Enabling Visible Light Sensitization of YbIII, NdIII and ErIII in Dimeric LnIII/GaIII Metallacrowns through Functionalization with RuII Complexes for NIR-II Multiplex Imaging.

Multiplex imaging in the second near-infrared window (NIR-II, 1000-1700 nm) provides exciting opportunities for more precise understanding of biological processes and more accurate diagnosis of diseases by enabling real-time acquisition of images with improved contrast and spatial resolution in deeper tissues. Today, the number of imaging agents suitable for this modality remains very scarce. In this work, we have synthesized and fully characterized, including theoretical calculations, a series of dimeric LnIII/GaIII metallacrowns bearing RuII polypyridyl complexes, LnRu-3 (Ln = YIII, YbIII, NdIII, ErIII). Relaxed structures of YRu-3 in the ground and the excited electronic states have been calculated using dispersion-corrected density functional theory methods. Detailed photophysical studies of LnRu-3 have demonstrated that characteristic emission signals of YbIII, NdIII and ErIII in the NIR-II range can be sensitized upon excitation in the visible range through RuII-centered metal-to-ligand charge transfer (MLCT) states. We have also showed that these NIR-II signals are unambiguously detected in an imaging experiment using capillaries and biological tissue-mimicking phantoms. This work opens unprecedented perspectives for NIR-II multiplex imaging using LnIII-based molecular compounds.

Visible and near-infrared emitting heterotrimetallic lanthanide-aluminum-sodium 12-metallacrown-4 compounds: discrete monomers and dimers.

The luminescence properties of two types of heterotrimetallic aluminum-lanthanide-sodium 12-metallacrown-4 compounds are presented here, LnNa(ben)4[12-MCAl(III)N(shi)-4] (LnAl4Na) and {LnNa[12-MCAl(III)N(shi)-4]}2(iph)4 (Ln2Al8Na2), where Ln = GdIII, TbIII, ErIII, and YbIII, MC is metallacrown, ben- is benzoate, shi3- is salicylhydroximate, and iph2- is isophthalate. The aluminum-lanthanide-sodium metallacrowns formed with benzoate are discrete monomers while, upon replacement of the benzoate with the dicarboxylate isophthalate, two individual metallacrowns can be joined to form a dimer. In the solid state, the terbium version of each structure type displays emission in the visible region, and the erbium and ytterbium complexes emit in the near-infrared. The luminescence lifetimes (τobs) and quantum yields have been collected under ligand excitation (QLLn) for both LnAl4Na monomers and Ln2Al8Na2 dimers. Several of these values tend to be shorter (luminescence lifetimes) and smaller (quantum yields) than the corresponding values recorded for the structurally similar gallium-lanthanide monomer and dimer 12-MC-4 molecules. However, the quantum yield value recorded for the visible emitting Tb2Al8Na2 dimer, 43.9%, is the highest value observed in the solid state to date for a TbIII based metallacrown.

Doxorubicin-Sensitized Luminescence of NIR-Emitting Ytterbium Liposomes: Towards Direct Monitoring of Drug Release.

Drug-loaded liposomes are typical examples of nanomedicines. We show here that doxorubicin, the anti-cancer agent in the liposomal drug Doxil, can sensitize Ytterbium (Yb3+ ) and generate its near-infrared (NIR) emission. When doxorubicin and amphiphilic Yb3+ chelates are incorporated into liposomes, the sensitized emission of Yb3+ is dependent on the integrity of the particles, which can be used to monitor drug release. We also established the first demonstration that the NIR Yb3+ emission signal is observable in living mice following intratumoral injection of the Yb3+ -doxorubicin-liposomes, using a commercial macroscopic setup equipped with a NIR camera.

Using Native Chemical Ligation for Site-Specific Synthesis of Hetero-bis-lanthanide Peptide Conjugates: Application to Ratiometric Visible or Near-Infrared Detection of Zn2.

