A zwitterionic near-infrared fluorophore for real-time ureter identification during laparoscopic abdominopelvic surgery

Kim S de Valk, Henricus J Handgraaf, Marion M Deken, Babs G Sibinga Mulder, Adrianus R Valentijn, Anton G Terwisscha van Scheltinga, Joeri Kuil, Michiel J van Esdonk, Jaap Vuijk, Rob F Bevers, Koen C Peeters, Fabian A Holman, John V Frangioni, Jacobus Burggraaf, Alexander L Vahrmeijer, Kim S de Valk, Henricus J Handgraaf, Marion M Deken, Babs G Sibinga Mulder, Adrianus R Valentijn, Anton G Terwisscha van Scheltinga, Joeri Kuil, Michiel J van Esdonk, Jaap Vuijk, Rob F Bevers, Koen C Peeters, Fabian A Holman, John V Frangioni, Jacobus Burggraaf, Alexander L Vahrmeijer

Abstract

Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing real-time anatomic and functional imaging, even through intact peritoneum. Here we present the first-in-human experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands.

Conflict of interest statement

J.V.F. is founder and CEO of Curadel, LLC, a for-profit company marketing the FLARE® technology platform for NIR fluorescence-guided surgery. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
High sensitivity detection of ZW800-1 near-infrared (NIR) fluorescence in patients using three different commercial imaging systems. Invisible NIR fluorescence of ZW800-1 is pseudo-colored in green and overlayed in real-time onto the anatomical images
Fig. 2
Fig. 2
Ureter residing under peritoneum. The ureter (dashed circle) is captured during a pulse of urine flow during surgery. The darker green areas in the near-infrared (NIR) fluorescence image (small arrows) is background fluorescence caused by the vessels in the surrounding tissue. The images were acquired using the Olympus® imaging system during laparoscopic surgery
Fig. 3
Fig. 3
Signal-to-background ratio (SBR) of the ureter. Note: the SBR of 5.0 mg is significantly lower than the SBR of 2.5 mg (unequal variance t test: p = 0.003) and 1.0 mg (unequal variance t test: p = 0.01) in the first hour post dose. The values represent the mean ± SD (n = 4 patients each group). Source data are provided as a Source Data file
Fig. 4
Fig. 4
Functional assessment of ureter flow and patency with ZW800-1 (acquired using the Olympus® imaging system)

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