Metal-carbonyl units for vibrational and luminescence imaging: towards multimodality.

DOI: 10.1002/chem.201404600

Review

& Bio-Imaging

Metal–Carbonyl Units for Vibrational and Luminescence Imaging: Towards Multimodality Sylvain Clde and Clotilde Policar*[a]

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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Review by techniques, past and recent developments in the application of metal–carbonyl complexes for vibrational and luminescence bio-imaging are reviewed. Finally, their potential as bimodal IR and luminescent probes is addressed.

Abstract: Metal–carbonyl complexes are attractive structures for bio-imaging. In addition to unique vibrational properties due to the CO moieties enabling IR and Raman cell imaging, the appropriate choice of ancillary ligands opens up the opportunity for luminescence detection. Through a classification

1. Introduction

complexes show intense CO absorption bands in this transparent region, with an intensity four- to tenfold higher than the bands from standard organic functional group,[8] such as C D, azide, alkyne, and nitrile, which have stretching modes in the same energy range. The number of CO ligands and the local symmetry of the M(CO)n moiety influence the number of bands as well as their energy.[9] Depending on the oxidation state of the metal and the ancillary ligands, the complex can be neutral, positively, or negatively charged, with shifts of the CO absorptions of dozen wavenumbers. Cationic metal– carbonyl complexes have n(CO) at higher wavenumbers than neutral and anionic complexes, since p-retrodonation is less effective.[10] This easy access to diversity in physicochemical properties is an asset in the development of tunable tools for IR imaging. The first example of the detection of a metal–carbonyl moiety in biological media using its IR absorption was performed by G. Jaouen et al. by recording the CO bands of a chromium–tricarbonyl complex conjugated with a modified estradiol in lamb uterine cytosol.[2] This strategy enabled the monitoring of the interaction of this organometallic hormone with estradiol receptors.[11] Applications were extended to other metal–carbonyl derivatives and quantitative analyses were performed using the height of a n(CO) peak in the transparency window and the minimum quantity detectable for an [alkyne-Co2(CO)6] complex was 0.3 pmol.[12] No imaging was attempted at that point, but this seminal work demonstrated the reliability of the IR signals of metal–carbonyl units for biological studies. Recent vibrational imaging based on these specific signatures are tackled in Section 2, including thermal and synchrotron-based FTIR microscopy, Raman imaging and near-field techniques. As for vibrational spectroscopy, luminescence cell-imaging must take into account the endogenous emission of biomolecules.[13] This cell autofluorescence, mainly due to nicotinamide adenine dinucleotide (NADH), flavins, riboflavins, porphyrins, collagen, and elastin,[14] induces a high background noise level that can prevent the easy detection of exogenous compounds.[15] Interestingly, [M(CO)n(L)X] complexes, in which L is a ligand with low-energy p* orbitals—typically dipicolylamine-like or an a-diimine ligand—and X is a halide ion or a pyridine, show luminescent properties[16] that have been intensively studied since the mid 1970s,[17] leading to an exhaustive literature about their excited states and luminescent properties.[18] All luminescent metal–carbonyl complexes exhibit similar photophysical behaviour:[17, 19]

Metal–carbonyl complexes are organometallic derivatives made of CO ligands coordinated to a transition-metal ion. Since the late 1970s, a great diversity of metal–carbonyl derivatives with various numbers of CO ligands have been synthesized and exploited in organic synthesis or industrial catalysis.[1] In the late 1980s, their potential as infrared (IR) probes for studies in biological media was explored,[2] which opened the way to a fruitful field in bio-organometallic chemistry.[3] Vibrational spectroscopy is attractive for bio-imaging.[4] As it involves no electronic transition, no photobleaching is induced, contrary to what is observed with organic fluorophores in the visible or UV excitation range.[5] Each chemical function exhibits its own IR signature, and the IR spectrum of a cell is the superimposition of complex IR patterns due to the absorption of endogenous biomolecules.[6] The development of IR probes is a real challenge in the emerging field of IR imaging with a key issue of sensitivity. Interestingly, biological media are almost transparent in the range 2200–1800 cm 1 (Figure 1).[7] This range is commonly called the mid-IR transparency window of cells. Metal–carbonyl

Figure 1. Typical FTIR spectrum of a cell, recorded by synchrotron radiation FTIR spectromicroscopy on a single MCF-7 cell.

[a] Dr. S. Clde, Prof. Dr. C. Policar Ecole Normale Suprieure PSL Research University, Dpartement de Chimie Sorbonne Universits—UPMC Univ Paris 06, CNRS-ENS-UPMC Laboratoire des Biomolcules, UMR7203 24, rue Lhomond, 75005 Paris (France) Fax: (+ 33) 1-4432-3389 E-mail: [email protected]

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Review 1) Their absorption spectra show a broad band corresponding to a metal-to-ligand charge transfer (MLCT), with the promotion of an electron from an orbital with a main metallic character to the lowest p* orbital of the L ligand. 2) Since spin-orbit coupling is efficient in heavy metal complexes, inter-system crossing leads to 3MLCT states, which are emissive.

the biological samples. Multimodal probes are a means to combine the advantages of complementary techniques on the same molecule. The growing interest for multimodality is addressed in Section 4, as well as recent works about the possibility to achieve both vibrational and luminescent imaging using a single Re(CO)3 core.

Interestingly, wavelengths of absorption and emission can be tuned by varying L, its nature[20] or its substituents,[21] and X.[20b, 22] For biological luminescent applications, rhenium(I)based carbonyl complexes are by far the most described metal-carbonyl fragments due to their simple preparation[21, 23] and suitable properties for experiments using luminescence.[20d, 24] First, they exhibit long excited-states lifetime—in the range of hundreds of nanoseconds at room temperature[20c,e]—and large Stokes shift[20f]—up to 200 nm.[20g, 24c] These characteristics are of interest to limit the autofluorescence noise, by decoupling the excitation and collection times and/ or selecting appropriate wavelength filter sets for excitation and emission. They also limit self-quenching by re-absorption and nonradiative mechanisms. In addition, in contrast to known organic fluorophores (e.g. derivatives of fluorescein or cyanin), their photostability[22] enables long experiments. The Re(CO)3 low-spin d6 center is kinetically inert to ligand substitution,[18h, 24b] which favors its stability in biological media and silences any toxicity that could be associated with metal release.[25] The development of probes to locate tagged xenobiotics is a real challenge in the emerging field of imaging techniques. The [M(CO)3(L)X] core is appropriate for easy grafting, through conjugation with L or X and its small size is attractive, as it is important to induce minimal physicochemical modifications with a tag.[18h] Extensive reviews are available on luminescent probes based on Re(CO)3,[16a,c,d, 20d, 24b, 26] and, for this reason, we have chosen to focus the following discussion in Section 3 to the use of Re(CO)3 cores for the functionalization of molecules to be tracked in biological medium and for organelle staining. Several independent techniques are presented in the following and we wish to comment quickly on their assets and limits. Vibrational techniques are attractive for bio-imaging: excitation in the IR leads to excitation in the vibrational levels and, as no electronic states are involved, no photobleaching of the probe occurs. Vibrational spectroscopy also provides local chemical endogenous information. Raman imaging involves higher energies for excitation—visible–UV range—but thus offers a better spatial resolution—ca. 1 mm—than IR spectromicroscopy—ca. 2.5 mm at 2000 cm 1 which is the limit due to diffraction (about l/2, see below) and attainable with a confocal arrangement and a synchrotron source.[27] Combining vibrational spectroscopy with scanning probe microscopy (SPM) enables a spatial resolution beyond the diffraction limit through near-field acquisition. Fluorescence microscopy is widespread and a large set of organelle trackers are commercially available. Its spatial resolution is well-adapted for sub-cellular imaging— resolution < 100 nm in confocal mode—but the high energy involved can lead to photobleaching and photodamages of

