# Centre de Biophysique Moléculaire - UPR 4301

## Bonnet Célia

Chargée de recherche

Groupe thématique : Complexes métalliques et IRM

### Publications

2017   Références trouvées : 4

Zhang, W., Martinelli, J., Peters, J. A., van Hengst, J. M. A., Bouwmeester, H., Kramer, E., Bonnet, C. S., Szeremeta, F., Tóth, É. and Djanashvili, K.  (2017)

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

ACS Applied Materials & Interfaces (2017) 9 (28) 23458-23465

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 GdIII ions. We evidence that as long as the surface grafting density of the PEG chains does not exceed the “mushroom” regime (conjugation of up to 6.2 wt % of PEG), Gd-LTL retains a remarkable longitudinal relaxivity (38 s–1 mM–1 at 7 T and 25 °C) as well as the pH-dependence of the longitudinal and transverse relaxation times. At higher PEG content, the more compact PEG layer (brush regime) limits proton/water diffusion and exchange between the interior of LTL and the bulk, with detrimental consequences on relaxivity. Furthermore, PEGylation of Gd-LTL dramatically decreases the leakage of toxic GdIII ions in biological media and in the presence of competing anions, which together with minimal cytotoxicity renders these materials promising probes for MRI applications.

Pollet, R., Bonnet, C.S., Retailleau, P., Durand, P. and Tóth, E.  (2017)

### Proton-exchange in a paramagnetic chemical exchange saturation transfer agent from experimental studies and ab initio metadynamicssimulation

Inorganic Chemistry (2017) 56, 4317-4323

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 $T_1$ 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 $\it ab initio$ simulation in aqueous solution sheds light on the reaction mechanism for this proton exchange, which involves structural Grotthuss diffusion.

Lavie-Cambot, A., Tron, A., Ducrot, A., Castet, F., Kauffmann, B., Beauté, L., Allouchi, H., Pozzo, J.-L., Bonnet, C. S. and McClenaghan, N. D.  (2017)

### Synthetic water soluble di-/tritopic molecular receptors exhibiting Ca2+/Mg2+ exchange

Organic and Biomolecular Chemistry (2017) 15 (20) 4367-4374

Structural integration of two synthetic water soluble receptors for Ca2+ and Mg2+, 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 Mg2+ and Ca2+ cannot be simultaneously complexed by the receptors, allosteric control of complexation results. Potentiometric measurements established stepwise protonation constants and showed high affinity for Ca2+ (log K = 6.08 and 8.70 for 1 and 2, respectively) and an excellent selectivity over Mg2+ (log K = 3.70 and 5.60 for 1 and 2, respectively), which is compatible with magnesium–calcium ion exchange. While ion-exchange of a single Mg2+ for a single Ca2+ is possible in both 1 and 2, the simultaneous binding of two Mg2+ by 2 appears prohibitive for replacement of these two ions by a single Ca2+. Ion-binding and exchange was further rationalized by DFT calculations.

Fredy, J. W., Scelle, J., Ramniceanu, G., Doan, B.-T., Bonnet, C. S., Tóth, É., Ménand, M., Sollogoub, M., Vives, G. and Hasenknopf, B.  (2017)

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

Organic Letters (2017) 19 (5) 1136-1139

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. In vitro and in vivo preclinical studies showed a higher contrast and retention in the kidney than gadolinium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex, demonstrating the potential of these rotaxanes as MRI contrast agent.

2016   Références trouvées : 5

Schmitt J., Heitz V., Sour A., Bolze F., Kessler P., Flamigni L., Ventura B., Bonnet C. S. and Toth E.  (2016)

### A Theranostic Agent Combining a Two-Photon-Absorbing Photosensitizer for Photodynamic Therapy and a Gadolinium(III) Complex for MRI Detection

Chemistry - A European Journal (2016) 22 (8) 2775-2786 - doi : 10.1002/chem.201503433

