Selective Anchoring of GdIII Chelates on the External Surface of Organo‐Modified Mesoporous Silica Nanoparticles: A New Chemical Strategy To Enhance Relaxivity

The optimization of the physico‐chemical properties of both Gd^III chelates and nanocarriers is of great importance for the development of effective nanosystems for magnetic resonance imaging (MRI) applications. With this aim, macrocyclic Gd^III chelates were selectively attached to the pendant amino groups exposed to the external surface of spheroidal mesoporous silica nanoparticles (MSNs). This was achieved by treating the metal complexes with MSNs that contained the templating surfactant molecules confined within the silica channels (hexadecyltrimethylammonium (CTA)/MSN), followed by extraction of the surfactant. The nanoparticles showed greatly improved ¹H relaxometric efficiency relative to corresponding systems that also feature Gd^III chelates conjugated inside the pores. A further significant relaxivity enhancement was observed after chemical transformation of the free amino groups into amides. The ionic relaxivity of the final nanoparticles (r_1p=79.1 mM ^?1 s^?1; 0.5 T, 310 K) is one of the highest reported so far.     

A Class of FeIII Macrocyclic Complexes with Alcohol Donor Groups as Effective T1 MRI Contrast Agents

Early studies suggested that Fe^III complexes cannot compete with Gd^III complexes as T₁ MRI contrast agents. Now it is shown that one member of a class of high‐spin macrocyclic Fe^III complexes produces more intense contrast in mice kidneys and liver at 30 minutes post‐injection than does a commercially used Gd^III agent and also produces similar T₁ relaxivity in serum phantoms at 4.7 T and 37 °C. Comparison of four different Fe^III macrocyclic complexes elucidates the factors that contribute to relaxivity in vivo including solution speciation. Variable‐temperature ¹⁷O NMR studies suggest that none of the complexes has a single, integral inner‐sphere water that exchanges rapidly on the NMR timescale. MRI studies in mice show large in vivo differences of three of the Fe^III complexes that correspond, in part, to their r₁ relaxivity in phantoms. Changes in overall charge of the complex modulate contrast enhancement, especially of the kidneys.     

A Chemical Strategy for the Relaxivity Enhancement of GdIII Chelates Anchored on Mesoporous Silica Nanoparticles

Functionalised MCM‐41 mesoporous silica nanoparticles were used as carriers of Gd^III complexes for the development of nanosized magnetic resonance imaging contrast agents. Three Gd^III complexes based on the 1,4,7,10‐tetraazacyclododecane scaffold (DOTA; monoamide‐, DOTA‐ and DO3A‐like complexes) with distinct structural and magnetic properties were anchored on the silica nanoparticles functionalised with NH₂ groups. The interaction between Gd^III chelates and surface functional groups markedly influenced the relaxometric properties of the hybrid materials, and were deeply modified passing from ionic ? NH₃⁺ to neutral amides. A complete study of the structural, textural and surface properties together with a full ¹H relaxometric characterisation of these hybrid materials before and after surface modification was carried out. Particularly for the anionic complex 2 attached to MCM‐41, an impressive increase in relaxivity (r_1p) was observed (from 20.3 to 37.8 mM ^?1 s^?1, 86.2 % enhancement at 20 MHz and 310 K), mainly due to a threefold faster water exchange rate after acetylation of the surface ? NH₃⁺ ions. This high r_1p value, coupled with the large molar amount of grafted 2 onto the silica nanoparticles gives rise to a value of relaxivity per particle of 29 500 mM ^?1 s^?1, which possibly allows it to be used in molecular imaging procedures. Smaller changes were observed for the hybrid materials based on neutral 1 and 3 complexes. In fact, whereas 1 shows a weak interaction with the surface and acetylation induced only some decrease of the local rotation, complex 3 appears to be involved in a strong interaction with surface silanols. This results in the displacement of a coordinated water molecule and in a decrease of the accessibility of the solvent to the metal centre, which is unaffected by the modification of ammonium ions to neutral amides.     

