Zinc Sensing with Pyridine-Based Lanthanide Contrast Agent: Structural Analysis in Aqueous Solution.

Zinc is an important physiological cation, and its misregulation is implicated in various diseases. It is therefore important to be able to image zinc by non-invasive methods such as Magnetic Resonance Imaging (MRI). In this work, we have successfully synthesized a novel Gd3+-based complex specifically for Zn2+ sensing by MRI.

A Bioinspired Cu-Responsive Magnetic Resonance Imaging Contrast Agent with Unprecedented Turn-On Response and Selectivity.

Imaging extracellular Cu in vivo is of paramount interest due to its biological importance in both physiological and pathological states. Magnetic resonance imaging (MRI) is a powerful technique to do so. However, the development of efficient MRI contrast agents selective for Cu, particularly versus the more abundant Zn ions, is highly challenging.

Investigation of Ln complexation by a DOTA derivative substituted by an imidazothiadiazole: synthesis, solution structure, luminescence and relaxation properties.

We investigated the coordination properties of original macrocyclic Ln complexes comprising an imidazothiadiazole heterocycle. The thermodynamic stability of the Gd complex was determined by a combination of potentiometric and photophysical measurements. The kinetic inertness was assessed in highly acidic media.

Lanthanide-Based Probes for Imaging Detection of Enzyme Activities by NIR Luminescence, T1- and ParaCEST MRI.

Applying a single molecular probe to monitor enzymatic activities in multiple, complementary imaging modalities is highly desirable to ascertain detection and to avoid the complexity associated with the use of agents of different chemical entities. We demonstrate here the versatility of lanthanide (Ln) complexes with respect to their optical and magnetic properties and their potential for enzymatic detection in NIR luminescence, CEST and T1 MR imaging, controlled by the nature of the Ln ion, while using a unique chelator. Based on X-ray structural, photophysical, and solution NMR investigations of a family of Ln DO3A-pyridine model complexes, we could rationalize the luminescence (Eu, Yb), CEST (Yb) and relaxation (Gd) properties and their variations between carbamate and amine derivatives.

Zinc-sensitive MRI contrast agents: importance of local probe accumulation in zinc-rich tissues.

We present the characterisation of a Gd-based contrast agent that responds to Zn upon interaction with Human Serum Albumin. We show that the contradictory behaviour is related to Gd-accumulation in Zn-rich tissues. This highlights the importance of the biodistribution of such contrast agents.

Gd Complexes for MRI Detection of Zn in the Presence of Human Serum Albumin: Structure-Activity Relationships.

Zn-responsive magnetic resonance imaging (MRI) contrast agents are typically composed of a Gd chelate conjugated to a Zn-binding moiety via a linker. They allow for Zn detection in the presence of human serum albumin (HSA). In order to decipher the key parameters that drive their Zn-dependent MRI response, we designed a pyridine-based ligand, , and compared the properties of to those of analogue complexes with varying Gd core, Zn-binding moiety, or linker sizes.

A phosphorylated zinc finger peptide bearing a gadolinium complex for zinc detection by MRI.

Two zinc finger peptides, namely ZFQD and ZFQE (Ln = Tb or Gd), with an appended Ln chelate and a phosphoserine able to coordinate the Ln ion are presented. The two peptides differ by the amino acid anchorage of the chelate, either aspartate (D) or glutamate (E). Both peptides are able to bind Zn and adopt the ββα fold.

Insights into the Responding Modes of Highly Potent Gadolinium-Based Magnetic Resonance Imaging Probes Sensitive to Zinc Ions.

Zn ions (Zn) play an important biological role in many diseases; hence, an imaging method for monitoring the Zn distribution in tissues could provide important clinical insights. Recently, we reported a potent Zn-sensitive probe based on the Gd-DO3A (DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylic acid), modified tyrosine. and di(2-picolyl)amine chelator for this metal cation, which generates an outstanding magnetic resonance imaging (MRI) response.

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 (Yb ) and generate its near-infrared (NIR) emission. When doxorubicin and amphiphilic Yb chelates are incorporated into liposomes, the sensitized emission of Yb is dependent on the integrity of the particles, which can be used to monitor drug release.

Lanthanide DO3A-Complexes Bearing Peptide Substrates: The Effect of Peptidic Side Chains on Metal Coordination and Relaxivity.