The convergent synthesis and characterization of a potential theranostic agent, [DPP-ZnP-GdDOTA](-) , which combines a diketopyrrolopyrrole-porphyrin component DPP-ZnP as a two-photon photosensitizer for photodynamic therapy (PDT) with a gadolinium(III) DOTA complex as a magnetic resonance imaging probe, is presented. [DPP-ZnP-GdDOTA](-) has a remarkably high longitudinal water proton relaxivity (19.94 mm(-1) s(-1) at 20 MHz and 25 degrees C) for a monohydrated molecular system of this size. The Nuclear Magnetic Relaxation Dispersion (NMRD) profile is characteristic of slow rotation, related to the extended and rigid aromatic units integrated in the molecule and to self-aggregation occurring in aqueous solution. The two-photon properties were examined and large two-photon absorption cross-sections around 1000 GM were determined between 910 and 940 nm in DCM with 1 % pyridine and in DMSO. Furthermore, the new conjugate was able to generate singlet oxygen, with quantum yield of 0.42 and 0.68 in DCM with 1 % pyridine and DMSO, respectively. Cellular studies were also performed. The [DPP-ZnP-GdDOTA](-) conjugate demonstrated low dark toxicity and was able to induce high one-photon and moderate two-photon phototoxicity on cancer cells.

Aríñez-Soriano J., Albalad J., Carné-Sánchez A., Bonnet C. S., Busqué F., Lorenzo J., Juanhuixe J., Terban M. W., Imaz I., Tóth É. and Maspoch D.  (2016)

### pH-responsive relaxometric behaviour of coordination polymer nanoparticles made of a stable macrocyclic gadolinium macrocyclic chelate

Chemistry - A European Journal (2016) 22 (37) 13162-13170 - doi : 10.1002/chem.201602356

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 =16.4 mm(-1) s(-1) at 10 MHz), but also for a pH responsiveness (Δr1 =108 % between pH 4 and 6.5), beyond the values obtained for the low molecular weight Gd-DOTA-4AmP itself. The CP can be miniaturised to the nanoscale to form colloids that are stable in physiological saline solution and in cell culture media and does not show cytotoxicity.

Sour A., Jenni S., Ortí-Suárez A., Schmitt J., Heitz V., Bolze F., Loureiro de Sousa P., Po C., Bonnet C. S., Pallier Agnè, Tóth É., Ventura B.  (2016)

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

Inorganic Chemistry (2016) 55 (9) 4545-4554 - doi : 10.1021/acs.inorgchem.6b00381

A molecular theranostic agent for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) consisting of four [GdDTTA]− complexes (DTTA4− = 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 = 43.7 mmol–1 s–1 per gadolinium center, is the highest reported for a bishydrated gadolinium(III)-based contrast agent of medium size and can be related to the rigidity of the molecule. The complex displays also a remarkable singlet oxygen quantum yield of ϕΔ = 0.45 in H2O, similar to that of a meso-tetrasulfonated porphyrin. We also evidenced the ability of the gadolinium(III) conjugate to penetrate in cancer cells with low cytotoxicity. Its phototoxicity on Hela cells was evaluated following incubation at low micromolar concentration and moderate light irradiation (21 J cm–2) induced 50% of cell death. Altogether, these results demonstrate the high potential of this conjugate as a theranostic agent for MRI and PDT.

Bonnet C. S. and Tóth E.  (2016)

### Smart Contrast Agents for Magnetic Resonance Imaging

Chimia (2016) 70 (1-2) 102-108 - doi : 10.2533/chimia.2016.102

He, J. Bonnet, C. S. Eliseeva, S. V. Lacerda, S. Chauvin, T. Retailleau, P. Szeremeta, F. Badet, B. Petoud, S. Tóth, E. and Durand, P.  (2016)

### Prototypes of Lanthanide(III) Agents Responsive to Enzymatic Activities in Three Complementary Imaging Modalities : Visible/Near-Infrared Luminescence, PARACEST-, and T-MRI

Journal of the American Chemical Society (2016) 138 (9) 2913-2916 - doi : 10.1021/jacs.5b12084

We report first prototypes of responsive lanthanide(III) complexes that can be monitored independently in three complementary imaging modalities. Through the appropriate choice of lanthanide(III) cations, the same reactive ligand can be used to form complexes providing detection by (i) visible (Tb3+) and near-infrared (Yb3+) luminescence, (ii) PARACEST- (Tb3+, Yb3+), or (iii) T1-weighted (Gd3+) MRI. The use of lanthanide(III) ions of different natures for these imaging modalities induces only a minor change in the structure of complexes that are therefore expected to have a single biodistribution and cytotoxicity.