2. Metal–Carbonyl Complexes as Vibrational Probes for Imaging

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2.1 FTIR imaging In FTIR imaging, the trade-off between spatial resolution and pixel size is a crucial point to consider. When optical detection is used, resolution is diffraction-limited to about l/2 (Abbe criteria). In the IR range from 4000 to 500 cm 1, the best attainable lateral resolution is about 2 to 15 mm, respectively. Another limitation is related to the signal-to-noise ratio. In order to detect subtle changes in the IR spectra, a sufficient number of photons needs to be collected to efficiently probe a given area.[6c] This requires higher aperture size or averaging of several pixels to record manageable IR spectra. This has to be considered to specify the actual resolution in IR imaging of biological samples.

Sylvain Clde is a molecular physicochemist who attended the Ecole Normale Suprieure— Cachan and Paris-Sud 11 University (France). He obtained his M.Sc. (2010) in biophysics at the University Pierre and Marie Curie (Paris, France), working with Prof. Clotilde Policar on the design of metal-based complexes dedicated to bio-imaging. He received his Ph.D. in 2013 in the same group, where he was involved in the development of rhenium– tricarbonyl bimodal complexes optimized for vibrational and luminescent detection in a cellular environment. His current interest is the IR imaging of these probes at the tissue level. For this work, Sylvain Clde received the Thesis Prize 2014 from the Division de Chimie Physique of the Socit Chimique de France. Clotilde Policar was trained in organic, inorganic, physical, and bio-inorganic chemistry at the Ecole Normale Suprieure—Cachan and Paris-Sud 11 University (France). After a Ph.D. under the supervision of Daniel Mansuy and Isabelle Artaud at Paris-Sud 11 and Paris V Universities on mimics of manganese-peroxidase, she pursued post-doctoral studies on high-field electron paramagnetic resonance and was then appointed assistant professor at Paris-Sud 11, where she dedicated her work to the development of Mn-complexes reproducing the activity of superoxide-dismutase in order to characterize Mn-OO adducts. Since 2008, she has had a professorship at the Ecole Normale Suprieure Paris, where she teaches at the chemistry department and has set up a thematic group in inorganic cellular chemistry dedicated to the study of inorganic compounds in a biological environment. Her current interests focus, on the one hand, on manganese-based anti-oxidants evaluated in cells and, on the other, on the development of metal–carbonyl as multimodal bioprobes.

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Review Using a thermal source and a raster-scanning detection (sequential recording with a single-element detector and confocal-like apertures), an aperture size smaller than 10 10 mm2 is not efficient, because of the low brightness of the source (power emitted per source area and solid angle).[28] This is a strong limitation to study small cells (diameter < 20 mm). With synchrotron sources, the aperture size can be down to 3 3 mm2 because of the high brightness of the source (ca. 2–3 orders of magnitude greater than thermal source),[27–29] which enables to focus about 100 more photons than thermal sources on an area of a few mm2.[6c] Regions corresponding to the diffraction-limited spot-size in the IR range (a few mm2) can thus be probed with an acceptable signal-to-noise ratio.[30] Note that if a 70 mm aperture is used, there is no advantage in terms of brightness of the synchrotron source over thermal source.[27] A thermal source coupled to an apertureless widefield detection through a focal plane array (FPA) detector allows for a projected pixel size of 5 5 mm2 and greatly reduces the time of acquisition (parallel recording). Decreasing the pixel size at the sample plane is ineffective, since the signal-to-noise ratio also decreases and longer collection times are required.[31]

Figure 2. a) IR spectra of control mucosa cells (bottom), cells treated with 1 (middle) and cells treated with 2 (top). Inside the red frame, carbonyl (CO) stretching vibrations. b) Bright field image of the mucosa cells treated with 1 and c) corresponding IR mapping at 2013 cm 1 (false color scale, from blue for weak signal to red for high signal). Adapted from reference [32].

2.1.1 Imaging with a thermal source coupled to a FPA detector

the distribution of the amide I band of proteins commonly used in IR imaging to define the overall cell-shape.[4e, 34] Concerning the spatial resolution, the choice of large cells like HL60 cells (up to 100 100 mm2)[7a] was judicious regarding the resolution that is achievable using this set-up (see above).[31, 35] This work demonstrated the feasibility of IR chemical imaging based on metal–carbonyl CO-bands in a biological environment.

The first IR bio-imaging of a metal-carbonyl complex was performed by Leong et al. in 2007.[32] To increase sensitivity, a cluster of three osmium-carbonyl cores was used and was grafted to a fatty acid providing 1 containing ten CO groups or to phosphatidylcholine to give 2 containing twenty CO groups.

2.1.2 Synchrotron radiation FTIR spectromicroscopy IR imaging of small cells (diameter < 20 mm) with a subcellular resolution was made possible by coupling an IR microscope to a synchrotron source. Jamin et al. demonstrated that chemical imaging of living cells with a micrometric-range resolution was achievable using synchrotron radiation FTIR spectromicroscopy (SR-FTIR SM).[6a] A wide range of biological applications was then reported, such as the study of cell-cycle and death,[36a,b] or that of the distribution of phosphorylated proteins[37] or unsaturated lipids.[38] The IR detection at the subcellular level of exogenous compounds is challenging and, as previously mentioned, metal– carbonyl complexes are attractive candidates with their strong absorption in the mid-IR transparency window of the cell (2200–1800 cm 1 range). Our group investigated IR imaging of conjugates containing a fac-Re(CO)3 core by SR-FTIR SM.[39] Its C3v local symmetry induces two bands of absorption in the 2200–1800 cm 1 range: an E-band (asymmetric stretching, doubly degenerate) at about 1920 cm 1 and an A1-band (symmetric stretching) at about 2020 cm 1.[12] The first proof that

These conjugates where then incubated in HL60 cells at 32 mm for 24 h. In both cases, the CO absorption at 2013 cm 1, easily distinguishable from the endogenous IR signals of the cell (Figure 2a), was detected. IR mappings of bands of interest were recorded to investigate the sub-cellular location of 1 and 2, using a globar source coupled to a focal plane array (FPA).[33] The distribution of the band at 2013 cm 1 was found to be homogenous over the whole cell (Figure 2b and c), and similar to &

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Review a Re(CO)3 moiety could be mapped using SR-FTIR SM was recently provided,[39a] with the study of 1,1-di(4-hydroxyphenyl)-2-cyrhetrenylbut-1-ene 3,[40] an organometallic conjugate in which a {(Cp)Re(CO)3} unit (Cp = cyclopentadienyl) is linked to a hydroxytamoxifen-like structure. The distribution of 3 in MDA-MB-231 breast cancer cells after incubation for 1 h at 10 mm was investigated using A1 and E IR bands. An uneven distribution was observed with a clear accumulation at the nucleus (stained with DAPI) or at least close to it. Developing carbon monoxide releasing molecules (CORMs), Zobi et al. demonstrated the uptake of a B12-MnCORM derivative and characterized the photoinduced CO release directly in live cells.[41] This approach is an original study combining IR imaging with functional bio-activity in live cells.

