Fluorescent Probes for Disease Diagnosis.

The identification and detection of disease-related biomarkers is essential for early clinical diagnosis, evaluating disease progression, and for the development of therapeutics. Possessing the advantages of high sensitivity and selectivity, fluorescent probes have become effective tools for monitoring disease-related active molecules at the cellular level and in vivo. In this review, we describe current fluorescent probes designed for the detection and quantification of key bioactive molecules associated with common diseases, such as organ damage, inflammation, cancers, cardiovascular diseases, and brain disorders. We emphasize the strategies behind the design of fluorescent probes capable of disease biomarker detection and diagnosis and cover some aspects of combined diagnostic/therapeutic strategies based on regulating disease-related molecules. This review concludes with a discussion of the challenges and outlook for fluorescent probes, highlighting future avenues of research that should enable these probes to achieve accurate detection and identification of disease-related biomarkers for biomedical research and clinical applications.

Ligand Chirality Transfer from Solution State to the Crystalline Self-Assemblies in Circularly Polarized Luminescence (CPL) Active Lanthanide Systems.

The synthesis of a family of chiral and enantiomerically pure pyridyl-diamide (pda) ligands that upon complexation with europium [Eu(CF3SO3)3] result in chiral complexes with metal centered luminescence is reported; the sets of enantiomers giving rise to both circular dichroism (CD) and circularly polarized luminescence (CPL) signatures. The solid-state structures of these chiral metallosupramolecular systems are determined using X-ray diffraction showing that the ligand chirality is transferred from solution to the solid state. This optically favorable helical packing arrangement is confirmed by recording the CPL spectra from the crystalline assembly by using steady state and enantioselective differential chiral contrast (EDCC) CPL Laser Scanning Confocal Microscopy (CPL-LSCM) where the two enantiomers can be clearly distinguished.

Formation of lanthanide luminescent di-metallic helicates in solution using a bis-tridentate (1,2,3-triazol-4-yl)-picolinamide (tzpa) ligand.

The chiral bis-tridentate (1,2,3-triazol-4-yl)-picolinamide (tzpa) ligand 1 was used in the formation of lanthanide di- and triple stranded di-metallic helicates in acetonitrile solution, where the changes in the ground and the Tb(III) excited state properties were used to monitor the formation of these supramolecular structures in situ under kinetic control.

Fluorescent 4-amino-1,8-naphthalimide Tröger's bases (TBNaps) possessing (orthogonal) 'α-amino acids', esters and di-peptides and their solvent dependent photophysical properties.

The synthesis of fifteen luminescent bis-naphthalimide based Tröger's bases (TBNaps) derived from 4-amino-1,8-naphthalimide (4-Amino-Nap) precursors is described; these scaffolds possess α-amino acids, esters or di-peptides conjugated at the imide site and show minor fluorescence in aqueous solution while being highly emissive in organic solvents. The investigation shows that these TBNaps possessing ICT excited state properties are capable of generating either positive or negative solvatochromic effects in response to changes in polarity and/or the hydrogen bonding capabilities of the medium.

Fluorescent supramolecular hierarchical self-assemblies from glycosylated 4-amino- and 4-bromo-1,8-naphthalimides.

An investigation into the self-assembly of two 4-amino- and a 4-bromo-1,8-naphthalimide (Nap) based structures (1-3) possessing an appended glycan unit, from protic polar media, is presented. The results demonstrate the formation of complex hierarchical luminescent aggregates, wherein the morphologies, sizes and spherical structures were highly dependent on both the media and the Nap structure. Upon cleaving the native glycosidic bond, using an enzyme, the structure/morphology of the self-assembly of 3 in buffered solution was significantly transformed.

Aggregation induced emission (AIE) active 4-amino-1,8-naphthalimide-Tröger's base for the selective sensing of chemical explosives in competitive aqueous media.

The 4-amino-1,8-naphthalimide-Tröger's base fluorophore, TBNap-TPy, adorned with phenyl-terpyridine moiety was synthesised and assessed for its aggregation-induced emission (AIE) behaviour. TBNap-TPy was further employed as a fluorescent sensor for the discriminative sensing of π-electron-deficient nitroaromatic; the TBNap-TPy displaying the largest fluorescence quenching with high selectivity for picric acid, a harmful environmental pollutant widely used in the dye industries.

Luminescent lanthanide (Eu(iii)) cross-linked supramolecular metallo co-polymeric hydrogels: the effect of ligand symmetry.