2015   Références trouvées : 2

Zhang, W. Y. Martinelli J., Mayer F., Bonnet C. S., Szeremeta F. and Djanashvili K.  (2015)

### Molecular architecture control in synthesis of spherical Ln-containing nanoparticles

Rsc Advances (2015) 5 (85) 69861-69869 - doi : 10.1039/c5ra09374k

Among the procedures to prepare lanthanide-containing nanoparticles a gap exists in the range between 5 and 40 nm. The miniemulsion technique presented here is intended to fill this discontinuity and offers a facile method that can be applied for the preparation of nanoparticles for various applications, e.g. medical imaging, optics and catalysis. We demonstrate that formation of nanodroplets under emulsion conditions is the key step in the size control of the nanoparticles. The type of surfactant and the nature of the dispersed and continuous phases strongly influence the interfacial activity and, consequently, the size of the final solid particles that result from the subsequent thermal decomposition. Moreover, the choice of the surfactant determines the final elemental composition of the particles, leading to either lanthanide oxides or oxysulfates when using Brij (R) 35 or sodium dodecyl sulfate, respectively. Nanoparticles of holmium and gadolinium were prepared and their applicability as magnetic resonance imaging contrast agents is shown.

Bonnet, C. S., Laine, S., Buron, F., Tircsó, G., Pallier, A., Helm, L., Suzenet, F., Tóth, É.  (2015)

### A Pyridine-Based Ligand with Two Hydrazine Functions for Lanthanide Chelation : Remarkable Kinetic Inertness for a Linear, Bishydrated Complex

Inorganic Chemistry (2015) 54 (12) 5991-6003 - doi : 10.1021/acs.inorgchem.5b00804

To study the influence of hydrazine functions in the ligand skeleton, we designed the heptadentate HYD ligand (2,2’,2″,2‴-(2,2’-(pyridine-2,6-diyl)bis(2-methylhydrazine-2,1,1-triyl)) tetraacetic acid) and compared the thermodynamic, kinetic, and relaxation properties of its Ln(3+) complexes to those of the parent pyridine (Py) analogues without hydrazine (Py = 2,6-pyridinebis(methanamine)-N,N,N’,N’-tetraacetic acid). The protonation constants of HYD were determined by pH-potentiometric measurements, and assigned by a combination of UV-visible and NMR spectroscopies. The protonation sequence is rather unusual and illustrates that small structural changes can strongly influence ligand basicity. The first protonation step occurs on the pyridine nitrogen in the basic region, followed by two hydrazine nitrogens and the carboxylate groups at acidic pH. Contrary to Py, HYD self-aggregates through a pH-dependent process (from pH ca. 4). Thermodynamic stability constants have been obtained by pH-potentiometry and UV-visible spectrophotometry for various Ln(3+) and physiological cations (Zn(2+), Ca(2+), Cu(2+)). LnHYD stability constants show the same trend as those of LnDTPA complexes along the Ln(3+) series, with log K = 18.33 for Gd(3+), comparable to the Py analogue. CuHYD has a particularly high stability (log K > 19) preventing its determination from pH-potentiometric measurements. The stability constant of CuPy was also revisited and found to be underestimated in previous studies, highlighting that UV-visible spectrophotometry is often indispensable to obtain reliable stability constants for Cu(2+) chelates. The dissociation of GdL, assessed by studying the Cu(2+)-exchange reaction, occurs mainly via an acid-catalyzed process, with limited contribution from direct Cu(2+) attack. The kinetic inertness of GdHYD is remarkable for a linear bishydrated chelate ; the 25-fold increase in the dissociation half-life with respect to the monohydrated commercial contrast agent GdDTPA (t1/2 = 5298 h for GdHYD vs 202 h for GdDTPA) is related to the rigidity of the HYD ligand due to the pyridine and methylated hydrazine functions of the backbone. A combined analysis of variable-temperature (17)O NMR and NMRD data on GdHYD yielded the microscopic parameters influencing relaxation properties. The high relaxivity (r1 = 7.7 mM(-1) s(-1) at 20 MHz, 25 °C) results from the bishydrated character of the complex combined with an optimized water exchange rate (kex(298) = 7.8 × 10(6) s(-1)). The two inner-sphere water molecules are not replaced through interaction with biological cations such as carbonate, citrate, and phosphate as monitored by (1)H relaxivity and luminescence lifetime measurements.

