A Fluorescent Probe for Rapid, High‐Contrast Visualization of Folate‐Receptor‐Expressing Tumors In Vivo

Abstract

Folate receptors (FRs) are membrane proteins involved in folic acid uptake, and the alpha isoform (FR‐α) is overexpressed in ovarian and endometrial cancer cells. For fluorescence imaging of FRs in vivo, the near‐infrared (NIR) region (650–900 nm), in which tissue penetration is high and autofluorescence is low, is optimal, but existing NIR fluorescent probes targeting FR‐α show high non‐specific tissue adsorption, and require prolonged washout to visualize tumors. We have designed and synthesized a new NIR fluorescent probe, FolateSiR‐1, utilizing a Si‐rhodamine fluorophore having a carboxy group at the benzene moiety, coupled to a folate ligand moiety through a negatively charged tripeptide linker. This probe exhibits very low background fluorescence and afforded a tumor‐to‐background ratio (TBR) of up to 83 in FR‐expressing tumor‐bearing mice within 30 min. Thus, FolateSiR‐1 has the potential to contribute to the research in the field of biology and the clinical medicine.

Recent Progress in Small Spirocyclic, Xanthene-Based Fluorescent Probes

“…The cells were stained with calcein-AM (calcein acetoxymethyl, a cell permeable fluorophore that is used to test cell viability with green fluorescence) and PI (propidium iodide, a red fluorophore that can stain DNA and is used to visualize necrotic and apoptotic cells, since it is not membrane-permeable) to show that only after addition of TPP the cells died ( Figure 13) [208]. Our group developed a fluorescent probe that can rapidly visualize folate-receptor-expressing tumors with high contrast [209]. The alpha isoform of folate receptor (FR-α) is upregulated in 40% of human cancers, especially in malignant tissues such as ovarian cancer [210,211].…”

“…Our group developed a fluorescent probe that can rapidly visualize folate-receptor-expressing tumors with high contrast [ 209 ]. The alpha isoform of folate receptor (FR-α) is upregulated in 40% of human cancers, especially in malignant tissues such as ovarian cancer [ 210 , 211 ].…”

“… Immunostaining of folate-receptor expressing tumors: ( a ) Molecular design of fluorescent probes for detection of folate receptors and the structures of FolateSiR-1 and FolateSiR-2 ; ( b ) Ovarian cancer tissue microarray with FolateSiR-1 and DAPI (nuclear stain). Adapted with permission from [ 209 ]. Scale bars = 2 mm.…”

Dye‐Sensitized Downconversion Nanoprobes with Emission Beyond 1500 nm for Ratiometric Visualization of Cancer Redox State

“…[ 5 ] Fluorescence (FL) imaging in the first near‐infrared region window (NIR‐I, 650–900 nm) that exhibits reduced scattering and absorption of light by biological tissues, in which the penetration depth is deeper than that of visible light. [ 6 ] However, for biological tissue imaging, the NIR‐I window is not ideal, because in this interval, biological tissue still has autofluorescence, which generates background, and photon scattering, and shows limited deep penetration of the tissue. [ 7 ] Biological imaging in the second NIR window (NIR‐II, 1000–1700 nm) has proven that autofluorescence and photon scattering of the NIR‐II window are low with enhanced spatial resolution and deeper imaging feature contrast.…”

Fluorine-18-Labeled Fluorescent Dyes for Dual-Mode Molecular Imaging

“…In vivo or in vitro OPI consists of detecting a luminescent probe emitting photons in the UV/visible (350–750 nm) to the near infrared (NIR; 750–1500 nm) ranges upon excitation with a higher energy light source [ 13 ]. Currently used luminescent probes include fluorescent proteins, organic fluorescent dyes, lanthanide coordination complexes, nanoparticles, and quantum dots [ 5 , 14 , 15 , 16 , 17 ]. For biomedical imaging applications, desirable emissions are usually located in the NIR region where autofluorescence from biomolecules such as hemoglobin and oxyhemoglobin are at the lowest [ 18 ].…”