Radioactivity-Synchronized Fluorescence Enhancement Using a Radionuclide Fluorescence-Quenched Dye

Abstract

Metal-sensitive fluorescent probes have been shown to accurately and rapidly report metal complexation through a change in the fluorophore's spectral properties [1][2][3] . Previous studies have focused on quasi-static metal-fluorophore complexes, where a single metal of interest complexes with the fluorophore, altering its emission in some discernable fashion. The resultant emission could be further modified by changing the ligands attached to metals or altering the metal oxidation states. Neither experimental nor theoretical studies have been conducted regarding dynamic metal-fluorophore complexes in which the nature of the bound metal itself is variable. Such changes, for example, may transform a non-fluorescent complex into a fluorescent system if a quencher metal could convert into a non-quencher metal. The difficulty in achieving this transformation arises from the high stability of metals. However, a select group of metals such as radionuclides, is ideally suited for this application because spontaneous radioactivity decay of an unstable parent metal could transform it to a different, more stable metal.Herein we propose the first molecular system that demonstrates the feasibility of altering the fluorescence properties of an organic dye as a function of radionuclide decay. Previous studies have shown that 64 Cu decays to 64 Zn and 64 Ni through two pathways, as shown in the following equation:We found a clear differentiation in fluorescence between Cu 2+ and its decay products, with Cu 2+ acting as a strong quencher, Zn 2+ as an enhancer, and Ni 2+ having no net effect on the dye fluorescence. Correlation of the radionuclide decay with the dye fluorescence enhancement validates the hypothesized metal effect and suggests a realm of possible applications for complementing fluorescence with radioactivity. To study the influence of inter-metal conversion through radioactive decay on the fluorescence properties of organic dyes, we prepared LS479, a novel near-infrared fluorescent dye with a covalently linked metal chelating group (Scheme 1). LS479 is structurally similar to a known dye 1,1′,3,3,3′,3′-hexamethylindotricarbocyanine (HITC), which is widely used in analytical chemistry and biological optical imaging studies 4 . The chelating group is derived from diethylenetriamine pentaacetic acid (DTPA). The synthesis of LS479 (Scheme 1) involves the methylation of 5-nitro-2,3,3-trimethylindolenine to provide the indole analog 2 in a 60% yield. Reduction of the nitro group, followed by N-alkylation using N,N-bis [(tert-butyloxycarbonyl) methyl]-2-bromoethylamine 1 afforded the indole derivative 4 in an overall yield of 65%. Treatment of 1,2,3,3-tetramethylindolinium iodide with glutacondialdehyde dianil, acetyl chloride, and acetic anhydride produced the hemicyanine intermediate 5 in an 87% yield. Reaction of 5 with the indole derivative 4 under reflux in anhydrous ethanol with anhydrous sodium acetate afforded Boc-protected intermediate 6, which was isolated in good yield (74.5%). The hydrolysis of 6 to affor...

Near infrared-fluorescent and magnetic resonance imaging molecular probe with high T1 relaxivity for in vivo multimodal imaging

“…At saturation (1:1 dye to metal ratio), LS479 displayed ~700% enhancement of fluorescence. The enhancement was attributed to the suppression of excited state electron transfer, as previously described 14. Photophysical properties of LS479 and LS479-Gd 3+ in 4% BSA are tabulated in Table S1.…”

“…1). The compound was synthesized as previously described 14. The sensitivity of LS479-Gd 3+ to serum albumin (we used bovine serum albumin as a model) was compared to Magnevist ® , a DTPA-based clinical contrast agent for MRI.…”

Blood triggered rapid release porous nanocapsules

“…The use of the UV light for crosslinking of polymer shell nanocapsules could be detrimental to ICG, resulting in permanent bleaching of the dye. Addition of ascorbic acid, a known antioxidant recently shown to protect NIR dyes from degradation by radiation, 36 alleviated this problem. The presence of ascorbic acid in the aqueous solution had no negative effect on the rate of polymerization and successful formation of nanocapsules.…”

Optical Imaging in Cancer Research: Basic Principles, Tumor Detection, and Therapeutic Monitoring

“…Recently published multimodal molecular imaging probes for single-photon emission computed tomography (SPECT)/optical [179] , PET/optical [154,180,181] , and MRI/optical [182] are promising candidates for multimodal imaging. One of these probes is based on 64 Cu-NIR dye conjugated to caspase-3 substrate [154] , where the PET radionuclide component is used to localize and quantify probe distribution, while NIR dye helps to monitor the activity of caspase-3 enzyme in vivo.…”