2014   Références trouvées : 5

Bonnet, C.S., Caillé, F., Pallier, A., Morfin, J.-F., Petoud, S., Suzenet, F., Tóth, É.  (2014)

### Mechanistic Studies of Gd3+-Based MRI Contrast Agents for Zn2+ Detection : Towards Rational Design

Chemistry – A European Journal (2014) 20 (35) 10959-10969 - doi : 10.1002/chem.201403043

A series of novel pyridine-based Gd3+ complexes have been prepared and studied as potential MRI contrast agents for Zn2+ detection. By independent assessment of molecular parameters affecting relaxivity, we could interpret the relaxivity changes observed upon Zn2+ binding in terms of variations of the rotational motion.

Fredy, J.W.,Scelle, J., Guenet, A., Morel, E., Adam de Beaumais, S., Ménand, M., Marvaud, V., Bonnet, C.S., Tóth, E., Sollogoub, M., Vives, G., Hasenknopf, B.  (2014)

### Cyclodextrin Polyrotaxanes as a Highly Modular Platform for the Development of Imaging Agents

Chemistry - A European Journal (2014) 20 (35) 10915-10920 - doi : 10.1002/chem.201403635

Selectively functionalized cyclodextrins with a bodipy fluorescent tag or Gd3+ complex were synthetized and threaded onto a polyammonium chain to form polyrotaxanes. This modular supramolecular assembly makes an ideal platform for bimodal (fluorescent and MRI) imaging applications.

Mayer, F., Zhang, W.Y., Brichart, T., Tillement, O., Bonnet, C.S., Toth, E., Peters, J. A. and Djanashvili, K.  (2014)

### Nanozeolite-LTL with Gd-III Deposited in the Large and Eu-III in the Small Cavities as a Magnetic Resonance Optical Imaging Probe

Chemistry - A European Journal (2014) 20 (12) 3358-3364 - doi : 10.1002/chem.201304457

The immense structural diversity of more than 200 known zeolites is the basis for the wide variety of applications of these fascinating materials ranging from catalysis and molecular filtration to agricultural uses. Despite this versatility, the potential of zeolites in medical imaging has not yet been much exploited. In this work a novel strategy is presented to selectively deposit different ions into distinct framework locations of zeolite-LTL (Linde type L) and it is demonstrated that the carefully ion-exchanged Gd/Eu-containing nanocrystals acquire exceptional magnetic properties in combination with enhanced luminescence. This smart exploitation of the framework structure yields the highest relaxivity density (13.7s(-1)Lg(-1) at 60MHz and 25 degrees C) reported so far for alumosilicates, rendering these materials promising candidates for the design of dual magnetic resonance/optical imaging probes, as demonstrated in preliminary phantom studies.

Roger M., Regueiro-Figueroa M., Ben Azzeddine C., Patinec V., Bonnet C. S., Platas-Iglesias C. and Tripier R  (2014)

### Lanthanide Complexes with Heteroditopic Ligands as Fluorescent Zinc Sensors

European Journal of Inorganic Chemistry (2014) (6) 1072-1081 - doi : 10.1002/ejic.201301426

We report the synthesis of two ligands containing a DO3A unit (H(3)DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) linked to a triazacyclononane (TACN) moiety by a 2,6-dimethylpyridine spacer designed to form stable Ln(3+) complexes in solution that respond to the presence of Zn2+ ions. The Eu3+ and Gd3+ complexes have been characterized by using a combination of experimental and theoretical techniques that include absorption and emission electronic spectroscopy, NMR spectroscopy, H-1 relaxometry, and DFT calculations. The Ln(3+) ions are eight-coordinated by the ligand, which binds to the metal ion through the seven donor atoms of the DO3A unit and the nitrogen atom of the pyridyl linker. Luminescence lifetime measurements recorded from solutions of the Eu3+ complexes in H2O and D2O and relaxometric measurements point to the absence of inner-sphere water molecules. The addition of Zn2+ causes important changes in the absorption spectra of the complexes that evidence the formation of both 1:1 and 2:1 (Ln(3+)/Zn2+) complex species. However, the emission lifetimes of the Eu3+ complexes and relaxivity experience weak changes, thus indicating that Zn2+ addition does not significantly affect the number of coordinated water molecules. The Gd3+ complexes show a weak emission band at 325 nm, the intensity of which dramatically increases in the presence of Zn2+. However, the turn-on behaviour induced by Zn2+ is not observed for other metal cations such as Ca2+, Mg2+ or Cu2+. DFT calculations indicate that a photoinduced electron-transfer (PET) process is responsible for the quenching of the luminescence in the absence of Zn2+.