Figure 3. A) Averaged Raman spectrum of the maximum 4 signal inside a HT29 human colon cancer cell. B) Typical averaged Raman spectrum from a region within the cell lacking any metal complex. Adapted from reference [47].

2.2. Raman imaging 2.2.1 Raman confocal imaging In the 1990s, it was demonstrated that living cells can be studied with confocal Raman microscopy.[42] The technique was applied at the subcellular level to locate organelles, such as the nucleus, the endoplasmic reticulum,[43] or the mitochondria,[44] and also in tissues to monitor biochemical changes, such as in vascular tissue.[45] Van Manen et al. and Diem et al. pioneered the cell imaging of exogenous deuterated compounds with confocal Raman microscopy[46] using C D stretching vibrations found between 2000 and 2300 cm 1 that are thus detectable in cells, but a large number of C D bonds must be involved for sensitivity reasons (detection of poly-deuterated lipids). In 2010 Havenith et al. performed the detection and mapping of a Mn(CO)3 complex, [Mn(tpm)(CO)3]Cl (4, tpm = tris(1pyrazolyl)methane), in HT29 human colon cancer cells.[47] This MnI core with a PF6 counterion had been previously shown to exhibit cytotoxicity towards cancer cells after photoinduced CO release.[48] The local C3v symmetry leads to two CO stretching bands at about 1950 and 2050 cm 1 (as for fac-Re(CO)3), but the bands are much weaker in Raman than in IR spectra.[47] One CO stretching band was clearly detectable by Raman spectroscopy in cells incubated in the mm range for 3 h with 4 (Figure 3). Complex 4 was shown to be internalized and to localize at the nuclear membrane and in the nucleolus using confocal Raman imaging with 3D-reconstruction images (Figure 4). The requirement of a concentration in the mm range can be a drawback for in vivo applications.[49] To circumvent the low absorption of CO in Raman spectra, it is possible to apply various multivariate approaches, such as principal component analysis (PCA) or hierarchical cluster analysis (HCA).[50] Chem. Eur. J. 2014, 20, 1 – 18

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Figure 4. A) Optical image of a HT29 cell incubated with an aqueous solution of 4 (2 mm, 3 h). B) and C) Raman images reconstructed from integrating the intensities of the C H and C O stretching peaks. The integration range was 2800–3050 cm 1 for B) and 1945–1965 cm 1 for C). D) Overlaid image of panels B) and C). E)–G) Cross-section Raman images along the x,zdirection of the same cell. Adapted from reference [47].

2.2.2 Surface-enhanced Raman spectroscopy (SERS) Surface-enhanced Raman spectroscopy (SERS) is a powerful vibrational technique based on the local amplification of electromagnetic fields generated by the excitation of localized surface plasmon resonances on metallic nanoscale structures.[51] SERS has been successfully applied to various biological samples.[52] Detection of analytes at low concentrations in an aqueous environment is possible using SERS,[53] and its efficient use to enhance CO stretching of metal–carbonyl complexes has been recently demonstrated by Leong et al.[49b] Gold nanoparticles (NPs) were functionalized with osmium–carbonyl clusters [Os3(CO)10(m-H)2], labeled hereafter OM (similar to those described above, see compounds 1 and 2 in Section 2.1.1). The CO signal at about 2000 cm 1 was greatly enhanced (by a factor ca. 15 000) in the case of OM-NPs in comparison with OM (Figure 5). OM-NPs were then coupled with a PEGylated antibody against epidermal growth factor receptors (L = anti-EGFR). Quite interestingly, cancer cells overexpressing a membrane receptor EGFR—namely, OSCC cells, epidermoid carcinoma— 5


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Review 2.3.1 Spectral information in scattered IR light Scattering scanning near-field optical microscopy or s-SNOM was developed in the IR range in the 1990s:[55] an AFM-tip set in close vicinity to a sample is illuminated by a tunable IR laser and the IR light scattered by the tip is collected. This scattered light measured in the far-field carries information about the sample’s local properties.[54b] Tuning the IR laser to a vibration band of interest enables the location of the areas in which the radiation is absorbed and to determine the distribution of the molecule bearing the corresponding chemical function. IR s-SNOM has been applied to the study of biomolecules, such as lipids,[56] single viruses[57] and whole cells.[58] Havenith et al. have recently demonstrated the detection of the Mn(CO)3 moiety of the cymantrene–peptide conjugate 5. Well-defined and laterally structured self-assembled monolayers (SAMs) prepared using thiol–gold bonds were mapped using IR s-SNOM with a very good lateral resolution (90 90 nm2 ; Figure 7),[5b] showing that IR s-SNOM enables sensitive and spatially resolved detection of metal–carbonyl conjugates.

Figure 5. Raman spectra of a) 10 mm and b) 50 mm OM in ethanol/water (1:4, v/v), and c) OM-NP conjugate (34 mm of OM on 4.31 10 5 mm NP) in aqueous solution. Adapted from reference [49b].

treated with OM-NP-(PEG)-L showed a strong CO stretching signal at 2030 cm 1(Figure 6), whereas EGFR-negative cells— namely SKOV cells, ovarian carcinoma—did not show any signal at that frequency. These results indicate that SERSenhanced signals can be obtained from a membrane receptor associated with a metal–carbonyl gold nanoparticle.

Figure 7. AFM topography and near-field contrast images at four distinct frequencies of a laterally structured 5 grafted to gold-coated silicon. 1944 cm 1: CO stretching of cymantrene of 5; 1658 cm 1: amide I of aminoacids; 1900 and 1798 cm 1: off-resonances. Scan size 7 7 mm2. Adapted from reference [5b].

Figure 6. Bright field and SERS mapping images of a)–e) OSCC cells (EGFR is overexpressed) treated with OM-NP-(PEG)-L conjugates, f)–j) SKOV cells (EGFR-negative) treated with OM-NP-(PEG)-L conjugates. 2030 and 1600 cm 1 correspond to CO and protein signals, respectively. Adapted from reference [49b].

