Abstract
Purpose
Iatrogenic ureteral injury (IUI) can complicate minimally invasive and open abdominopelvic surgery. The incidence of IUI is low and dependent on the type of surgery (< 10 %), but it is associated with high morbidity. Therefore, intraoperative visualization of the ureter is critical to reduce the incidence of IUI, and some methodologies for ureter visualization have been developed. Amongst these, near-infrared fluorescence (NIRF) visualization is thought to bring an advantage with real-time retroperitoneal visualization through the retroperitoneum. We investigated an indocyanine green (ICG) derivative, ASP5354, which emits NIRF at 820 nm when exposed to near-infrared light at a wavelength of 780 nm, in a rodent and porcine model.
Procedures
Wistar rats and Göttingen minipigs under anesthesia were laparotomized and then administered ASP5354 chloride intravenously at dose of 0.03 and 0.3 mg/kg for rats and 0.001 and 0.01 mg/kg for minipigs, respectively. Videos of the abdominal cavity in minipigs were taken using a near-infrared fluorescent camera (pde-neo) and assessed visually by three independent clinicians. Toxicological evaluation was demonstrated with cynomolgus monkeys.
Results
The proportion of animals whose ureters were visible up to 3 h after administration of ASP5354 chloride were 33 % at 0.001 mg/kg and 100 % at 0.01 mg/kg, respectively. In a toxicological study in cynomolgus monkeys, ASP5354 chloride demonstrated no significant toxicity, suggesting that 0.01 mg/kg provides an optimal dose when used clinically and could allow for ureter visualization during routine surgical procedures.
Conclusions
The dose of 0.01 mg/kg provided an optimal dose for ureter visualization up to 3 h after administration. ASP5354 shows promise for ureter visualization during abdominopelvic surgery, which may potentially lower the risk of IUI.
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Acknowledgements
The authors would like to thank Drs. Keni Nii, Jason Schwartz, Jeffrey Raizer, and Evan Graf for their discussion and manuscript review. The authors appreciate the excellent technical assistance provided by Nihon Bioresearch Inc. (Gifu, Japan), Shin Nippon Biomedical Laboratories, LTD (Kagoshima, Japan), and Sekisui Medical Co. LTD (Tokai, Japan). We thank DMC Corp. (www.dmed.co.jp <http://www.dmed.co.jp/>) for editing a draft of this manuscript.
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This study was funded by Astellas Pharma Inc.
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All authors are employees of Astellas Pharma, Inc.
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All procedures were approved by the Committee for Animal Experiments of Astellas Pharma Inc., which was awarded accreditation status by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International.
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Fushiki, H., Yoshikawa, T., Matsuda, T. et al. Preclinical Development and Validation of ASP5354: A Near-Infrared Fluorescent Agent for Intraoperative Ureter Visualization. Mol Imaging Biol 25, 74–84 (2023). https://doi.org/10.1007/s11307-021-01613-0
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DOI: https://doi.org/10.1007/s11307-021-01613-0