Bonnet C.S. and Toth E.  (2014)

### Radiodiagnostic agents and Magnetic Resonance Imaging (MRI) agent

In "Ligand Design In Medicinal Inorganic Chemistry" (2014) John Wiley & Sons - ISBN : 978-1-118-48852-2

Increasing the potency of therapeutic compounds, while limiting side-effects, is a common goal in medicinal chemistry. Ligands that effectively bind metal ions and also include specific features to enhance targeting, reporting, and overall efficacy are driving innovation in areas of disease diagnosis and therapy.

Ligand Design in Medicinal Inorganic Chemistry presents the state-of-the-art in ligand design for medicinal inorganic chemistry applications. Each individual chapter describes and explores the application of compounds that either target a disease site, or are activated by a disease-specific biological process.

2013   Références trouvées : 5

Bonnet C.S., Tei L., Botta M. and Tóth E.  (2013)

### Responsive probes

In "The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging" - John Wiley & Sons, chap 8, 343-385

Carne-Sanchez A., Bonnet C.S., Imaz I., Lorenzo J., Toth E. and Maspoch D.  (2013)

### Relaxometry studies of a highly stable nanoscale metal-organic framework made of Cu(II), Gd(III), and the macrocyclic DOTP

Journal of the American Chemical Society (2013) 135 (47) 17711-17714 - doi : 10.1021/ja4094378

The macrocyclic ligand DOTP is used to assemble a porous, heterometallic metal-organic framework (MOF). This MOF is miniaturizable down to the nanoscale to form stable colloids, is stable in physiological saline solution and cell culture media, and is not cytotoxic. It shows interesting relaxometric properties with r1 at high field (500 MHz) of 5 mM(-1).s(-1) and a maximum r1 = 15 mM(-1).s(-1) at 40 MHz, which remains constant over a wide pH range and increases with temperature.

de Sá A., Bonnet C.S., Geraldes C.F., Tóth É., Ferreira P.M. and André J.P.  (2013)

### Thermodynamic stability and relaxation studies of small, triaza-macrocyclic Mn(II) chelates

Dalton Trans. 42 (13) 4522-4532

Due to its favorable relaxometric properties, Mn(2+) is an appealing metal ion for magnetic resonance imaging (MRI) contrast agents. This paper reports the synthesis and characterization of three new triazadicarboxylate-type ligands and their Mn(2+) chelates (NODAHep, 1,4,7-triazacyclononane-1,4-diacetate-7-heptanil ; NODABA, 1,4,7-triazacyclononane-1,4-diacetate-7-benzoic acid ; and NODAHA, 1,4,7-triazacyclononane-1,4-diacetate-7-hexanoic acid). The protonation constants of the ligands and the stability constants of the chelates formed with Mn(2+) and the endogenous Zn(2+) ion have been determined by potentiometry. In overall, the thermodynamic stability of the chelates is lower than that of the corresponding NOTA analogues (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetate), consistent with the decreased number of coordinating carboxylate groups. Variable temperature (1)H NMRD and (17)O NMR measurements have been performed on the paramagnetic chelates to provide information on the water exchange rates and the rotational dynamics. The values of the (17)O chemical shifts are consistent with the presence of one water molecule in the first coordination sphere of Mn(2+). The three complexes are in the slow to intermediate regime for the water exchange rate, and they all display relatively high rotational correlation times, which explain the relaxivity values between 4.7 and 5.8 mM(-1) s(-1) (20 MHz and 298 K). These relaxivities are higher than expected for Mn(2+) chelates of such size and comparable to those of small monohydrated Gd(3+) complexes. The amphiphilic [Mn(NODAHep)] forms micelles above 22 mM (its critical micellar concentration was determined by relaxometry and fluorescence), and interacts with HSA via its alkylic carbon chain providing a 60% relaxivity increase at 20 MHz due to a longer tumbling time.

Mendonça A.C., Martins A.F., Melchior A., Marques S.M., Chaves S., Villette S., Petoud S., Zanonato P.L., Tolazzi M., Bonnet C.S., Tóth E., Di Bernardo P., Geraldes C.F. and Santos M.A.  (2013)

