Targeted, Molecular Europium (III) Probes Enable Luminescence-Guided Surgery and 1 Photon Post-Surgical Luminescence Microscopy of Solid Tumors - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of the American Chemical Society Année : 2023

Targeted, Molecular Europium (III) Probes Enable Luminescence-Guided Surgery and 1 Photon Post-Surgical Luminescence Microscopy of Solid Tumors

Raphael Lengacher
  • Fonction : Auteur
Kirsten Martin
  • Fonction : Auteur
Dariusz Śmiłowicz
  • Fonction : Auteur
Helena Esseln
  • Fonction : Auteur
Piyusha Lotlikar
  • Fonction : Auteur
Alexei Grichine
  • Fonction : Auteur
Olivier Maury
Eszter Boros

Résumé

Discrete luminescent lanthanide complexes represent a potential alternative to organic chromophores due to their tunability of optical properties, insensitivity to photobleaching, and large pseudo-Stokes shifts. Previously, we demonstrated that the lack of depth penetration of UV excitation required to sensitize discrete terbium and europium complexes can be overcome using Cherenkov radiation emitted by clinically employed radioisotopes in situ. Here, we show that the second-generation europium complexes [Eu(III)(pcta-PEPA2)] and [Eu(III)(tacn-pic-PEPA2)] (Φ = 57% and 76%, respectively) lower the limit of detection (LoD) to 1 nmol in the presence of 10 μCi of Cherenkov emitting isotopes, 18F and 68Ga. Bifunctionalization provides access to cysteine-linked peptide conjugates with comparable brightness and LoD. The conjugate, [Eu(tacn-(pic-PSMA)-PEPA2)], displays high binding affinity to prostate-specific membrane antigen (PSMA)-expressing PC-3 prostate cancer cells in vitro and can be visualized in the membrane-bound state using confocal microscopy. Biodistribution studies with the [86Y][Y(III)(tacn-(pic-PSMA)-PEPA2)] analogue in a mouse xenograft model were employed to study pharmacokinetics. Systemic administration of the targeted Cherenkov emitter, [68Ga][Ga(III)(PSMA-617)], followed by intratumoral injection or topical application of 20 or 10 nmol [Eu(III)(tacn-(pic-PSMA)-PEPA2)], respectively, in live mice resulted in statistically significant signal enhancement using conventional small animal imaging (620 nm bandpass filter). Optical imaging informed successful tumor resection. Ex vivo imaging of the fixed tumor tissue with 1 and 2 photon excitation further reveals the accumulation of the administered Eu(III) complex in target tissues. This work represents a significant step toward the application of luminescent lanthanide complexes for optical imaging in a clinical setting.

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Dates et versions

hal-04327007 , version 1 (06-12-2023)

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Raphael Lengacher, Kirsten Martin, Dariusz Śmiłowicz, Helena Esseln, Piyusha Lotlikar, et al.. Targeted, Molecular Europium (III) Probes Enable Luminescence-Guided Surgery and 1 Photon Post-Surgical Luminescence Microscopy of Solid Tumors. Journal of the American Chemical Society, 2023, 145 (44), pp.24358-24366. ⟨10.1021/jacs.3c09444⟩. ⟨hal-04327007⟩
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