Clickable Radiocomplexes With Trivalent Radiometals for Cancer Theranostics: In vitro and in vivo Studies

Alice D'Onofrio; Francisco Silva; Lurdes Gano; Urszula Karczmarczyk; Renata Mikołajczak; Piotr Garnuszek; António Paulo

doi:10.3389/fmed.2021.647379

Clickable Radiocomplexes With Trivalent Radiometals for Cancer Theranostics: In vitro and in vivo Studies

Front Med (Lausanne). 2021 Jun 11:8:647379. doi: 10.3389/fmed.2021.647379. eCollection 2021.

Authors

Alice D'Onofrio¹, Francisco Silva¹, Lurdes Gano^{1

2}, Urszula Karczmarczyk³, Renata Mikołajczak³, Piotr Garnuszek³, António Paulo^{1

2}

Affiliations

¹ Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Campus Tecnológico e Nuclear, Lisbon, Portugal.
² Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
³ National Centre for Nuclear Research, Radioisotope Centre POLATOM, Otwock, Poland.

Abstract

Pre-targeting approaches based on the inverse-electron-demand Diels-Alder (iEDDA) reaction between strained trans-cyclooctenes (TCO) and electron-deficient tetrazines (Tz) have emerged in recent years as valid alternatives to classic targeted strategies to improve the diagnostic and therapeutic properties of radioactive probes. To explore these pre-targeting strategies based on in vivo click chemistry, a small family of clickable chelators was synthesized and radiolabelled with medically relevant trivalent radiometals. The structure of the clickable chelators was diversified to modulate the pharmacokinetics of the resulting [¹¹¹In]In-radiocomplexes, as assessed upon injection in healthy mice. The derivative DOTA-Tz was chosen to pursue the studies upon radiolabelling with ⁹⁰Y, yielding a radiocomplex with high specific activity, high radiochemical yields and suitable in vitro stability. The [⁹⁰Y]Y-DOTA-Tz complex was evaluated in a prostate cancer PC3 xenograft by ex-vivo biodistribution studies and Cerenkov luminescence imaging (CLI). The results highlighted a quick elimination through the renal system and no relevant accumulation in non-target organs or non-specific tumor uptake. Furthermore, a clickable bombesin antagonist was injected in PC3 tumor-bearing mice followed by the radiocomplex [⁹⁰Y]Y-DOTA-Tz, and the mice imaged by CLI at different post-injection times (p.i.). Analysis of the images 15 min and 1 h p.i. pointed out an encouraging quick tumor uptake with a fast washout, providing a preliminary proof of concept of the usefulness of the designed clickable complexes for pre-targeting strategies. To the best of our knowledge, the use of peptide antagonists for this purpose was not explored before. Further investigations are needed to optimize the pre-targeting approach based on this type of biomolecules and evaluate its eventual advantages.

Keywords: iEDDA; in vivo click-chemistry; pre-targeting; radiometals; theranostics.