2.3 IR coupled to near field acquisition 2.3.2 Spectral information through photothermal-induced effects

To overcome the diffraction limit associated with optical detection, near-field techniques in the IR regime have been considered. Combining scanning probe microscopy with spectroscopy is a way to get rid of optical detection and to record highly spatially resolved spectral information in which the spatial resolution is mainly governed by a nanometric probe, typically an atomic force microscope (AFM) tip.[54] Interestingly, both the topography—through the AFM—and local spectral data can be collected simultaneously.

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Dazzi et al. published in 2005[59] and patented in 2008[60] a cutting-edge technique for IR mapping that relies on photo-induced thermal resonance principle (PTIR) with a few 10 nm lateral resolution. The set-up—namely atomic force microscope infrared (AFMIR) spectroscopy[59, 61]—couples a near-field detection with an AFM and excitation with a pulsed tunable IR laser. The AFM tip is in contact with the sample that is deposited on an IR transparent prism (typically ZnSe) and irradiated with the IR pulsed laser. If the IR laser is tuned to a wavelength corresponding to an IR absorption band from the sample, the absorbed light induces a photothermal response in the sample, 6



Review with excitation in the vibrational levels and dissipation as heat.[62] The local heating results in a rapid thermal expansion that is detected by the AFM tip, which starts to oscillate as if it were punched (but the contact with the sample is kept). The maximal amplitude of this oscillation, which corresponds to the AFMIR signal, is proportional to the local absorbance.[63] This technique thus enables: 1) to record simultaneously the topography and the distribution of a chemical function by tuning the laser at various wavelengths and mapping the sample with a scanning AFM-tip and 2) to record a IR spectrum at a given position by varying the IR laser energy. AFMIR has a spatial resolution from 100 to 20 nm[64] enabling subcellular IR mapping of endogenous components (DNA, lipids, proteins) within biological samples.[61a,c, 65] Interestingly, the technique is sensitive enough to map exogenous molecules tagged with metal–carbonyl complexes after incubation for one hour in the mm range and fixation, as we have shown recently with tamoxifen[5a] or mestranol (see Section 4.2)[39c] both tagged with a Re(CO)3 moiety. The tamoxifen conjugate, compound 3 (see Section 2.1.2) was incubated for 1 h at 10 mm in MDA-MB-231 breast cancer cells, which were mapped in the IR at different characteristic wavelengths (Figure 8). As expected the E and A1 mappings (at 1915 and 2017 cm 1, respectively) were superimposed for treated cells (bottom row) and control cells (top row) exhibited only a weak signal assigned to residual water (Figure 8, columns d and e). The E and A1 mappings were found to be partly overlaid with amide I (Figure 8, column c) and phosphate asymmetric (Figure 8, column b) stretchings, pointing out a possible accumulation of 3 at the nucleus of MDA-MB-231 cells or close to. This result was confirmed by a correlative SR-FTIR SM/fluorescence experiment.[39a] FTIR quantification using a calibration curve allowed for estimating the intracellular content of 3 in the femtomole range.[5a] Vibrational imaging has already shown a great potential for biological applications and emerging techniques aim at making the best all the assets of this spectral range—lowenergy involved and chemical specificity enabling label-free imaging. Future developments will most certainly expand and

strengthen the use of vibrational spectroscopy in biological studies. In that challenging context, metal–carbonyl probes have proved their relevance and we can expect that they will tend to be increasingly used.

3. Metal–carbonyl complexes as luminescent probes: chosen examples A great diversity of molecules or moieties meant for organelle delivery have already been appended to [Re(CO)3(L)X] + ,0 complexes—overall charge (0) if X = (Cl , Br ) and (+ 1) if X = pyridine—and two particular routes have been explored in the literature depending on the choice for the coupling platform. 1) Through reliable reductive amination with quinoline-2carboxaldehyde derivatives and a chosen primary amine, dipicolylamine-like ligands (L) can be prepared with an easy access to the corresponding rhenium complex (Figure 9). 2) Grafting using activated functions on pyridine (X) or adiimine ligand (L) has also been exhaustively described. Isothiocyanate (NCS) derivatives are widely used to tag proteins by reacting with the amine group of lysine residues at the N-terminal position of proteins to form a stable thiourea conjugate.[67] Maleimide moieties are suitable for tagging cysteine-containing proteins (Figure 10).

Figure 9. Dipicolylamine-like strategy. Adapted from reference [66].

Figure 8. Images of MDA-MB-231 cells. Top row: control cells; bottom row: cells treated with a 10 mm solution of 3 for 1 h at 37 8C. a) AFM topography; b–f) PTIR mappings at different wavelengths, with the AFM contours superimposed as black lines; the wavelengths correspond to the following bands: b) phosphate, c) amide, d) tricarbonyl (E-band, e) tricarbonyl (A1-band), and f) a band showing residual absorption of water. Adapted from reference [5a]. Chem. Eur. J. 2014, 20, 1 – 18

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Figure 10. Top frame: molecular units grafted to X = pyridine or L = a-diimine ligand. Bottom: examples of activated pyridine ligands (top: with isothiocyanate NCS, bottom: with maleimide) and corresponding conjugation with biomolecules.

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Review 3.1 Dipicolyl-amine like chelators: the central nitrogen as an anchoring point

py. The positive overall charge of the complex, through interaction with the negatively charged DNA backbone, is also ascribed to contribute to the cytotoxicity that is associated with the thymidine moiety, which interacts with DNA, thus disturbing the replication.

Technetium-99m is a radionucleide widely used in medical diagnosis.[68] Since the coordination chemistry of 99mTc is similar to that of Re,[69] rhenium complexes, including fac-Re(CO)3, were considered in the literature as non-radioactive analogues for the corresponding Tc complexes.[26b, 70] As described above, when Re is coordinated with ligands exhibiting low-energy p* orbitals, the complexes are luminescent from their 3MLCT excited state, with large Stokes shift and long excited-states lifetime. Their use for cellular imaging was pioneered by Valliant, Zubieta et al.[66] They designed a pair of isostructural Re/99mTc complexes [M(CO)3(L)] + to bridge the gap between in vivo imaging with the radionucleide 99mTc and cellular fluorescent imaging with the Re probe. Easy functionalization of peptides from a lysine group was developed leading to an appended tridentate bisquinoline chelate (L), referred to as a single amino acid chelate or SAAC.[71] As an example, it was included in a short peptide sequence meant to target the formyl peptide receptor FPR known to be overexpressed in neutrophyls and previously used in radioimaging.[72] The final compound is 6 (with all l-amino-acids) was incubated at 1 nm on leukocytes and was successfully imaged by live-fluorescence microscopy, showing the internalization of 6 into the cytoplasm of the cells at room temperature (Figure 11). Interestingly, 6 was co-localized with a known FPR fluorescein-labeled compound, which confirmed that the coupling to the rhenium carbonyl had not altered the cellular distribution. Bartholoma, Zubieta et al.[73] also used this strategy to obtain Re(CO)3–thymidine complexes as anticancer derivatives.[73a] The cellular internalization of 7, enabled by the lipophilic {C12– Re(CO)3} + moiety was monitored using fluorescence microsco-