Two DO3A-type ligands conjugated to substrates of urokinase (L3) and caspase-3 (L4) via a propyl-amide linker were synthesized and their lanthanide(III) (Ln) complexes studied. A model compound without peptide substrate (L2) and an amine derivative ligand mimicking the state after enzymatic cleavage (L1) were also prepared. Proton Nuclear Magnetic Relaxation Dispersion (NMRD) profiles recorded on the gadolinium(III) (Gd) complexes, complemented with the assessment of hydration numbers via luminescence lifetime measurements on the Eu analogues, allowed us to characterize the lanthanide coordination sphere in the chelates.

Metal-based environment-sensitive MRI contrast agents.

Interactions of paramagnetic metal complexes with their biological environment can modulate their magnetic resonance imaging (MRI) contrast-enhancing properties in different ways, and this has been widely exploited to create responsive probes that can provide biochemical information. We survey progress in two rapidly growing areas: the MRI detection of biologically important metal ions, such as calcium, zinc, and copper, and the use of transition metal complexes as smart MRI agents. In both fields, new imaging technologies, which take advantage of other nuclei (F) and/or paramagnetic contact shift effects, emerge beyond classical, relaxation-based applications.

From Zn(II) to Cu(II) Detection by MRI Using Metal-Based Probes: Current Progress and Challenges.

Zinc and copper are essential cations involved in numerous biological processes, and variations in their concentrations can cause diseases such as neurodegenerative diseases, diabetes and cancers. Hence, detection and quantification of these cations are of utmost importance for the early diagnosis of disease. Magnetic resonance imaging (MRI) responsive contrast agents (mainly Lanthanide(+III) complexes), relying on a change in the state of the MRI active part upon interaction with the cation of interest, e.

Synthesis and In Vitro Studies of a Gd(DOTA)-Porphyrin Conjugate for Combined MRI and Photodynamic Treatment.

With the aim of developing new molecular theranostic agents, a π-extended Zn(II) porphyrin as photosensitizer for photodynamic therapy (PDT) linked to two GdDOTA-type complexes for magnetic resonance imaging (MRI) detection was synthesized. The relaxivity studies revealed a much higher relaxivity value per Gd ion for this medium sized molecule (19.32 mM s at 20 MHz and 298 K) compared to clinical contrast agents-a value which strongly increases in the presence of bovine serum albumin, reaching 25.

Aza-BODIPY Platform: Toward an Efficient Water-Soluble Bimodal Imaging Probe for MRI and Near-Infrared Fluorescence.

In this study, an original aza-BODIPY system comprising two Gd complexes has been designed and synthesized for magnetic resonance imaging/optical imaging applications, by functionalization of the boron center. This strategy enabled the obtainment of a positively charged bimodal probe, which displays an increased water solubility, optimized photophysical properties in the near-infrared region, and very promising relaxometric properties. The absorption and emission wavelengths are 705 and 741 nm, respectively, with a quantum yield of around 10% in aqueous media.

High-Field Detection of Biomarkers with Fast Field-Cycling MRI: The Example of Zinc Sensing.

Many smart magnetic resonance imaging (MRI) probes provide response to a biomarker based on modulation of their rotational correlation time. The magnitude of such MRI signal changes is highly dependent on the magnetic field and the response decreases dramatically at high fields (>2 T). To overcome the loss of efficiency of responsive probes at high field, with fast-field cycling magnetic resonance imaging (FFC-MRI) we exploit field-dependent information rather than the absolute difference in the relaxation rate measured in the absence and in the presence of the biomarker at a given imaging field.

A Porphyrin Dimer-GdDOTA Conjugate as a Theranostic Agent for One- and Two-Photon Photodynamic Therapy and MRI.

A molecular theranostic agent designed for photodynamic therapy (PDT) treatment in the near-infrared and for imaging tissue tumors with magnetic resonance imaging (MRI) is reported. It consists of a linear π-conjugated Zn(II) porphyrin dimer linked at each extremity to a GdDOTA-type complex. This agent has shown very promising potential for PDT applications with good singlet oxygen generation in DMSO and high linear absorption in the near-infrared (λ = 746 nm, ε ≈ 10 M cm).

MRI and luminescence detection of Zn with a lanthanide complex-zinc finger peptide conjugate.