Two lanthanide luminescent naphthyl-dipicolinic amide (dpa) methacrylate monomers for the synthesis of grafted supramolecular co-polymer gels (hydrogels), and their use as additional crosslinks in robust covalently cross-linked HEMA hydrogels is presented; the results demonstrate the importance of the ligand symmetry for the Eu(iii) emission from the hydrogels.

Recent advances in the development of luminescent lanthanide-based supramolecular polymers and soft materials.

Combination of different properties has always proven effective in the generation of hybrid materials with novel interesting properties. Ln(iii) containing materials possessing multiple properties are useful in a wide range of applications. In this article, key and recent examples of metallo-supramolecular polymers in the formation of gels, soft polymeric materials and films are discussed. There is a focus on the use of trivalent lanthanide, Ln(iii), ions to provide soft materials with advanced mechanical and luminescence properties for applications in developing electronic- and bio-technologies. This frontier article has been written with the intention of reaching a broad range of readers from various backgrounds such as chemistry, materials chemistry, spectroscopy and biochemistry. Additionally, we evaluate how the unique and versatile properties of such hybrid materials can be tuned and explored to enhance the efficiency, as well as research, for new ones. Finally, an assessment of the current state-of-the-art and our outlook for the future of this field is made.

The effect of the linker size in C2-symmetrical chiral ligands on the self-assembly formation of luminescent triple-stranded di-metallic Eu(iii) helicates in solution.

Chiral lanthanide-based supramolecular structures have gained significant importance in view of their application in imaging, sensing and other functional purposes. We have designed chiral C2-symmetrical ligands (L) based on the use of two 2,6-pyridine-dicarboxylic-amide moieties (pda), that differ from one another by the nature of the diamine spacer groups (from 1,3-phenylenedimethanamine (1(S,S), 2(R,R)) and benzene-1,3-diamine (3(S,S), 4(R,R)) to much bulkier 4,4'-(cyclohexane-1,1-diyl)bis(2,6-dimethylaniline) (5(S,S), 6(R,R))) between these two pda units. The self-assembly between L and Eu(iii) ions were investigated in CH3CN solution at low concentration whereby the changes in the absorbance, fluorescence and Eu(iii)-centred emission spectra allowed us to model the binding equilibria occurring in the solution to the presence of [Eu:L2], [Eu2:L2], [Eu2:L3] assemblies and reveal their high binding constant values. The self-assembly in solution were also studied at higher concentration by following the changes in the 1H NMR spectra of the ligands upon Eu(iii) addition, as well as by using MALDI-MS of the isolated solid state complexes. The chiroptical properties of the ligands were used in order to study the structural changes upon self-assembly between the ligands and Eu(iii) ions using circular dichroism (CD) and circularly polarised luminescence (CPL) spectroscopies. The photophysical properties of [Eu2:L3] complexes were evaluated in solution and showed a decrease of luminescence quantum yield when going from the ligand with smaller (1(S,S)) to bulkier (5(S,S)) linker from ∼5.8% to ∼2.6%. While mass-spectrometry revealed the possible formation of trinucler assemblies such as [Eu3:L3] and [Eu3:L2].

Surface-Modified Gold Nanoparticles Possessing Two-Channel Responsive EuIII /TbIII Cyclen Complexes as Luminescent Logic Gate Mimics.

The development of material-supported molecular logic gate mimics (MGLMs) for contained application and device fabrication has become of increasing interest. Herein, we present the formation of ≈5 nm gold nanoparticles (AuNPs) that have been surface-modified (via a thiol linkage) with heptadentate cyclen-based complexes of europium and terbium for sensing applications using delayed lanthanide luminescence and as integrated logic gate mimics within competitive media.

White-light emission from discrete heterometallic lanthanide-directed self-assembled complexes in solution.

White-light-emitting materials have attracted significant interest in recent years due to their potential applications in solid-state lighting and flat-panel displays. Design of such materials is challenging and often relies on the use of multiple fluorophores despite the fact that single component systems yield materials with enhanced stability and reproducibility. Herein, we have developed a white-light-emitting system based on the formation of discrete lanthanide-based self-assembled complexes using a newly-designed ligand. We demonstrate that fine tuning of the lanthanide ions molar ratio in the self-assemblies combined with the intrinsic blue fluorescence of the ligand allows for the successful emission of pure white light with CIE coordinates of (0.33, 0.34).

Exploring the Effect of Ligand Structural Isomerism in Langmuir-Blodgett Films of Chiral Luminescent Eu(III) Self-Assemblies.