Using this dipicolylamine-like design, numerous {Re(CO)3} + bioconjugates were developed by this group and others, including derivatives of peptides,[74] folate,[75] vitamins,[76] biotin,[77] and peptide nucleic acid (PNA).[78] Since the seminal work of Zubieta’s group,[66] a great deal of work has been dedicated to the development and bio-imaging applications of Re-based luminescent probes and very well documented reviews are available.[16, 20d, 24b,c, 26, 79] In the following, we focus on a few chosen examples in which these moieties have been chemically designed for the functionalization of molecules or for organelle targeting. 3.2 Coupling using an activated aromatic position on pyridine or a-diimine ligand 3.2.1 Photophysical properties Interestingly, Coogan et al. showed in 2007 that the luminescent properties of [Re(CO)3(L)(pyridine)] + with L being a diimine (bipyridine, orthophenanthroline, etc.) can be put to good use in luminescent imaging with a possible tuning of the properties through functionalization of the pyridine.[80] The methodology consisting of exploiting one of the positions of the pyridine ring for functionalization to tune the properties of the unit [Re(CO)3(L)(pyridine)] + is by far the most used. This strategy is a way to develop series of compounds, varying the substitutions on pyridine but keeping L constant, which is advantageous as L most strongly influences the photophysical properties of [Re(CO)3(L)(pyridine)] + .[20d] Coogan et al. designed a series of cationic conjugates 8 with functionalized pyridine to vary the lipophilicity and of anionic complexes 9 obtained with L = bathophenanthroline sulfate. The long lipidic chain in 8 was shown to have little effect on the absorption and emission, but in a more recent paper the same group showed that solvent shielding by chain-folding onto the [Re(CO)3(L)pyridine)] + can occur and influence the emission.[24a] Anionic complexes (9) exhibit a valuable red-shifted absorption (lmax = 370 nm) with regard to the bipyridine analogues (lmax = 360 nm), but show very weak penetration in liposomes. The two series of complexes were found to fluoresce inside cells.[80] This is an important step towards the development of ReIbased probes with tunable properties through molecular

Figure 11. Leukocytes incubated with 1 nm 6 (left), fluorescein labeled FPR (middle) and 50 nm 6. Adapted from reference [66].

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Review states.[17, 18g, 19b, 22, 23, 83] However, the preparation of monofunctionalized derivatives generally requires multiple-step syntheses and/or fastidious purification steps.[84] Interestingly 4-(2-pyridyl)-1,2,3-triazole (pyta) can chelate Re(CO)3 to give luminescent complexes and the introduction of a molecular unit using the nitrogen N1 from the triazole ring is much easier.[84] Functionalized pyta can be prepared very easily with a wide range of R moieties by copper-catalyzed azide–alkyne cycloaddition (CuAAC) from 2-ethynyl-pyridine and an organic azide (R N3). Recently, we investigated the impact of structural modifications of a bidentate pyridyl–triazole ligand on the luminescent properties of the complexes.[20a] 1-(2-Pyridyl)-1,2,3-triazole (tapy) complexes (11) bearing long alkyl chains show an impressive enhancement in their luminescent quantum yield relative to the pyta complex, in organic solvents and aqueous solutions (Figure 12). Preliminary cellular imaging studies in breast cancer cells revealed a strong increase in the luminescence signal in cells incubated with a C12-substituted tapy complex.[20a] changes. We have shown that the characteristics of the emission can be used as a reporter of the direct environment of the probes in cells: water induces a hypsochromic effect (blueshift) in comparison with organic-like environments.[81] In a recent study by Fernandez-Moreira et al., the effect of the substituent position on the pyridine on biological activity was investigated.[82] Compounds 10 a and 10 b with an aminoacid methyl ester in the meta- or para-position, respectively, of the pyridine were prepared. Whereas the photophysical prop-

erties of both para and meta series are very close, their effect on cells was clearly different. The para-conjugates induced morphologic damage in MCF-7 cells and underwent considerable photobleaching in cells. After incubation with the metaconjugates, the cells remained healthy and no significant photobleaching was observed. The authors suggested that an amino acid radical can be easily produced in the case of the para-analogues, but the whole explanation remains unclear. Anyway, this study clearly highlighted the huge biological effects that small molecular changes can trigger. The bipyridine and orthophenanthroline derivatives have also been extensively used to generate [Re(CO)3(L)] complexes and were among the first bidentate ligands described to 3 enable radiative emission from MLCT excited Chem. Eur. J. 2014, 20, 1 – 18

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Figure 12. Pyta– and tapy–Re(CO)3 complexes. Emission of the corresponding complexes at room temperature in H2O (2 % DMSO) after excitation in the MLCT band. Adapted from reference [20a].

Many bio-active molecules coupled with [Re(CO)3(L)(pyridine)] + have been designed, with imaging studies—polylactides[85]—or without imaging—biotin,[86] indole,[87] and estrogens.[88] Some groups have demonstrated that it was possible to graft peptide nucleic acids (PNA) onto dinuclear rhenium(I)– tricarbonyl moieties and to image them inside cells.[89] Other multi-rhenium carbonyl units have also been used elsewhere for bio-imaging.[20c, 90] 9


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Review In the following, we focus on a few imaging examples with mononuclear Re probes, to give an insight into the possibilities offered by these valuable luminescent moieties. 3.2.2 Luminescent biotinylated probes Figure 13. Bright-field (left), fluorescence (right) and overlay (middle) microscopy images of HeLa cells incubated with complex 13 (10 mm) at 37 8C for 24 h. Adapted from reference [95].

Biotin, or vitamin H, exhibits a very high affinity for the avidin and streptavidin proteins. The strong biotin–(strept)avidin noncovalent interaction makes it a suitable pair for biological applications requiring a highly specific binding, such as immunological assays or flow cytometry.[91] Interestingly, the terminal carboxylic acid of the biotin can be derivatized for conjugation, without altering the interaction with (strept)avidin.[92] The molecule of interest—a protein, a nucleic acid, a lowmolecular weight compound, and so forth—can be grafted to biotin, that is, biotinylated, to be then recognized by a (strept)avidin system. Biotinylation reagents—activated derivatives bearing a biotin molecule[92]—have been developed in order to conjugate biotin to the studied molecule and, for instance, monitor its uptake. Lo et al. designed a series of [Re(CO)3(L)(pyridine)] + complexes activated by an isothiocyanate (R-NCS)[93] or a maleimide[94] moiety in the meta-position of pyridine to react with amine and sulfhydryl groups, respectively (Figure 10). They used this strategy to develop a new class of luminescent biotinylation reagents based on ReI complexes (12).[95] They showed that 12 was able to react with different synthetic and proteic amines to give the corresponding thioureas 13. Interestingly, in this series, the uptake of the conjugate 13 (R1 = H, R2 = C6H5) was monitored in Hela cells and was shown to display a non-homogenous distribution in the cytoplasm and with a localization in a perinuclear region, although no particular targeting was aimed at in the molecule design. The authors suggested an accumulation in hydrophobic organelles, possibly in the Golgi apparatus, but no co-localization experiment was performed (Figure 13). As no uptake was observed upon incubation at 4 8C, the authors concluded that an energy-dependent internalization process was at work. This uptake study highlights the potential of such moieties to tag specifically organelles (see Section 3.2.4). Bipyridine (bipy) and orthophenanthroline (phen) derivatives are among the most used a-diimine ligands for Re(CO)3 chelation.[16a, 24b] Lo et al. exemplified a direct coupling of two biotin pendants to a 2,2’-bipyridine ligand to give two bis-biotin

