212 Pb-PSMA-617 were tested in athymic nude mice with C4-2 xenografts (41).…”

Section: Pb In One Solutionmentioning

confidence: 80%

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Juzeniene

Stenberg²,

Bruland³

et al. 2023

Front. Med.

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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.

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Section: Pb In One Solutionmentioning

confidence: 80%

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Juzeniene

Stenberg²,

Bruland³

et al. 2023

Front. Med.

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“…In a study by Tschan et al, 161 Tb-labelled albumin-binder-conjugated PSMA-targeting agents demonstrated high tumour uptake and an enhanced tumour-to-kidney absorbed dose ratio [143]. Another study compared the dosimetry and therapeutic efficacy of 161 Tb and 177 Lu in tumour-bearing mice using SibuDAB and PSMA I&T [144]. 161 Tb decays with a similar half-life to 177 Lu, but in addition to the emission of β − -particles and γ-rays, 161 Tb also emits conversion and Auger electrons [144].…”

Section: Terbium: a Novel Nuclear Medicine "Swiss Army Knife"mentioning

confidence: 99%

PSMA-targeted radiotheranostics in modern nuclear medicine: then, now, and what of the future?

Sallam,

Nguyen,

Sainsbury

et al. 2024

Theranostics

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In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such as [ 18 F]DCFPyL (PYLARIFY ® , Lantheus Holdings), [ 18 F]rhPSMA-7.3 (POSLUMA ® , Blue Earth Diagnostics) and [ 68 Ga]Ga-PSMA-11 (Locametz ® , Novartis/ ILLUCCIX ® , Telix Pharmaceuticals), as well as PSMA-targeted radiotherapeutic agents, such as [ 177 Lu]Lu-PSMA-617 (Pluvicto ® , Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.

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“…Similar to the DOTAMTATE conjugate, a p -SCN-Bn-TCMC conjugated urea-based PSMA ligand has been studied for the diagnosis and therapy of prostate cancer. ,− Two research groups reported the synthesis and preclinical evaluation of p -SCN-Bn-TCMC-PSMA (NG001/CA09 , ). [ 212 Pb]Pb(NG001) compares well with [ 177 Lu]Lu(PSMA-617), with a greater potential to irradiate microscopic metastases. , …”

Section: The Rise Of Targeted α Particle Therapymentioning

confidence: 99%

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides

Morgan,

Rudd,

Noor

et al. 2023

Chem. Rev.

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Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term “theranostics” describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or β+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, β-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain β+-emitting gallium-68 and β-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.

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Factors Influencing the Therapeutic Efficacy of the PSMA Targeting Radioligand 212Pb-NG001

Cited by 9 publications

References 84 publications

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

PSMA-targeted radiotheranostics in modern nuclear medicine: then, now, and what of the future?

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides

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