Impact of C4'-O-Alkyl Linker on in Vivo Pharmacokinetics of Near-Infrared Cyanine/Monoclonal Antibody Conjugates.
Near-infrared (NIR) fluorophores have several advantages over visible-light fluorophores, including superior tissue penetration and lower autofluorescence. We recently accessed a new class of readily synthesized NIR cyanines containing a novel C4'-O-alkyl linker, which provides both high chemical stability and excellent optical properties. In this study, we provide the first in vivo analysis of this new class of compounds, represented by the tetrasulfonate FNIR-774 (Frederick NIR 774). Monoclonal antibody (mAb) conjugates of FNIR-774 were compared to conjugates of the commercially available dye (IRDye800CW (IR800)), one of the most widely used NIR fluorophores for clinical translation. Both dyes were conjugated to panitumumab (pan) or cetuximab (cet) with ratios of 1:2 or 1:5. Conjugates of both dyes demonstrated similar quenching capacity, stability, and brightness in target cells in vitro. In contrast, in vivo imaging in mice showed different pharmacokinetics between pan-FNIR-774 (1:5) and pan-IR800 (1:5), or cet-FNIR-774 (1:5) and cet-IR800 (1:5). Particularly at the higher labeling density, mAb-FNIR-774 conjugates showed superior specific accumulation in tumors compared with mAb-IR800 conjugates. Thus, FNIR-774 conjugates showed superior in vivo pharmacokinetics compared with IR800 conjugates, independent of the mAb. These results suggest that FNIR-774 is a promising fluorescent probe for NIR optical imaging.
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892, United States.
Kazuhide
K
Sato
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892, United States.
Tadanobu
T
Nagaya
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892, United States.
Yuko
Y
Nakamura
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892, United States.
Toshiko
T
Harada
Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health , Frederick, Maryland 21702, United States.
Roger R
RR
Nani
Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health , Frederick, Maryland 21702, United States.
James B
JB
Shaum
Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health , Frederick, Maryland 21702, United States.
Alexander P
AP
Gorka
Applied/Developmental Research Directorate, Leidos Biomedical Research Inc. , Frederick National Laboratory, Frederick, Maryland 21702, United States.
Insook
I
Kim
Nuclear Medicine Department, Warren Grant Magnuson Clinical Center, Radiology and Imaging Science, Warren Grant Magnuson Clinical Center, National Institutes of Health , Bethesda, Maryland 20892, United States.
Chang H
CH
Paik
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892, United States.
Peter L
PL
Choyke
Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health , Frederick, Maryland 21702, United States.
Martin J
MJ
Schnermann
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892, United States.
Hisataka
H
Kobayashi
D000478:Alkylation; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D041702:BALB 3T3 Cells; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002232:Carbocyanines / Q000737:chemistry*; D002478:Cells, Cultured; D000068818:Cetuximab / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D000077544:Panitumumab; D019265:Spectroscopy, Near-Infrared; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002232:Carbocyanines; D005456:Fluorescent Dyes; D000077544:Panitumumab; D000068818:Cetuximab
cyanine; in vivo imaging; monoclonal antibody (mAb) conjugates; near-infrared (NIR) fluorophores