Near infrared fluorescence for image-guided surgery

Abstract

Near infrared (NIR) image-guided surgery holds great promise for improved surgical outcomes. A number of NIR image-guided surgical systems are currently in preclinical and clinical development with a few approved for limited clinical use. In order to wield the full power of NIR image-guided surgery, clinically available tissue and disease specific NIR fluorophores with high signal to background ratio are necessary. In the current review, the status of NIR image-guided surgery is discussed along with the desired chemical and biological properties of NIR fluorophores. Lastly, tissue and disease targeting strategies for NIR fluorophores are reviewed.

Keywords: Near infrared (NIR); image-guided surgery.

Figure 1

Chemical structures of FDA approved NIR fluorophores methylene blue (700 nm NIR fluorophore) and indocyanine green (800 nm fluorophore)

Figure 2

Chemical base structures of known classes of NIR fluorophores including cyanine, phthalocyaninie, xanthene, borondipyrromethane (BODIPY), benzo[c]heterocycle, porphyrin, and squaraine (squarylium). Each of the base structures can have their physical and optical properties tuned through the addition of functional groups

Figure 3

Fluorophore Targeting Strategies. In tumor tissue angiogenesis is responsible for the formation of new blood vessels to support the growth of the tumor. These vessels often lack the tight endothelial junctions of normal blood vessels and are inherently leaky. A. The enhanced permeability and retention (EPR) effect is illustrated where the blood pool NIR fluorophore accumulates in the tumor due to the leaky vasculature; B. Many tumor cells have antigens that are overexpressed, and thus can be targeted to generate signal to background ratio for visualization of the tissue. The NIR fluorophore is conjugated to a tumor-targeting agent specific for the cell surface antigen on the tumor cells. Once deposited into the tumor tissue due to the EPR effect, the NIR fluorophore will bind specifically to the tumor tissue while unbound fluorophore clears increasing the possible signal to background ratio; C. The example demonstrates an enzyme activatable NIR fluorophore where two NIR molecules are quenched due to their proximity to one another by a peptide sequence. Enzymes within the tumor tissue are specific for the peptide sequence and once deposited into the tumor tissue through the EPR effect, the NIR compound can be cleaved by the enzymes resulting in fluorescence emission. This also serves to increase the signal to background ratio by decreasing background fluorescence through quenching of untargeted NIR fluorophores provided that the appropriate interval between administration and imaging is used