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complexes 14.[96] Interestingly the these two complexes displayed emission enhancement and lifetimes elongation upon binding to avidin. Confocal microscopy showed internalization of the conjugates in HeLa cells, making these constructs reliable tools as bifunctional luminescence/avidin linking probes. This group also performed the conjugation of biotin and estradiol derivatives to bipy in the case of iridium complexes.[97]

3.2.3 Luminescent carbohydrate probes Glucose consumption is an important parameter of cell physiology with an increased rate in cancer cells. Probes have thus been developed to monitor glucose uptake and used for cancer diagnosis with reporters including radioactive labels,[98] or organic fluorophores.[99]

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Review The preparation of mono-functionalized derivatives of bipy or phen ligands generally requires multiple-step syntheses and/or fastidious purification steps,[84] and the functionalization of L = 4-(2-pyridyl)-1,2,3-triazole (pyta) has been described as an easier route.[100] Obata et al. published the coupling of a carbohydrate derivative to a [(pyta)Re(CO)3Cl] core and reported the photophysical properties of 15, but no imaging study was provided.[20g] Lo et al. have explored the possible use of Re-based luminescent probes as glucose tracers. An a-d-glucose unit was grafted on the pyridine of a [Re(CO)3(L)(pyridine)] + moiety with L = phen derivatives to give 16 and uptake and imaging studies were performed using cancer cells, namely HeLa cells.[101] Compound 16 (R1 = H, R2 = C6H5) was found to effi-

work to other carbohydrate transporters with the study of a rhenium–tricarbonyl with a fructose pendant that exhibits photocytotoxicity and selective accumulation in breast cancer cells.[102]

3.2.4 Targeting of specific organelles Mitochondria are responsible for energy production and are central to cell life and death. Strategies to target this organelle have been developed in the literature, mainly aimed at the specific delivery of bio-active molecules. To reach the mitochondrion, the plasmic and then the mitochondrial membranes must be crossed. As shown by Murphy et al. the charge imbalance—or electrochemical gradient—between the mitochondrion and the cytosol induces significant accumulation of lipophilic cations at this organelle.[103] Most commercially available mitochondrion trackers are based on this principle. Because ReI-based probes bearing pyridine, bipyridine, or orthophenanthroline are highly hydrophobic with a positive charge, they are attractive moieties for the design of mitochondrion trackers. With the commercially available Mitotracker Red (chloromethyl-X-rosamine), localization in the mitochondrion is thought to be due to the combination of a lipophilic cation with a chloromethyl function that reacts with reduced thiols, which are highly concentrated in this organelle. In 2008, Coogan et al. designed a [(bipy)Re(CO)3(pyr-CH2Cl)] + complex 17 bearing a chloromethyl thiol-reactive group as a fluorescent tracker for the mitochondria.[104] Interestingly, under physiological conditions, 17 was not reactive towards amines but only towards thiols, undergoing S-alkylation from cysteine and reduced glutathione. Performing confocal microscopy on MCF-7 cells incubated with 17, the authors showed that 17 was co-localized with a mitochondrial tracker (tetramethyl rhodamine methyl ester or TMRE) (Figure 15), thus validating their strategy of combining cationic and thiol-reactive moieties as in the Mitotracker Red compound. Over the last decade novel L ligands also allowing 3MLCT luminescence of [Re(CO)3(L)X] + ,0 moieties have emerged: pyridyl, pyrazinyltriazine, triazolopyridine,[105] pyridylbenzothiazole, pyridylbenzoxazole, pyridylbenzimidazole,[106] di(2-pyridyl)amine

ciently enter HeLa cells after incubation at 100 mm for 5 min in a glucose-free medium, with a decrease in the cellular uptake when the culture medium was supplied with high concentration in d-glucose (5 to 50 mm). This observation supports an uptake mediated by glucose transporters (GLUTs) known to be overexpressed in cancer cells, indicating that the functionalization of glucose does not impair its recognition by GLUTs. Living HeLa cells incubated with 16 (R1 = H, R2 = C6H5) under the same conditions in a glucose-free medium were imaged using confocal fluorescence microscopy (Figure 13). The complex 16 was found to be excluded from the nucleus and colocalized with a mitotracker (Figure 14). They extended this

Figure 14. Laser-scanning confocal microscopy images of a HeLa cell upon incubation successively with MitoTracker Deep Red FM (100 nm, 20 min, exc. 633 nm) and 16 (R1 = H, R2 = C6H5) (100 mm, 5 min, exc. 405 nm) in a glucosefree medium at 37 8C. Adapted from reference [101]. Chem. Eur. J. 2014, 20, 1 – 18

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Figure 15. MCF7 cells. Luminescence images of 17 (left), TMRE (middle) and overlay with intensities along cross sections (right). Adapted from reference [104].

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Review derivatives,[107] quinolinetriazoles (quinta[20a, 108] and taquin[20a]), pyridyltriazoles (pyta[20g, 84, 100, 109] and tapy[20a]) and even N-heterocyclic carbenes.[110] Some will be described further below for their multimodal properties.

1) Luminescence spectroscopy is a technique widely used in biology, with ready-made analytic protocols ranging from immunofluorescence tests, cytochemistry, to organelle staining in imaging. Moreover access to microscopes with a large set of adequate filter-cubes and excitation sources is now easy. In addition, a large range of fluorophores are commercially available for organelle tracking or molecule tagging. 2) IR spectroscopy probes vibrational levels without changing the electronic state of a molecule, so that no photobleaching occurs. In addition, as energies involved are weaker than in fluorescent imaging requiring electronic state excitation, photo-damage is strongly reduced. The IR range is also suitable for tissue imaging, since the radiation penetrates deeper due to lower Rayleigh scattering. One additional advantage of IR spectroscopy resides in the absorption of a wavelength corresponding to the resonance of a specific chemical function. Label-free detection of endogenous biomolecules, characterized by a specific set of absorptions, is then possible using IR microspectroscopy. Since organelles accumulate specific biomolecules that can be identified by their spectral vibrational signature, IR spectroscopy can also be used to detect and locate organelles without the resort to any external marker.[4d,e] Moreover lots of efforts have been recently made to develop microfluidic devices and live-cell IR imaging is now available.[117]

