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

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

doi:10.1038/s41467-019-11014-1

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.

Highlights

IntroductionZwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding
Iatrogenic injury of the ureters is a feared complication of abdominal surgery
ZW800-1 is a small zwitterionic molecule with peak absorption of 770 nm, an extinction coefficient at peak absorption 253,900 M−1 cm−1, peak emission of 788 nm, and a quantum yield in serum of 15.0%. It was manufactured as a sterile, lyophilized powder under Good Manufacturing Practices (GMPs) in the GMP Facility of Leiden University Medical Center, The Netherlands

Summary

Introduction

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 realtime anatomic and functional imaging, even through intact peritoneum. A fundamental problem with NIR fluorescence imaging is that conventional NIR fluorophores are polysulfonated, and highly anionic, in order to shield the central hydrophobic resonance structure and improve solubility, and exhibit non-specific uptake in tissues and organs after intravenous (IV) injection. This results in high background fluorescence and a lower signal-to-background ratio (SBR). While passing from the kidneys to the bladder, ZW800-1 provided exquisite visualization of the ureters, including structure (i.e., anatomical traverse) and function (i.e., flow and patency)

Methods

Results

Conclusion