Here we have investigated the influence of the antenna group position on both the formation of chiral amphiphilic Eu(III) -based self-assemblies in CH3 CN solution and, on the ability to form monolayers on the surface of quartz substrates using the Langmuir-Blodgett technique, by changing from the 1-naphthyl (2(R), 2(S)) to the 2-naphthyl (1(R), 1(S)) position. The evaluation of binding constants of the self- assemblies in CH3 CN solution was achieved using conventional techniques such as UV/Visible and luminescence spectroscopies along with more specific circular dichroism (CD) spectroscopy. The binding constants obtained for EuL, EuL2 and EuL3 species in the case of 2-naphthyl derivatives were comparable to those obtained for 1-naphthyl derivatives. The analysis of the changes in the CD spectra of 1(R) and 1(S) upon addition of Eu(III) not only allowed us to evaluate the values of the binding constants but the resulting recalculated spectra may also be used as fingerprints for assignment of the chiral self-assembly species formed in solution. The obtained monolayers were predominantly formed from EuL3 (≈85 %) with the minor species present in ≈15 % EuL2 .

Cross-Linking the Fibers of Supramolecular Gels Formed from a Tripodal Terpyridine Derived Ligand with d-Block Metal Ions.

The tripodal terpyridine ligand, L, forms 1D helical supramolecular polymers/gels in H2O-CH3OH solution mediated through hydrogen bonding and π-π interactions. These gels further cross-link into 3D supramolecular metallogels with a range of metal ions (M) such as Fe(II), Ni(II), Cu(II), Zn(II), and Ru(III); the cross-linking resulting in the formation of colored or colorless gels. The fibrous morphology of these gels was confirmed using scanning electron microscopy (SEM); while the self-assembly processes between L and M were investigated by absorbance and emission spectroscopy from which their binding constants were determined by using a nonlinear regression analysis.

Healable luminescent self-assembly supramolecular metallogels possessing lanthanide (Eu/Tb) dependent rheological and morphological properties.

Herein we present the use of lanthanide directed self-assembly formation (Ln(III) = Eu(III), Tb(III)) in the generation of luminescent supramolecular polymers, that when swelled with methanol give rise to self-healing supramolecular gels. These were analyzed by using luminescent and (1)H NMR titrations studies, allowing for the identification of the various species involved in the subsequent Ln(III)-gel formation. These highly luminescent gels could be mixed to give a variety of luminescent colors depending on their Eu(III):Tb(III) stoichiometric ratios. Imaging and rheological studies showed that these gels prepared using only Eu(III) or only Tb(III) have different morphological and rheological properties, that are also different from those determined upon forming gels by mixing of Eu(III) and Tb(III) gels. Hence, our results demonstrate for the first time the crucial role the lanthanide ions play in the supramolecular polymerization process, which is in principle a host-guest interaction, and consequently in the self-healing properties of the corresponding gels, which are dictated by the same host-guest interactions.

The application of chiroptical spectroscopy (circular dichroism) in quantifying binding events in lanthanide directed synthesis of chiral luminescent self-assembly structures.

The binding of asymmetrical and optically pure tridentate ligands (L = 1(S) and 1(R)) containing one carboxylic group and 2-naphthyl as an antenna to lanthanide ions (M = La(iii) and Eu(iii)) was studied in CH3CN, showing the successive formation of M:L, M:L2 and M:L3 stoichiometric species in solution. The europium complexes EuL3 were also synthesised, structurally characterised and their photophysical properties probed in CH3OH and CH3CN. The changes in the chiroptical properties of both 1(S) and 1(R) were used (by circular dichroism (CD) spectroscopy) to monitor the formation of these chiral self-assemblies in solution. While circularly polarised luminescence (CPL) showed the formation of Eu(1(S))3 and Eu(1(R))3 as enantiomers, with high luminescence dissymmetry factors (glum), fitting the CD changes allowed for binding constants to be determined that were comparable to those seen in the analyses of absorbance and luminescence changes.

Synthesis, structural, photophysical and electrochemical studies of various d-metal complexes of btp [2,6-bis(1,2,3-triazol-4-yl)pyridine] ligands that give rise to the formation of metallo-supramolecular gels.

