Synthesis and Preclinical Evaluation of PSMA-Targeted 111In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

22/11/2023

Nuclear DNA is the canonical target for biological damage induced by Auger electrons (AE) in the context targeted radionuclide therapy (TRT) of cancer, but other subcellular components might be also relevant for this purpose, such as the energized mitochondria of tumor cells. Having this in mind, we have synthesized novel DOTA-based chelators carrying a prostate-specific membrane antigen (PSMA) inhibitor and a triphenyl phosphonium (TPP) group that were used to obtain dual-targeted 111In-radioconjugates([111In]In-TPP-DOTAGA-PSMA and [111In]In-TPP-DOTAGA-G3-PSMA), aiming to promote a selective uptake of an AE-emitter radiometal (111In) by PSMA+ prostate cancer (PCa) cells and an enhanced accumulation in the mitochondria. These dual-targeted 111In-radiocomplexes are highly stable under physiological conditions and in cell culture media. The complexes showed relatively similar binding affinities towards the PSMA compared to the reference tracer [111In]In-PSMA-617, in line with their high cellular uptake and internalization in PSMA+ PCa cells. The complexes compromised cell survival in a dose-dependent manner, and in the case of [111In]In-TPP-DOTAGA-G3-PSMA to a higher extent than observed for the single-targeted congener [111In]In-PSMA-617. µSPECT imaging studies in PSMA+ PCa xenografts showed that the TPP pharmacophore did not interfere with the excellent in vivo tumor uptake of the “golden standard” [111In]In-PSMA-617, although leading to a higher kidney retention. Such kidney retention does not necessarily compromise their usefulness as radiotherapeutics, due to the short tissue range of the Auger/conversion electrons emitted by 111In. Overall, our results provide valuable insights into the potential use of mitochondrial targeting by PSMA-based radiocomplexes for efficient use of AE-emitting radionuclides in TRT, giving impetus to extend the studies to other AE-emitting trivalent radiometals (e.g., 161Tb or 165Er) and to further optimize the designed dual-targeting constructs.

Autores da comunidade :

• 

  F

  Filipa Fernandes Mendes

  ist25493

  Afiliações e fontes

  IST > C2TN

  Centro de Ciências e Tecnologias Nucleares

  IST > DECN

  Departamento de Engenharia e Ciências Nucleares

  De: orcid

  ID: 147206500

• 

  A

  António Manuel Rocha Paulo

  ist126677

  Afiliações e fontes

  IST > C2TN

  Centro de Ciências e Tecnologias Nucleares

  IST > DECN

  Departamento de Engenharia e Ciências Nucleares

AM - Versão aceite após revisão

American Chemical Society

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.3c00787

Molecular Pharmaceutics

216

233

21

1

10.1021/acs.molpharmaceut.3c00787

chemical-sciences - Química

Palavras-chave

• dual-targeting
• PSMA
• mitochondria
• radiopharmaceuticals
• Auger electron emitters
• cancer theranostics

eng - Inglês