期刊
ANALYTICAL CHEMISTRY
卷 91, 期 4, 页码 3110-3117出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.analchem.8b05709
关键词
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资金
- National Center for Research Resources [S10 OD010580]
- National Science Foundation [CHE-1112194]
- Department of Energy [DE-SC0008397]
- Ben and Catherine Ivy Foundation
- National Cancer Institute [R21 CA205564, F32 CA213620, T32 CA118681]
An optical molecular imaging contrast agent that is tailored toward lymphatic mapping techniques implementing near-infrared (NIR) fluorescence image-guided navigation in the planning and surgical treatment of cancers would significantly aid in enabling the real-time visualization of the potential metastatic tumor-draining lymph node(s) for their needed surgical biopsy and/or removal, thereby ensuring unmissed disease to prevent recurrence and improve patient survival rates. Here, the development of the first NIR fluorescent rosol dye (THQ-Rosol) tailored to overcome the limitations arising from the suboptimal properties of the generic molecular fluorescent dyes commonly used for such applications is described. In developing THQ-Rosol, we prepared a progressive series of torsionally restrictive N-substituted non-NIR fluorescent rosol dyes based on density functional theory (DFT) calculations, wherein we discerned high correlations amongst their calculated energetics, modeled N-C3' torsion angles, and evaluated properties. We leveraged these strong relationships to rationally design THQ-Rosol, wherein DFT calculations inspired an innovative approach and synthetic strategy to afford an uncharged xanthene core-based scaffold/molecular platform with an aptly elevated pK(a) value alongside NIR fluorescence emission (ca.700-900 nm). THQ-Rosol exhibited 710 nm. NIR fluorescence emission, a 160 nm Stokes shift, robust photostability, and an aptly elevated pK(a) value (5.85) for affording pH-insensitivity and optimal contrast upon designed use. We demonstrated the efficacy of THQ-Rosol for lymphatic mapping with in vitro and in vivo studies, wherein it revealed timely tumor drainage and afforded definitive lymph node visualization upon its administration and accumulation. THQ-Rosol serves as a proof-of-concept for the effective tailoring of an uncharged xanthene core-based scaffold/molecular platform toward a specific imaging application using rational design.
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