4. Combining both vibrational and luminescence modalities for correlative bio-imaging Since no imaging technique exhibits the highest resolution and sensitivity, the deepest penetration, and the best time observation timescale, it is often compulsory to investigate a biological issue using different complementary set-ups. For that purpose, multimodal objects are required: after a unique incubation, the study of a whole organism, an organ, a tissue, or a cell using a range of techniques is possible. Multimodal imaging is indeed a growing field that deals with the correlation between independent techniques, enabling the collection of more complete and reliable data. Multimodal probes are thus needed for detection using different techniques. Being both luminescent and vibrational active, [Re(CO)3(L)X] + ,0 complexes could play that role and could be envisioned as bimodal units. For the last fifteen years, designing compounds with multimodal properties has become the high road towards correlative imaging.[111] The general strategy consists of combining fragments with complementary physicochemical properties, each being endowed with a single imaging modality. This approach is very successful for the design of molecular conjugates as bimodal radio/fluorescence[112] and magnetic resonance imaging (MRI)/fluorescence[113] probes. There are few examples of bimodal constructs with [Re(CO)3(L)X] + ,0 as a luminescent core, the other modality being radio-imaging[114] or magnetic resonance imaging (MRI).[115] Multimodal systems based on nanomaterials with a core-shell structure are also tremendously developed.[116] However, most of these multimodal constructs, such as monomolecular multimodal imaging agents (MOMIAs),[112c] end up with highly steric hindered derivatives, which is a major drawback, since the larger the probe, the more modified the properties of the tagged-molecule and the stronger the steric disturbance. Another issue is associated with probes consisting of the conjugation of several units with different modalities: indeed, in case of cleavage in vivo or in cells, the imaging using each modality will correspond to different molecules with possible different location. This has been shown to happen for instance with cleavage of units appended to nanoparticle surfaces and leaching of PET metals (64Cu) from multimodal fluorescence/radioimaging agents.[112a] To address these issues, our group has worked on the development of single core objects enabling multimodal detection based on a unique molecular unit. As described in the two previous sections, metal–carbonyl complexes are attractive moieties for both IR and luminescent bio-imaging. Hence, our strategy was to challenge the feasibility of correlative IR and luminescent mappings in a biological context through a metal–carbonyl core, taking advantage of both spectroscopic techniques. &

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Combining both vibrational and luminescence properties on the same molecular unit would provide a small non-disturbing tag detectable through complementary and biocompatible techniques. 4.1 Single core multimodal probe for imaging (SCoMPI) We have recently shown that a rhenium–tricarbonyl moiety [Re(CO)3Cl(L)] with L = 4-(2-pyridyl)-1,2,3-triazole (pyta, see Section 3.2.3) can be imaged inside cells with both spectroscopic techniques. We have coined the acronym SCoMPI—for single core multimodal probe for imaging—to describe these high valuable building blocks.[39b] A C12 side chain grafted to the triazole ring enhanced the cellular uptake of 18, the distribution of which inside breast cancer cell line MDA-MB231 was queried both with IR and luminescence techniques. As expected, IR carbonyl stretching bands, namely A1 and E bands, were detected in the transparency window of cells at 2025 and 1920 cm 1, respectively, after cell incubation with a solution of 18 in the micromolar range. They were recorded both on a population of cells deposited on a nitrocellulose membrane and at the single-cell level using synchrotron radiation FTIR spectromicroscopy (SR-FTIR SM) (Figure 16 A, traces c and d, respectively). The weak asymmetric stretching of the azide group at 2096 cm 1 was also detected in the two cases. Lumines12



Review phosphate being one of the IR signatures of the nucleus,[5a, 119] the merge of the IR mappings of the E band from 18 and phosphate asymmetric stretching at 1240 cm 1 (Figure 17 b: overlay of c and b) indicated a perinuclear distribution for 18. Exclusion from the nucleus was confirmed by confocal microscopy and colocalization studies showed 18 was co-localized with a Golgi apparatus tracker. This study underlined the feasibility of bimodal IR and luminescent imaging inside cells relying on a single metal–carbonyl unit. Figure 16. A) IR spectra in the cell transparency window: a) FTIR spectrum of a collection of control MDA-MB-231 cells deposited on a nitrocellulose membrane; b) FTIR spectrum of solid compound 18; c) FTIR spectrum of a collection of MDA-MB-231 cells incubated with 18 (25 mm, 1 h, about 41 000 cells) and deposited on a nitrocellulose membrane; d) SR-FTIR SM spectrum (recorded at the black cross in Figure 17g) on a single cell incubated with 18 (10 mm, 1 h). B) Emission spectra (exc. 350 nm): a) of a MDA-MB-231 single control cell, b) of a MDA-MB-231 single cell incubated with 18 (10 mm, 1 h), c) of a 6.10 5 m solution of 18 in water:ethanol 1:1. Spectra a) and b) recorded at the DISCO beamline, SOLEIL synchrotron (France). Adapted from reference [39b].

4.2 SCoMPIs to track molecules inside cells The next step was to prove that a SCoMPI could be grafted to a molecule to track it into cells. 3-Methoxy-17a-ethynylestradiol or mestranol (see below) is the estrogen component of some oral contraceptive formulations and a prodrug leading to the active metabolite, 17a-ethynyl estradiol. Since bulky substituents could be introduced at the 17a-position without modifying the binding affinity for estrogen receptors,[120] mestranol was tagged using click chemistry, coupling its terminal alkyne and an azide function on the SCoMPI 19 to give the SCoMPI–mestranol conjugate 20.[39c]

cence emission of 18 after excitation in the MLCT band was recorded by synchrotron radiation UV spectromicroscopy (SR-UVSM) and matched emission spectrum recorded in vitro (Figure 16 B, traces b and c respectively). This signal was not detected on control cells (Figure 16 B, trace a). Using the SMIS beamline at the SOLEIL synchrotron (France) combining luminescence and IR microscopes,[118] it was possible to correlate luminescence imaging and IR mappings on the same cell incubated with 18 (Figure 17). Both A1 and E bands mappings (Figure 17 c and d) corresponded to each other (Figure 17 g: overlay of c and d) and superimposed with the luminescence signal of 18 (Figure 17 e), proving the rhenium–carbonyl–pyta core kept its integrity inside cell and was reliable as a bimodal complex. A high concentration in amide and