2,6-Bis(1,2,3-triazol-4-yl)pyridine (btp) is a terdentate binding motif that is synthesised modularly via the CuAAC reaction. Herein, we present the synthesis of ligands 1 and 2 and the investigation of the coordination chemistry, photophysical behaviour and electrochemistry of complexes of these with a number of d-metal ions (e.g. Ru(II), Ir(III), Ni(II) and Pt(II)). The X-ray crystal structures of ligand 1 and the complexes [Ru·2(2)](PF6)Cl, [Ni·1(2)](PF6)Cl and [Ir·1Cl3] are also presented. All of the complexes displayed non-classical triazolyl C-H···Cl(-) hydrogen bonding. All but one complex showed no metal-based luminescence at room temperature, while all of the Pt(ii) complexes displayed luminescence at 77 K. The electrochemistry of the Ru(II) complexes was also studied and these complexes were found to have higher oxidation potentials than analogous compounds. The redox behaviour of [RuL2](2+) complexes with both 1 and 2 was nearly identical, while [Ru·1Cl2(DMSO)] was oxidised at significantly lower potential. We also show that the Ru(II) complex of 2, [Ru·2(2)](PF6)Cl, gave rise to the formation of a metallo-supramolecular gel, the morphology of which was studied using scanning electron and helium ion microscopy.

Lanthanide-functionalized nanoparticles as MRI and luminescent probes for sensing and/or imaging applications.

The combination of lanthanides and nanoparticles to develop new hybrid nanomaterials has become a highly topical area of research in the field of sensing, biomedical imaging, drug delivery, etc. However, these novel nanomaterials have to be carefully designed to ensure that the unique properties conveyed by each component, i.e., lanthanide ions and nanoparticles, are maximized and not negatively affected by one another. In this Forum Article, the main advances in the design of lanthanide-based nanoparticles will be discussed, with the first part focusing on the design of gadolinium(III)-based nanoparticles and their use as magnetic resonance imaging agents. The second part will then describe the main and most recent designs of luminescent lanthanide-based nanoparticles and their applications as sensors or imaging agents, with a special emphasis on our contribution to this area.

Probing the effects of ligand isomerism in chiral luminescent lanthanide supramolecular self-assemblies: a europium "Trinity Sliotar" study.

"Trinity Sliotar" family: Chiral ligands containing pyridyl and naphthalene moieties were synthesized and characterized. These ligands were successfully used for the synthesis of Eu(III) bundles where chirality of the ligand is successfully transferred onto the lanthanide centre resulting in circularly polarized red luminescence.

Chemical nano-gardens: growth of salt nanowires from supramolecular self-assembly gels.

In this article, we examine the phenomenon of single-crystal halide salt wire growth at the surface of porous materials. We report the use of a single-step casting technique with a supramolecular self-assembly gel matrix that upon drying leads to the growth of single-crystal halide (e.g., NaCl, KCl, and KI) nanowires with diameters ~130-200 nm. We demonstrate their formation using electron microscopy and electron-dispersive X-ray spectroscopy, showing that the supramolecular gel stabilizes the growth of these wires by facilitating a diffusion-driven base growth mechanism. Critically, we show that standard non-supramolecular gels are unable to facilitate nanowire growth. We further show that these nanowires can be grown by seeding, forming nanocrystal gardens. This study helps understand the possible prefunctionalization of membranes to stimulate ion-specific filters or salt efflorescence suppressors, while also providing a novel route to nanomaterial growth.

New trick for an old ligand! The sensing of Zn(II) using a lanthanide based ternary Yb(III)-cyclen-8-hydroxyquinoline system as a dual emissive probe for displacement assay.

A novel near-infrared (NIR) emissive lanthanide-based zinc sensor was designed, based on the self-assembly in aqueous solution between the nonemissive coordinatively unsaturated Yb(III) cyclen complex 2·Yb and the sulfonated 8-hydroxyquinoline (8-HQS) chromophore, which was employed as a sensitizing antenna. The resulting ternary complex, 2·Yb·8-HQS, displayed metal-centered emission in the NIR range upon excitation of the antenna with high quantum yield of Q = 0.23 ± 0.03% in pH 7.4 buffered aqueous solution; demonstrating efficient sensitization from 8-HQS. The addition of zinc led to quenching of the NIR emission as a result of the dissociation of the luminescent ternary 2·Yb·8-HQS complex, where the 8-HQS antenna was displaced from the Yb(III) center in favor of the formation of more stable chelates with Zn(II). These newly formed Zn(II) complexes were shown to exhibit strong green fluorescence; allowing for the simultaneous sensing of Zn(II) both within the visible and the NIR regions at physiological pH in competitive media. Furthermore, 2·Yb·8-HQS was shown to be able to detect Zn(II) with good selectivity and in a reversible manner, even in the presence of competitive group (I) and (II) metal ions as well as in the presence of several biologically important d-metal ions.