A bioinspired probe based on a zinc finger peptide functionalized by a lanthanide(iii)-DOTA monoamide complex turns out to be active for both luminescence and MRI detection of Zn2+, depending on the lanthanide cation. A mechanism for MRI-based detection is proposed.

A cocktail of Er(iii) and Gd(iii) complexes for quantitative detection of zinc using SPECT and MRI.

We propose quantitative assessment of zinc by combining nuclear and MR imaging. We use a cocktail of a Gd3+-complex providing a Zn2+-dependent MRI response and its 165Er3+ analogue allowing for concentration assessment. 165Er is readily obtained in a cyclotron and purified, which is indispensable for successful quantification of metal ions.

Surface PEG Grafting Density Determines Magnetic Relaxation Properties of Gd-Loaded Porous Nanoparticles for MR Imaging Applications.

Surface PEGylation of nanoparticles designed for biomedical applications is a common and straightforward way to stabilize the materials for in vivo administration and to increase their circulation time. This strategy becomes less trivial when MRI active porous nanomaterials are concerned as their function relies on water/proton-exchange between the pores and bulk water. Here we present a comprehensive study on the effects of PEGylation on the relaxometric properties of nanozeolite LTL (dimensions of 20 × 40 nm) ion-exchanged with paramagnetic Gd ions.

Synthetic water soluble di-/tritopic molecular receptors exhibiting Ca/Mg exchange.

Structural integration of two synthetic water soluble receptors for Ca and Mg, namely 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and o-aminophenol-N,N,O-triacetic acid (APTRA), respectively, gave novel di- and tritopic ionophores (1 and 2). As Mg and Ca cannot be simultaneously complexed by the receptors, allosteric control of complexation results. Potentiometric measurements established stepwise protonation constants and showed high affinity for Ca (log K = 6.

Proton Exchange in a Paramagnetic Chemical Exchange Saturation Transfer Agent from Experimental Studies and ab Initio Metadynamics Simulation.

The proton-exchange process between water and a carbamate has been studied experimentally and theoretically in a lanthanide-based paramagnetic chemical exchange saturation transfer agent endowed with potential multimodality detection capabilities (optical imaging, or T MRI for the Gd(III) analogue). In addition to an in-depth structural analysis by a combined approach (using X-ray crystallography, NMR, and molecular dynamics), our ab initio simulation in aqueous solution sheds light on the reaction mechanism for this proton exchange, which involves structural Grotthuss diffusion.

Mechanostereoselective One-Pot Synthesis of Functionalized Head-to-Head Cyclodextrin [3]Rotaxanes and Their Application as Magnetic Resonance Imaging Contrast Agents.

A versatile, five-component, one-pot synthesis of cyclodextrin (CD) [3]rotaxanes using copper-catalyzed azide-alkyne cycloaddition has been developed. Head-to-head [3]rotaxanes of α-CD selectively functionalized by one or two gadolinium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid monoamide complexes were obtained mechanostereoselectively. The magnetic resonance imaging efficiency, expressed by the longitudinal proton relaxivity of the rotaxanes, was significantly improved as compared to the functionalized CD.

pH-Responsive Relaxometric Behaviour of Coordination Polymer Nanoparticles Made of a Stable Macrocyclic Gadolinium Chelate.

Lanthanide-containing nanoscale particles have been widely explored for various biomedical purposes, however, they are often prone to metal leaching. Here we have created a new coordination polymer (CP) by applying, for the first time, a stable Gd(III) chelate as building block in order to prevent any fortuitous release of free lanthanide(III) ion. The use of the Gd-DOTA-4AmP complex as a design element in the CP allows not only for enhanced relaxometric properties (maximum r1 =16.

Four Gadolinium(III) Complexes Appended to a Porphyrin: A Water-Soluble Molecular Theranostic Agent with Remarkable Relaxivity Suited for MRI Tracking of the Photosensitizer.

A molecular theranostic agent for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) consisting of four [GdDTTA](-) complexes (DTTA(4-) = diethylenetriamine-N,N,N″,N″-tetraacetate) linked to a meso-tetraphenylporphyrin core, as well as its yttrium(III) analogue, was synthesized. A variety of physicochemical methods were used to characterize the gadolinium(III) conjugate 1 both as an MRI contrast agent and as a photosensitizer. The proton relaxivity measured in H2O at 20 MHz and 25 °C, r1 = 43.