“Off‐Label Use” of the Siderophore Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti (IV)

Koller, Angus J.; Glaser, Owen; DeLuca, Molly C.; Motz, Rachel N.; Amason, Edith K.; Carbo‐Bague, Imma; Mixdorf, Jason C.; Guzei, Ilia A.; Aluicio‐Sarduy, Eduardo; Śmiłowicz, Dariusz; Barnhart, Todd E.; Ramogida, Caterina F.; Nolan, Elizabeth M.; Engle, Jonathan W.; Boros, Eszter

doi:10.1002/anie.202319578

Title: “Off‐Label Use” of the Siderophore Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti ^(IV)

Journal Article · 25 March 2024 · Angewandte Chemie (International Edition)

DOI: https://doi.org/10.1002/anie.202319578 · OSTI ID:2328639

Koller, Angus J. ^[1]; Glaser, Owen ^[2]; DeLuca, Molly C. ^[3]; Motz, Rachel N. ^[4]; Amason, Edith K. ^[2]; Carbo‐Bague, Imma ^[5]; Mixdorf, Jason C. ^[3]; Guzei, Ilia A. ^[2]; Aluicio‐Sarduy, Eduardo ^[3]; Śmiłowicz, Dariusz ^[2]; Barnhart, Todd E. ^[3]; Ramogida, Caterina F. ^[5]; Nolan, Elizabeth M. ^[4]; Engle, Jonathan W. ^[3];

^[2]

Department of Chemistry Stony Brook University Stony Brook New York 11794 United States
Department of Chemistry University of Wisconsin-Madison 1101 University Avenue Madison Wisconsin 53706 United States
Department of Medical Physics University of Wisconsin-Madison 1111 Highland Avenue Madison Wisconsin 53705 United States
Department of Chemistry Massachusetts Institute of Technology Cambridge Massachusetts 02139 United States
Department of Chemistry Simon Fraser University Burnaby British Columbia V5A 1S6 Canada

Abstract The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide ⁴⁵ Ti for radiopharmaceutical applications. Herein, we evaluate the Ti ^(IV) ‐coordination chemistry of four catechol‐based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN‐CAM readily form mononuclear Ti ^(IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN‐CAM form mononuclear complexes with the short‐lived, positron‐emitting radionuclide ⁴⁵ Ti ^(IV) , and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the ⁴⁵ Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent‐DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [ ⁴⁵ Ti][Ti(Ent‐DUPA)] ²⁻ complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n =5), and low off‐target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with ⁴⁵ Ti ^(IV) , provides a foundation for advancing the application of ⁴⁵ Ti in nuclear medicine, and reveals that Ent can be repurposed as a ⁴⁵ Ti‐complexing cargo for targeted nuclear imaging applications.

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Sponsoring Organization:: USDOE

OSTI ID:: 2328639

Journal Information:: Angewandte Chemie (International Edition), Journal Name: Angewandte Chemie (International Edition); ISSN 1433-7851

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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