High-Contrast Detection of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

Author:

Hernandez Vargas, Servando [ORCID]

AghaAmiri, Solmaz

Ghosh, Sukhen C

Luciano, Michael P [ORCID]

Borbon, Luis C

Ear, Po Hien

Howe, James R

Bailey-Lundberg, Jennifer M

Simonek, Gregory D

Halperin, Daniel M

Tran Cao, Hop S

Ikoma, Naruhiko

Schnermann,Martin [ORCID]

Azhdarinia, Ali [ORCID]
Author Address

The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas77054, United States., Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland21702, United States., Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa52242, United States., Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas77030, United States., Center for Laboratory Animal Medicine and Care, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas77030, United States., Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas77030, United States., Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas77030, United States.,

Abstract:

Dye design can influence the ability of fluorescently labeled imaging agents to generate tumor contrast and has become an area of significant interest in the field of fluorescence-guided surgery (FGS). Here, we show that the charge-balanced near-infrared fluorescent (NIRF) dye FNIR-Tag enhances the imaging properties of a fluorescently labeled somatostatin analogue. In vitro studies showed that the optimized fluorescent conjugate MMC(FNIR-Tag)-TOC bound primarily via somatostatin receptor subtype-2 (SSTR2), whereas its negatively charged counterpart with IRDye 800CW had higher off-target binding. NIRF imaging in cell line- and patient-derived xenograft models revealed markedly higher tumor contrast with MMC(FNIR-Tag)-TOC, which was attributed to increased tumor specificity. Ex vivo staining of surgical biospecimens from primary and metastatic tumors, as well as involved lymph nodes, demonstrated binding to human tumors. Finally, in an orthotopic tumor model, a simulated clinical workflow highlighted our unique ability to use standard preoperative nuclear imaging for selecting patients likely to benefit from SSTR2-targeted FGS. Our findings demonstrate the translational potential of MMC(FNIR-Tag)-TOC for intraoperative imaging and suggest broad utility for using FNIR-Tag in fluorescent probe development.

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Author Address