The interest in ratiometric luminescent probes that detect and quantify a specific analyte is growing. Owing to their special luminescence properties, lanthanide(III) cations offer attractive opportunities for the design of dual-color ratiometric probes. Here, the design principle of hetero-bis-lanthanide peptide conjugates by using native chemical ligation is described for perfect control of the localization of each lanthanide cation within the molecule. Two zinc-responsive probes, r-LZF1Tb|Cs124|Eu and r-LZF1Eu|Cs124|Tb are described on the basis of a zinc finger peptide and two DOTA (DOTA=1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetraacetic acid) complexes of terbium and europium. Both display dual-color ratiometric emission in response to the presence of Zn2+ . By using a screening approach, anthracene was identified for the sensitization of the luminescence of two near-infrared-emitting lanthanides, Yb3+ and Nd3+ . Thus, two novel zinc-responsive hetero-bis-lanthanide probes, r-LZF3Yb|Anthra|Nd and r-LZF3Nd|Anthra|Yb were assembled, the former offering a neat ratiometric response to Zn2+ with emission in the near-infrared around 1000 nm, which is unprecedented.

Toward MRI and Optical Detection of Zwitterionic Neurotransmitters: Near-Infrared Luminescent and Magnetic Properties of Macrocyclic Lanthanide(III) Complexes Appended with a Crown Ether and a Benzophenone Chromophore.

Thanks to their versatile magnetic and luminescence features, lanthanide complexes have gained a central position in biomedical imaging as magnetic resonance imaging (MRI) contrast agents and optical imaging probes. In addition, appropriate chemical design allows modification of the magnetic relaxation properties of GdIII complexes and the optical properties of visible- or near-infrared (NIR)-emitting lanthanide chelates upon interaction with various biomarkers, which makes them ideal candidates for the creation of responsive agents. In this Forum Article, we demonstrate such design principles as well as the difficulties encountered in the context of neurotransmitter (NT) detection. Lanthanide(III) complexes of a macrocyclic ligand incorporating a benzophenone chromophore and a monoazacrown ether (LnL3) have been synthesized as responsive probes to monitor amino acid NTs either in MRI (Ln = Gd) or in NIR optical detection (Ln = Nd or Yb). The parameters characterizing the water exchange and rotational dynamics of the gadolinium(III) complex were assessed by 17O NMR and 1H NMRD. In the presence of zwitterionic NTs, the inner-sphere water molecule is replaced by the carboxylate function of the NTs in the gadolinium(III) complex, leading to a decrease of the longitudinal relaxivity from 6.7 to 2-2.5 mM-1 s-1 (300 MHz and 37 °C). The apparent affinity constants range from Ka = 35 for γ-aminobutyric acid (GABA) to 80 M-1 for glycine and glutamate, and there is no selectivity with respect to hydrogen carbonate (Ka = 232; pH 7.4). The gadolinium(III) complex interacts with human serum albumin (HSA), resulting in a 60% increase in the relaxivity (20 MHz, 37 °C) in the absence of NTs. The HSA-bound complex, however, was revealed to be less responsive to NTs because of displacement of the GdIII-bound water by HSA, which was confirmed by the hydration number calculated from luminescence lifetimes of the HSA-bound europium(III) complex. The creation of an imaging agent suitable for NIR detection of NTs for an enhanced sensitivity in biological systems using the benzophenone (BP) moiety as the sensitizer of lanthanide luminescence was also attempted. Upon excitation at 300 nm of the BP chromophore in aqueous solutions of NdL3 and YbL3, characteristic NIR emissions of NdIII and YbIII were observed because of 4F3/2 → 4IJ (J = 9/2-13/2) and 2F5/2 → 2F7/2 transitions, respectively, indicating that this chromophore is a suitable antenna. Despite these promising results, luminescence titrations of NdIII and YbIII complexes with NTs were not conclusive because of chemical conversion of the ligand triggered by light, preventing quantitative analysis. The observed photochemical reaction of the ligand is strongly dependent on the nature of the lanthanide chelated; it is considerably slowed down in the presence of NdIII and EuIII.

A new metallostar complex based on an aluminum(III) 8-hydroxyquinoline core as a potential bimodal contrast agent.