This conjugate was mapped after incubation in two breast cancer cell lines using a correlative multimodal approach: 1) luminescence studies were performed with wide field and confocal microscopes, SR-UV-SM and 2) vibrational imaging with SRFTIR SM, synchrotron-based multiple beam FTIR,[35] confocal Raman and AFMIR spectromicroscopes. All the vibrational and luminescence mappings were consistent. For instance, Figure 18 shows the correlative study led on MCF-7 cells incubated with 20 for 1 h at 25 mm. The AFMIR signal for the E band of 20 (Figure 18b) matched the luminescence emission (Figure 18c, green area) and was excluded from the nucleus stained with DAPI (Figure 18c, blue area). Co-localization experiments demonstrated 20 was co-localized with the Golgi apparatus, which can be rationalized by the presence of GPR30, an estrogen receptor, described to be potentially distributed in Golgi apparatus and/or endoplasmic reticulum.[121] Very interestingly 20 shows an estrogenic activity close to that of mestranol, which indicates that the complex is able to interact with nuclear estrogen receptor. The cellular uptake of the unconjugated probe [(pyta-C3N3)Re(CO)3Cl] (19) was studied by fluorescence microscopy and SR-UV-SM and was almost insignificant, which suggests that the mestranol moiety is in-

Figure 17. MDA-MB-231 cell incubated with 18 (10 mm, 1 h). a) Bright field image (scale bar 10 mm). b)–d) SR-FTIR mappings, hot spots (pixel size: 3 3 mm2): b) phosphate asymmetric stretching (green), c) E-band (red), d) A1-band (cyan). e) Epifluorescence image, localization of 18 (green). f)– g) Overlays of SR-FTIR hot spots: f) overlay (yellow) of b (green) and c (red), g) overlay (white) of c (red) and d (cyan). The black cross on g) locates the d) trace in Figure 16. Chem. Eur. J. 2014, 20, 1 – 18

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Review longer the side chain, the greater the cellular uptake and thus the cytotoxicity. This work has underlined that IC50 values correspond to an apparent cytotoxicity that reflects both the intrinsic toxicity and the cellular uptake.

5. Summary and Outlook

Figure 18. MCF-7 breast cancer cell incubated with 20 (25 mm, 1 h). Scale bar: 10 mm. AFMIR imaging: a) topography of the cell recorded with the AFM (maximum of altitude 2.2 mm; cell outline drawn in gray), b) AFMIR mapping of the E-band of 20 (laser tuned at 1920 cm 1); fluorescence imaging: c) bright field image merged with nucleus staining (DAPI, blue) and luminescence signal of 20 (green).

In the context of bio-imaging, we have reviewed the great potential of metal–carbonyl complexes as both vibrational and luminescent probes. The strong IR absorptions due to CO stretching bands occur in the transparency window of the cell (2200–1800 cm 1), which is a real asset to detect unambiguously exogenous compounds among the complex IR absorption pattern of biological media. These specific bands have been used in diverse biological applications, such as Raman imaging, synchrotron radiation FTIR spectromicroscopy, surface-enhanced Raman spectroscopy (SERS), and near-field techniques (IR s-SNOM and AFMIR). IR imaging is still a fast growing field. It is a nondestructive method with the possibility to locate biomolecules without the need of labels and it enables to perform direct easy quantification.[81] The next frontiers to conquer in the near future are the improvement of the resolution, the shortening of the recording time, and the exploration of live-cell imaging. Techniques using multiple beams coupled with FPA are now emerging[35, 124] and enable fast recording, with easy access to large sampling and better statistics and make live-cell imaging possible. Indeed, microfluidic devices are now being designed[117] that make IR imaging in an aqueous environment possible. Very often in science, new tools and technical advances open up new avenues for research, new ideas, and unexpected findings: this is what can now be expected in the field of IR imaging. Metal–carbonyl complexes chelated by the adequate ligands are luminescent upon irradiation. Rhenium(I)–tricarbonyl cores, containing a-diimine or dipicolylamine-like ligands, are the most cited and studied moieties due to their ease of synthesis, small size, inertness, and their adequate photophysical properties (reduced photobleaching, large Stokes shift, long-life excited states). We have classified examples of luminescence imaging using Re(CO)3 unit by differentiating the way of its coupling. This diversity of anchoring points, allowing for the introduction of almost every kind of bio-active molecule, have really contributed to the advent of rhenium–tricarbonyl complexes as one of the part of the canon of luminescent imaging agents. Multimodality arising from a unique molecular core is very challenging and it offers correlation between diverse and complementary techniques. It solves issues associated with physicochemical disturbances unavoidable when conjugating a large hindered multi-unit probes and with the risk of cleavage in vivo. Metal–carbonyl complexes, being both luminescent and vibrational active with bio-compatible spectral characteristics, are the ideal candidates to perform bimodal bio-imaging.

volved in the uptake of 20. This uptake was also examined at 4 8C, a temperature that abolishes active transport mechanisms and at which only passive diffusion occurs and compared with uptake at 37 8C. Internalization of 20 was observed at 4 8C, but represented only about 10 % of the uptake at 37 8C. These results were compared with the uptake of the compound 19 that we previously described. This compound was shown to display a log Po/w of 7.3 (5.7 for 20) and an uptake at 4 8C, representing 54 % of the uptake at 37 8C. This indicates that 20 enters cells by active transport to a larger extent than 18, which does not bear the mestranol moiety, and suggests further that the penetration of 20 involves the mestranol moiety and its recognition. 4.3. Cellular uptake and cytotoxicity This bimodality can also be made valuable to better characterize the relationship between cellular uptake and cytotoxicity. The cytotoxicity is commonly estimated by IC50 values that evaluate the minimum incubation concentration of a molecule necessary to inhibit 50 % of cell growth. Hence, they carry information about both the intrinsic toxicity of the compound and its ability to be uptaken by the cells.[122] Generally speaking, luminescence cannot be directly implemented for intracellular quantification,[123] since the quantum yield is highly dependent on the environment.[25] In contrast, IR absorptions are weakly influenced by environmental effects and the IR signature of metal–carbonyl complexes is known to be appropriate for titration in biological media.[5a, 12] We designed a series of compounds based on the {(pyta)Re(CO)3Cl} moiety and differing in the length of an aliphatic side chain appended on the pyta ligand.[81] Thanks to an IR calibration curve, we were able to perform an easy quantification of the number of moles of M CO internalized per cell. In the particular case of these pyta complexes, we demonstrated that the value of lmax(emission) can be used as a reporter of their direct environment. Interestingly, in the cellular context, we showed that the {(pyta)Re(CO)3Cl} unit exhibits the same photophysical properties inside a cell, whatever the length of the side chain. Hence we could rely on the intracellular luminescence intensity to evaluate the cellular uptake of the derivatives: the same trend as in the IR study was obtained. The study showed that the &

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Review Keywords: bio-imaging · carbonyl · IR spectroscopy luminescence · rhenium

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Review

REVIEW & Bio-Imaging S. Clde, C. Policar* && – && Metal–Carbonyl Units for Vibrational and Luminescence Imaging: Towards Multimodality

Good vibrations: The use of metal– carbonyl moieties as probes for bio-imaging is a fast growing field of research.

In particular their use in IR and Raman cell imaging as well as their use in luminescent tagging is discussed.

Bio-Imaging In their Review article on page && ff. S. Clde and C. Policar discuss the potential and versatility of metal– carbonyl complexes as both vibrational and luminescent probes in the context of bio-imaging.

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Chem. Eur. J. 2014, 20, 1 – 18

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