Article In: orcid

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

Molecular Pharmaceutics

Joana F. Santos; Maria T. Braz; António Paulo — 2023 — American Chemical Society

Key information

Authors:

Joana F. Santos; Maria T. Braz; Paula Raposinho; Frederik Cleeren; Irwin Cassells; Simon Leekens; Christopher Cawthorne; Filipa Mendes (Filipa Fernandes Mendes); Célia Fernandes; António Paulo (António Manuel Rocha Paulo)

Published in

11/22/2023

Abstract

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.

Publication details

Authors in the community:

Publication version

AM - Accepted manuscript

Publisher

American Chemical Society

Link to the publisher's version

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

Title of the publication container

Molecular Pharmaceutics

First page or article number

216

Last page

233

Volume

21

Issue

1

DOI

10.1021/acs.molpharmaceut.3c00787

Fields of Science and Technology (FOS)

chemical-sciences - Chemical sciences

Keywords

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

Publication language (ISO code)

eng - English

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