Mitochondria-tropic radioconjugates to enhance the therapeutic potential of terbium-161

EJNMMI Radiopharmacy and Chemistry, Год журнала: 2025, Номер 10(1)

Опубликована: Апрель 11, 2025

Strategies that focus on delivering Auger electron emitters to highly radiosensitive intracellular targets-such as the nucleus, cell membrane, or mitochondria-are gaining attention. Targeting these organelles could enhance therapeutic efficacy while minimizing off-target toxicity by allowing lower administered doses. In this context, study explores potential of 161Tb-labeled radiocomplexes integrate mitochondria-targeting triphenylphosphonium (TPP) moiety with a prostate-specific membrane antigen (PSMA) targeting vector. The goal is assess dual-targeted for their ability deliver conversion electrons (CE) and (AEs) prostate cancer (PCa) cells, specifically mitochondria efficacy. Two novel radiocomplexes, [161Tb]Tb-TPP-PSMA [161Tb]Tb-TPP-G3-PSMA, were synthesized high radiochemical yield purity. proposed structures validated using HPLC ESI-MS analysis, natTb counterparts serving reference compounds. vitro experiments included cellular uptake, internalization, mitochondrial DNA damage assays in PSMA-positive PCa lines. Clonogenic performed evaluate survival post-treatment. vivo studies conducted SCID/Beige mice bearing xenografts involved µSPECT/CT imaging radiometabolite analysis biodistribution, pharmacokinetics, tumor uptake stability radiocomplexes. Both [161Tb]Tb-TPP-G3-PSMA showed efficiently internalized showing minimal PSMA-negative cells. These demonstrated significantly higher compared non-TPP-containing [161Tb]Tb-PSMA-617, leading increased enhanced radiocytotoxicity. vivo, complexes PSMA-specific pharmacokinetics comparable effective clearance from non-target tissues. TPP-modified 161Tb-radiocomplexes effectively targeted reduced viability single-targeted findings suggest dual-targeting strategies, which combine PSMA targeting, can radiopharmaceuticals treatment.

Язык: Английский

Palladium-103 (¹⁰³Pd/^103mRh), a promising Auger-electron emitter for targeted radionuclide therapy of disseminated tumor cells - absorbed doses in single cells and clusters, with comparison to ¹⁷⁷Lu and ¹⁶¹Tb

Theranostics, Год журнала: 2024, Номер 14(11), С. 4318 - 4330

Опубликована: Янв. 1, 2024

Early use of targeted radionuclide therapy (TRT) to eradicate disseminated tumor cells (DTCs) might offer cure.Selection appropriate radionuclides is required.This work highlights the potential 103 Pd (T1/2 = 16.991d) which decays 103m Rh 56.12min) then stable with emission Auger and conversion electrons.Methods: The Monte Carlo track structure code CELLDOSE was used assess absorbed doses in single (14-μm diameter; 10-μm nucleus) clusters 19 cells.The distributed on cell surface, within cytoplasm, or nucleus.Absorbed from Pd, 177 Lu 161 Tb were compared after energy normalization.The impact non-uniform targeting, benefit dual-targeting investigated.Additional results related Rh, if directly, are provided.Results: In cell, depending distribution, delivered 7-to 10-fold higher nuclear dose 9-to 25-fold membrane than Lu.In 19-cell clusters, also largely exceeded both situations, stood in-between Lu.Non-uniform considering four unlabeled cluster, resulted moderate-to-severe heterogeneity.For example, intranuclear received only 14% expected dose.Targeting two Pd-labeled radiopharmaceuticals minimized heterogeneity.Conclusion: a next-generation emitter, can deliver substantially clusters.This may open new horizons for TRT adjuvant neoadjuvant settings, targeting minimal residual disease.

Язык: Английский

Current Status and Perspectives of Novel Radiopharmaceuticals with Heterologous Dual-targeted Functions: 2013–2023

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 8, 2024

Radiotracers provide molecular- and cellular-level information in a noninvasive manner have become important tools for precision medicine. In particular, the successful clinical application of radioligand therapeutic (RLT) has further strengthened role nuclear medicine treatment. The complicated microenvironment lesion rendered traditional single-targeted radiopharmaceuticals incapable fully meeting requirements. design development dual-targeted multitargeted rapidly emerged. recent years, significant progress been made heterologous radiopharmaceuticals. This perspective aims to comprehensive overview these radiopharmaceuticals, with special focus on ligand structures, pharmacological properties, preclinical evaluation. Furthermore, future directions are discussed from this perspective.

Язык: Английский