A ditopic DTPA monoamide derivative containing an 8-hydroxyquinoline moiety was synthesized and the corresponding gadolinium(III) complex ([Gd(H5)(H(2)O)](-)) was prepared. After adding aluminum(III), the 8-hydroxyquinoline part self-assembled into a heteropolymetallic triscomplex [(Gd5)(3)Al(H(2)O)(3)](3-). The magnetic and optical properties of this metallostar compound were investigated in order to classify it as a potential in vitro bimodal contrast agent. The proton nuclear magnetic relaxation dispersion measurements indicated that the relaxivity r(1) of [Gd(H5)(H(2)O)](-) and [(Gd5)(3)Al(H(2)O)(3)](3-) at 20 MHz and 310 K equaled 6.17 s(-1) mM(-1) and 10.9 s(-1) mM(-1) per Gd(III) ion respectively. This corresponds to a relaxivity value of 32.7 s(-1) mM(-1) for the supramolecular complex containing three Gd(III) ions. The high relaxivity value is prominently caused by an increase of the rotational tumbling time τ(R) by a factor of 2.7 and 5.5 respectively, in comparison with the commercially used MRI contrast agent Gd(III)-DTPA (Magnevist®). Furthermore, upon UV irradiation, [(Gd5)(3)Al(H(2)O)(3)](3-) exposes green broad-band emission with a maximum at 543 nm. Regarding the high relaxivity and the photophysical properties of the [(Gd5)(3)Al(H(2)O)(3)](3-) metallostar compound, it can be considered as a lead compound for in vitro bimodal applications.

A tripodal ruthenium-gadolinium metallostar as a potential α(v)ß(3) integrin specific bimodal imaging contrast agent.

Gd(III)-containing metallostar contrast agents are gaining increased attention, because their architecture allows for a slower tumbling rate, which, in turn, results in larger relaxivities. So far, these metallostars find possible applications as blood pool contrast agents. In this work, the first example of a tissue-selective metallostar contrast agent is described. This RGD-peptide decorated Ru(II)(Gd(III))(3)metallostar is synthesized as an α(v)ß(3)-integrin specific contrast agent, with possible applications in the detection of atherosclerotic plaques and tumor angiogenesis. The contrast agent showed a relaxivity of 9.65 s(-1) mM(-1), which represents an increase of 170%, compared to a low-molecular-weight analogue, because of a decreased tumbling rate (τ(R) = 470 ps). The presence of the MLCT band (absorption 375-500 nm, emission 525-850 nm) of the central Ru(II)(Ph-Phen)(3)-based complex grants the metallostar attractive luminescent properties. The (3)MLCT emission is characterized by a quantum yield of 4.69% and a lifetime of 804 ns, which makes it an interesting candidate for time-gated luminescence imaging. The potential application as a selective MRI contrast agent for α(v)ß(3)-integrin expressing tissues is shown by an in vitro relaxometric analysis, as well as an in vitroT(1)-weighted MR image.

Eu(III) complexes of tetradentate ligands related to 2,9-di(pyrid-2'-yl)-1,10-phenanthroline and 2,2'-bi-1,10-phenanthroline.

A series of six tetradentate polypyridine-type ligands (L) have been used to prepare the corresponding Eu(III) complexes [Eu(L)(2)(S)](n+) (n = 2, 3) where S = H(2)O or CF(3)SO(3)(-). Two of the ligands, 2,9-di(pyrid-2'-yl)-1,10-phenanthroline (4) and its dipyridophenazine analogue (6) are symmetrical around a central phenanthroline ring. The other four ligands are 2,2'-bi-1,10-phenanthroline and its 3,3'-di-, tri-, and tetramethylene-bridged analogues (5a-d) whose conformations are governed by the length of the polymethylene bridge. (1)H NMR and X-ray analysis indicate that all of the complexes have a C(2v) symmetry. The biphenanthroline series shows a strong correlation of the conjugation between the two halves of the ligand, as governed by the bridge, with the absorption and emission properties of the Eu(III) complex. The complex having the most distorted, tetramethylene-bridged ligand exhibits a weak, high energy pi-pi* absorption and low sensitization efficiency. The luminescence decays are monoexponential for complexes of 4 and either monoexponential or biexponential for the complexes of 5 depending on its solution concentration and the length of the bridge. The complexes of 4 exhibit much longer lifetime, higher overall quantum yield, and higher sensitization efficiency than complexes of 5 while the complex of 6 emits very weakly. The Eu((5)D(0)) lifetime for [Eu(4)(2)(H(2)O)](ClO(4))(3) is shorter than for [Eu(4)(2)(CF(3)SO(3))](CF(3)SO(3))(2), reflecting the effect of the coordinated water. The complexes are examined for stability in the presence of water and found to retain most of their luminescent properties even in the presence of a large excess of water.