Hydrophilic Cyanine Dyes as Contrast Agents for Near-infrared Tumor Imaging: Synthesis, Photophysical Properties and Spectroscopic In vivo Characterization¶

Abstract

We have synthesized a group of glucamine and gluosamine-substituted cyanine dyes structurally related to indocyanine green (ICG) and have characterized these compounds with regard to their potential as contrast agents for biomedical optical imaging. The compounds reported herein exhibit increased hydrophilicity and less plasma protein binding (< 50%), and are thus expected to have different pharmacokinetic properties compared with ICG. Furthermore, we measured enhanced fluorescence quantum yields (7-15%) in a physiological environment with respect to ICG. For the derivative with the highest hydrophilicity (5a) the efflux from tumor and normal tissue was monitored by intensity-modulated diffuse optical spectroscopy after intravenous injection into tumor-bearing rats. In comparison with ICG, 5a exhibited a considerably enhanced tissue-efflux half-life (73 min versus less than 10 min for ICG in tumor tissue), a two-fold higher initial tissue absorption coefficient compared to ICG, and finally, it generated an elevated tumor-to-tissue concentration gradient up to 1 h after injection. In conclusion, compounds such as 5a are promising contrast agents for optical imaging, and could facilitate highly sensitive and specific detection of breast cancer or other malignancies by utilizing mechanisms similar to contrast-enhanced magnetic resonance imaging or computerized tomography.

Shedding light onto live molecular targets

“…In addition, it has been used in at least one clinical study as an absorber (not a fluorochrome) for enhanced tumor detection31. Near-infrared fluorochromes with improved biophysical properties (solubility, quantum yield, stability, synthetic yield, conjugatability) have recently been developed [47][48][49] and open new avenues for high efficiency labeling of affinity molecules. Before they can enter routine clinical use, however, these fluorochromes will need to undergo testing and receive approval from the US Food and Drug Administration.…”

Nanoscale control of Ag nanostructures for plasmonic fluorescence enhancement of near-infrared dyes

“…Indeed, the sensitivity of many clinical assays is limited by sample autofluorescence. To design and synthesise Near Infra-red (NIR) dyes with high quantum yield and photostability has proven to be extremely challenging, due to the complex synthetic routes required for these large, complex molecules [4]. The amplification of light from NIR fluorophores by coupling to metal nanostructures is a promising strategy for dramatically improving both the detection sensitivity and image enhancement, thereby realizing the potential advantages of the NIR fluorophores.…”

Intraoperative Near-infrared Fluorescence Imaging with Novel Indocyanine Green-Loaded Nanocarrier for Spinal Metastasis: A Preliminary Animal Study

“…Recently, there has been considerable focus on the potential use of indocyanine green (ICG) in intraoperative real-time imaging [10][11][12][13][14][15][16]. However, the strong binding of plasma proteins with ICG and its subsequent rapid clearance by the liver results in binding of ICG to the tumor only for a short duration after administration; thus, the use of ICG for tumor imaging applications is limited [17]. A potential approach to overcoming this disadvantage is delivering ICG in a nanocarrier that can provide increased stability and protection from nonspecific plasma protein binding and offer enhanced circulation time [18][19][20].…”