### New tris-3,4-HOPO lanthanide complexes as potential imaging probes : complex stability and magnetic properties

Dalton Transactions 42 (17) 6046-6057

There is a growing interest in the development of new medical diagnostic tools with higher sensibility and less damage for the patient body, namely on imaging reporters for the management of diseases and optimization of treatment strategies. This article examines the properties of a new class of lanthanide complexes with a tripodal tris-3-hydroxy-4-pyridinone (tris-3,4-HOPO) ligand - NTP(PrHP)3. Among the studies herein performed, major relevance is given to the thermodynamic stability of the complexes with a series of Ln(3+) ions (Ln = La, Pr, Gd, Er, Lu) and to the magnetic relaxation properties of the Gd(3+) complex. This hexadentate ligand enables the formation of (1 : 1) Ln(3+) complexes with high thermodynamic stability following the usual trend, while the Gd-chelates show improved relaxivity (higher hydration number), as compared with the commercially available Gd-based contrast agents (CAs) ; transmetallation of the Gd(3+)-L complex with Zn(2+) proved to be thermodynamically and kinetically disfavored. Therefore, NTP(PrHP)3 emerges as part of a recently proposed new generation of CAs with prospective imaging sensibility gains.

Lacerda, S., Bonnet, C.S., Pallier, A., Villette, S., Foucher, F., Westall, F., Buron, F., Suzenet, F., Pichon, C., Petoud, S. and Tóth, E.  (2013)

### Lanthanide-Based, Near-Infrared Luminescent and Magnetic Lipoparticles : Monitoring Particle Integrity

Small (2013) 9 (16) 2662-2666 - doi : 10.1002/smll.201201923

Near-infrared emitting, magnetic particles for combined optical and MR detection based on liposomes or artificial lipoproteins are presented. They provide a novel strategy for the luminescence sensitization of lanthanide cations (Yb3+, Nd3+) without covalent bonds between the chromophore and the lanthanide, and provide an unambiguous tool for monitoring the integrity of the liponanoparticles, via emission in the NIR region.

2012   Références trouvées : 5

Bonnet, C.S. and Tóth, E.  (2012)

### MRI Contrast Agents, In Supramolecular Chemistry : From Molecules to Nanomaterials

In Self-Assembly and Supramolecular Devices, Eds. Gale, P. and Steed, J. John, Wiley & Sons (2012) vol. 5, 2693-2723

Magnetic resonance imaging is one of the most efficient diagnostic modalities in clinical radiology and biomedical research. To enhance image contrast, paramagnetic complexes, mainly Gd3+ chelates, are used. In recent years, molecular imaging has emerged as a new area aiming at noninvasive visualization of expression and function of bioactive molecules at the cellular level. This chapter is devoted to the description of supramolecular approaches in the development of highly efficient and smart contrast agents. We demonstrate via representative examples (micellar systems, liposomes, protein-bound chelates, etc.) how supramolecular approaches are applied to increase the efficacy of Gd3+-based contrast agents. We also include an introduction to chemical exchange saturation transfer (CEST) agents and show how supramolecular systems, such as liposomes, can be beneficial to decrease the sensitivity limit of CEST detection. Supramolecular assemblies offer an important advantage regarding the metabolic fate. While covalent polymers are excreted slowly from the body, supramolecular systems facilitate the body elimination via the excretion pathway of the small constituents. Finally, we discuss molecular imaging probes that provide an MRI response mainly through the modulation of supramolecular interactions to various biochemical variables, such as pH, temperature, metal ions, and enzymes.

Roca-Sabio, A., Bonnet, C.S., Mato-Iglesias, M., Esteban-Gómez, D., Tóth, E., de Blas, A., Rodríguez-Blas T. and C. Platas-Iglesias, C.  (2012)

### Lanthanide Complexes Based on a Diazapyridinophane Platform containing Picolinate Pendants

Inorg. Chem. (2012) 51 10893-10903

A new macrocyclic ligand, N,N’-bis[(6-carboxy-2-pyridyl)methyl]-2,11-diaza[3.3](2,6)pyridinophane (H(2)BPDPA), was prepared, and its coordination properties toward the Ln(III) ions were investigated. The hydration numbers (q) obtained from luminescence lifetime measurements in aqueous solution of the Eu(III) and Tb(III) complexes indicate that they contain one inner-sphere water molecule. The structure of the complexes in solution has been investigated by (1)H and (13)C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (B3LYP) level. The minimum-energy conformation calculated for the Yb(III) complex is in excellent agreement with the experimental structure in solution, as demonstrated by analysis of the Yb(III)-induced paramagnetic (1)H shifts. Nuclear magnetic relaxation dispersion (NMRD) profiles and (17)O NMR measurements recorded on solutions of the Gd(III) complex were used to determine the parameters governing the relaxivity. The results show that this system is endowed with a relatively fast water-exchange rate k(ex)(298) = 63 × 10(6) s(-1). Thermodynamic stability constants were determined by pH-potentiometric titration at 25 °C in 0.1 M KCl. The stability constants, which fall within the range logK(LnL) = 12.5-14.2, point to a relatively low stability of the complexes primarily as a consequence of the low basicity of the ligand.

