[reaction: see text] A new near-infrared (NIR) fluorescent molecular probe derived from indocarbocyanine dye and galactose was prepared, and the procedure was optimized. The presence of a nonionic polyhydroxyl moiety between hydrophobic groups enhances solubility and possibly minimizes aggregation in aqueous solutions. The structural framework of this molecule provides multivalent sites for labeling diverse molecules.

Removal of a hydroxylsulfonylbutyl arm from indocyanine green dye produced a pH-sensitive near-infrared (NIR) fluorescent indicator that is useful at physiological range.

We have developed a generic approach to determine enzyme activities in vitro and monitor their functional status in vivo. Specifically, a method to generate donor (CbOH)-acceptor (Me2NCp) near infrared (NIR) fluorescent dye pairs for preparing enzyme activatable molecular systems were developed based on the structural template of heptamethine cyanine dyes. Using caspase-3 as a model enzyme, we prepared two new caspase-3 sensitive compounds with high fluorescence quenching efficiency: Me2NCp-DEVD-K(CbOH)-OH (4) and AcGK(Me2NCp)-DEVD-APK(CbOH)-NH2 (5). The mechanism of quenching was based on combined effects of direct (classical) and reverse fluorescence resonance energy transfer (FRET). Caspase-3 cleavage of the scissile DEVD amide bond regenerated the NIR fluorescence of both donor and acceptor dyes. While both compounds were cleaved by caspase-3, substrate 5 was cleaved more readily than 4, yielding kcat and KM, values of 1.02 ± 0.06 s−1 and 15 ± 3 μM, respectively. Treatment of A549 tumor cells with paclitaxel resulted in >2-fold increase in the fluorescence intensity by NIR confocal microscopy, suggesting the activation of pro-caspase-3 to caspase-3. A similar trend was observed in a mouse model, where the fluorescence intensity was nearly twice the value in caspase-3-rich tissue relative to the control. These results demonstrate the use of the same NIR activatable molecular systems for monitoring the activities of enzymes across a wide spatial scale ranging from in vitro kinetics measurements to in cellulo and in vivo localization of caspase-3 activation. The NIR activatable molecular probes provide an effective strategy to screen new drugs in vitro and monitor treatment response in living organisms.

Diagnosis of diseases by different imaging methods can provide complementary information about the functional status of diseased tissues or organs. To overcome the current difficulties in coregistering images from different imaging modalities with a high degree of accuracy, we prepared near-infrared (NIR) monomolecular multimodal imaging agents (MOMIAs) consisting of a heptamethine carbocyanine and 111In-DOTA chelate that served as antennae for optical and scintigraphic imaging, respectively. Their spectral properties clearly show that coordination of indium to MOMIA increased the fluorescence intensity of the compounds. The MOMIAs are exceptionally stable in biological media and serum up to 24 h at 37 degrees C. Biodistribution of the compounds in mice obtained by fluorescence photon and gamma-counts demonstrated a similar distribution trend of the molecular probe in different tissues, suggesting that the detected fluorescence and gamma-emissions emanated from the same source (MOMIA). At 24 h postinjection, the MOMIAs were excreted by the renal and hepatobiliary systems and the blood level of a representative MOMIA was very low, thereby reducing background noise caused by circulating molecular probes. These findings demonstrate the feasibility of preparing single molecules with the capacity to emit discernible and diagnostic fluorescent and gamma-radiations for optical and nuclear imaging of living organisms.

Aims-Receptor-specific small molecules and nanoparticles are widely used in molecular imaging of tumors. Although some studies have described the relative strengths and weaknesses of the two approaches, reports of a direct comparison and analysis of the two strategies are lacking. Herein, we compared the tumor targeting characteristics of a small near-infrared (NIR) fluorescent compound (cypate -peptide conjugate) and a relatively large perfluorocarbon-based nanoparticles (250 nm diameter) for imaging α ν β 3 -integrin receptor expression in tumors.Materials and Methods-NIR fluorescent small molecules and nanoparticles were administered to living mice bearing subcutaneous or intradermal syngeneic tumors and imaged with whole-body and high resolution optical imaging systems.Results-The nanoparticles, designed for vascular constraint, remained within the tumor vasculature while the small integrin-avid ligand diffused into tissue to target integrin expression NIH Public Access Author ManuscriptNanomedicine (Lond). Author manuscript; available in PMC 2011 July 1. Conclusions-Fluorescent small molecular probes show greater overall early tumor contrast and rapid visualization of tumors, but the vascular-constrained nanoparticles are more selective for detecting cancer-induced angiogenesis. A combination of both imaging agents provides a strategy to image and quantify integrin expression in tumor tissue and tumor-induced neovascular system.

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Monomolecular multimodal imaging agents (MOMIAs) are able to provide complementary diagnostic information of a target diseased tissue. We developed a convenient solid-phase approach to construct two pro-MOMIAs (before incorporating radiometal) derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and cypate, a near-infrared (NIR) fluorescent dye analogous to indocyanine green (ICG). The possible interaction between d orbitals of transition metal DOTA complexes or free metals and the p orbitals of cypate chromophore could quench the fluorescence of pro-MOMIAs. However, we did not observe significant changes in the spectral properties of cypate upon conjugation with DOTA and subsequent chelation with metals. The fluorescence intensity of the chelated and nonmetal-chelated PRO-MOMIAs remained fairly the same in dilute 20% aqueous dimethylsulfoxide (DMSO) solution (1 x 10(-6) M). Significant reduction in the fluorescence intensity of pro-MOMIAs occurred in the presence of a large excess of metal ions (>1 molar ratio for indium and 20-fold for a copper relative to pro-MOMIA). This study suggests the feasibility of using MOMIAs for combined optical and radioisotope imaging.