Caillé, F, Bonnet, CS, Buron, F, Villette, S, Helm, L, Petoud, S, Suzenet, F. & Tóth E.  (2012)

### Isoquinoline-Based Lanthanide Complexes : Bright NIR Optical Probes and Efficient MRI Agents

Inorganic Chemistry 51 (4) 2522-2532

In the objective of developing ligands that simultaneously satisfy the requirements for MRI contrast agents and near-infrared emitting optical probes that are suitable for imaging, three isoquinoline-based polyaminocarboxylate ligands, L1, L2 and L3, have been synthesized and the corresponding Gd(3+), Nd(3+) and Yb(3+) complexes investigated. The specific challenge of the present work was to create NIR emitting agents which (i) have excitation wavelengths compatible with biological applications and (ii) are able to emit a sufficient number of photons to ensure sensitive NIR detection for microscopic imaging. Here we report the first observation of a NIR signal arising from a Ln(3+) complex in aqueous solution in a microscopy setup. The lanthanide complexes have high thermodynamic stability (log K(LnL) =17.7-18.7) and good selectivity for lanthanide ions versus the endogenous cations Zn(2+), Cu(2+), and Ca(2+) thus preventing transmetalation. A variable temperature and pressure (17)O NMR study combined with nuclear magnetic relaxation dispersion measurements yielded the microscopic parameters characterizing water exchange and rotation. Bishydration of the lanthanide cation in the complexes, an important advantage to obtain high relaxivity for the Gd(3+) chelates, has been demonstrated by (17)O chemical shifts for the Gd(3+) complexes and by luminescence lifetime measurements for the Yb(3+) analogues. The water exchange on the three Gd(3+) complexes is considerably faster (k(ex)(298) = (13.9-15.4) × 10(6) s(-1)) than on commercial Gd(3+)-based contrast agents and proceeds via a dissociative mechanism, as evidenced by the large positive activation volumes for GdL1 and GdL2 (+10.3 ± 0.9 and +10.6 ± 0.9 cm(3) mol(-1), respectively). The relaxivity of GdL1 is doubled at 40 MHz and 298 K in fetal bovine serum (r(1) = 16.1 vs 8.5 mM(-1) s(-1) in HEPES buffer), due to hydrophobic interactions between the chelate and serum proteins. The isoquinoline core allows for the optimization of the optical properties of the luminescent lanthanide complexes in comparison to the pyridinic analogues and provides significant shifts of the excitation energies toward lower values which therefore become more adapted for biological applications. L2 and L3 bear two methoxy substituents on the aromatic core in ortho and para positions, respectively, that further modulate their electronic structure. The Nd(3+) and Yb(3+) complexes of the ligand L3, which incorporates the p-dimethoxyisoquinoline moiety, can be excited up to 420 nm. This wavelength is shifted over 100 nm toward lower energy in comparison to the pyridine-based analogue. The luminescence quantum yields of the Nd(3+) (0.013-0.016%) and Yb(3+) chelates (0.028-0.040%) are in the range of the best nonhydrated complexes, despite the presence of two inner sphere water molecules. More importantly, the 980 nm NIR emission band of YbL3 was detected with a good sensitivity in a proof of concept microscopy experiment at a concentration of 10 μM in fetal bovine serum. Our results demonstrate that even bishydrated NIR lanthanide complexes can emit a sufficient number of photons to ensure sensitive detection in practical applications. In particular, these ligands containing an aromatic core with coordinating pyridine nitrogen can be easily modified to tune the optical properties of the NIR luminescent lanthanide complexes while retaining good complex stability and MRI characteristics for the Gd(3+) analogues. They constitute a highly versatile platform for the development of bimodal MR and optical imaging probes based on a simple mixture of Gd(3+) and Yb(3+)/Nd(3+) complexes using an identical chelator. Given the presence of two inner sphere water molecules, important for MRI applications of the corresponding Gd(3+) analogues, this result is particularly exciting and opens wide perspectives not only for NIR imaging based on Ln(3+) ions but also for the design of combined NIR optical and MRI probes.

Bonnet, CS, Buron, F, Caillé, F, Shade, CM, Drahoš, B, Pellegatti, L, Zhang, J, Villette, S, Helm, L, Pichon, C, Suzenet, F, Petoud, S. & Tóth E.  (2012)

### Pyridine-Based Lanthanide Complexes Combining MRI and NIR Luminescence Activities

Chemistry - a european journal 18 (5) 1419-1431

A series of novel triazole derivative pyridine-based polyamino-polycarboxylate ligands has been synthesized for lanthanide complexation. This versatile platform of chelating agents combines advantageous properties for both magnetic resonance (MR) and optical imaging applications of the corresponding Gd(3+) and near-infrared luminescent lanthanide complexes. The thermodynamic stability constants of the Ln(3+) complexes, as assessed by pH potentiometric measurements, are in the range log K(LnL) =17-19, with a high selectivity for lanthanides over Ca(2+) , Cu(2+) , and Zn(2+) . The complexes are bishydrated, an important advantage to obtain high relaxivities for the Gd(3+) chelates. The water exchange of the Gd(3+) complexes (k(ex) (298) =7.7-9.3×10(6)  s(-1) ) is faster than that of clinically used magnetic resonance imaging (MRI) contrast agents and proceeds through a dissociatively activated mechanism, as evidenced by the positive activation volumes (ΔV(≠) =7.2-8.8 cm(3) mol(-1) ). The new triazole ligands allow a considerable shift towards lower excitation energies of the luminescent lanthanide complexes as compared to the parent pyridinic complex, which is a significant advantage in the perspective of biological applications. In addition, they provide increased epsilon values resulting in a larger number of emitted photons and better detection sensitivity. The most conjugated system PheTPy, bearing a phenyl-triazole pendant on the pyridine ring, is particularly promising as it displays the lowest excitation and triplet-state energies associated with good quantum yields for both Nd(3+) and Yb(3+) complexes. Cellular and in vivo toxicity studies in mice evidenced the non-toxicity and the safe use of such bishydrated complexes in animal experiments. Overall, these pyridinic ligands constitute a highly versatile platform for the simultaneous optimization of both MRI and optical properties of the Gd(3+) and the luminescent lanthanide complexes, respectively.

Bonnet, C.S., Devocelle, M. & Gunnlaugsson, T.  (2012)

### Luminescent lanthanide-binding peptides : sensitising the excited states of Eu(III) and Tb(III) with a 1,8-naphthalimide-based antenna

Organic & Biomolecular Chemistry 10 (1) 126-133

The investigation into the luminescence properties of a lanthanide-binding peptide, derived from the Ca-binding loop of the parvalbumin, and modified by incorporating a 1,8-naphthalimide (Naph) chromophore at the N-terminus is described. Here, the Naph is used as a sensitising antenna, which can be excited at lower energy than classical aromatic amino acids, such as tryptophan (the dodecapeptide of which was also synthesised and studied herein). The syntheses of the Naph antenna, its solid phase incorporation into the dodecapeptide, and the NMR investigation into the formation of the corresponding lanthanide complexes in solution is presented. We also show that this Naph antenna can be successfully employed to sensitize the excited states of both europium and terbium ions, the results of which was used to determined the stability constants of their formation complexes, and we demonstrated that our peptide ’loop’ can selectively bind these lanthanide ions over Ca(II).

2011   Références trouvées : 2

Drahoš, B., Kubíček, V., Bonnet, C.S., Hermann, P., Lukeš, I. and Tóth, E.  (2011)

### Dissociation kinetics of Mn2+ complexes of NOTA and DOTA

Dalton Trans. 40 (9) 1945-1951

Surman, A. J., Bonnet, C.S., Lowe, M.P., Kenny, G.D., Bell, J.D., Tóth, E. & Vilar, R.  (2011)

### A pyrophosphate-responsive gadolinium(III) MRI contrast agent

Chem. Eur. J. 17 (1) 223-230

2010   Références trouvées : 4

Bonnet, C. S. & Toth, E.  (2010)

### MRI probes for sensing biologically relevant metal ions.

Future Medicinal Chemistry 3 (2) 367-384

Bonnet, C.S. & Toth, E.  (2010)

### Towards highly efficient, intelligent and bimodal imaging probes : novel approaches provided by lanthanide coordination chemistry.

C. R. Chimie 13, 700-714

Bonnet, C.S. & Toth, E.  (2010)