Preparation of Highly Efficient MRI Contrast Agents through Complexation of Cationic GdIII‐Containing Metallosurfactant with Biocompatible Polyelectrolytes

Novel contrast agents were developed through assembling of Gd^III‐containing metallosurfactant (MS) with biocompatible polyelectrolytes sodium hyaluronate (HA), heparinsodium (HS) and dextran sulfate sodium (DSS). The formed polyelectrolyte–surfactant complexes showed different structural patterns as the charge ratio increased, including spherical aggregates, rod‐like aggregates and network patterns in monovalent HA system, while spherical structures emerged in multivalent HS and DSS systems. Energy dispersive spectroscopy analysis and scanning electron microscopy mapping showed the presence of Gd^III in these complexes. Inductively coupled plasma atomic emission spectrometry was further used to quantify the contents of Gd^III in the assemblies. T1 magnetic resonance imaging showed that these Gd^III‐loaded complexes exhibited relaxivity of up to 63.81 mM ^?1 s^?1, much higher than that of Ominiscan (4.64 mM ^?1 s^?1). The cytotoxicity test in vitro demonstrated the excellent biocompatibility of these complexes, which is essential for clinical application.     

Approaching the Kinetic Inertness of Macrocyclic Gadolinium(III)‐Based MRI Contrast Agents with Highly Rigid Open‐Chain Derivatives

A highly rigid open‐chain octadentate ligand (H₄cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6′‐[(ethane‐1,2 diylbis{(carboxymethyl)azanediyl})bis(methylene)]dipicolinic acid (H₄octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd³⁺ complex slightly (log K_GdL=20.68 vs. 20.23 for [Gd(octapa)]^?) while other MRI‐relevant parameters remain unaffected (one coordinated water molecule; relaxivity r₁=5.73 mm ^?1 s^?1 at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton (half‐life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)]^? (t_1/2=1.49×10⁵ h) than for [Gd(octapa)]^?. The kinetic inertness of this novel chelate is superior by 2–3 orders of magnitude compared to non‐macrocyclic MRI contrast agents approved for clinical use.     

Self‐Aggregated Dinuclear Lanthanide(III) Complexes as Potential Bimodal Probes for Magnetic Resonance and Optical Imaging

Homodinuclear lanthanide complexes (Ln=La, Eu, Gd, Tb, Yb and Lu) derived from a bis‐macrocyclic ligand featuring two 2,2′,2′′‐(1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl)triacetic acid chelating sites linked by a 2,6‐bis(pyrazol‐1‐yl)pyridine spacer (H₂L³) were prepared and characterized. Luminescence lifetime measurements recorded on solutions of the Eu^III and Tb^III complexes indicate the presence of one inner‐sphere water molecule coordinated to each metal ion in these complexes. The overall luminescence quantum yields were determined (?=0.01 for [Eu₂(L³)] and 0.50 for [Tb₂(L³)] in 0.01 M TRIS/HCl, pH 7.4; TRIS=tris(hydroxymethyl)aminomethane), pointing to an effective sensitization of the metal ion by the bispyrazolylpyridyl unit of the ligand, especially with Tb. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd₂(L³)] are characteristic of slowly tumbling systems, showing a low‐field plateau and a broad maximum around 30 MHz. This suggests the occurrence of aggregation of the complexes giving rise to slowly rotating species. A similar behavior is observed for the analogous Gd^III complex containing a 4,4′‐dimethyl‐2,2′‐bipyridyl spacer ([Gd₂(L¹)]). The relaxivity of [Gd₂(L³)] recorded at 0.5 T and 298 K (pH 6.9) amounts to 13.7 mM ^?1 s^?1. The formation of aggregates has been confirmed by dynamic light scattering (DLS) experiments, which provided mean particle sizes of 114 and 38 nm for [Gd₂(L¹)] and [Gd₂(L³)], respectively. TEM images of [Gd₂(L³)] indicate the formation of nearly spherical nanosized aggregates with a mean diameter of about 41 nm, together with some nonspherical particles with larger size.     

Serum Albumin Targeted,pH‐Dependent Magnetic Resonance Relaxation Agents

The objective of this work was the synthesis of serum albumin targeted, Gd^III‐based magnetic resonance imaging (MRI) contrast agents exhibiting a strong pH‐dependent relaxivity. Two new complexes ( Gd‐glu and Gd‐bbu ) were synthesized based on the DO3A macrocycle modified with three carboxyalkyl substituents α to the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide nitrogen coordinates the Gd in a pH‐dependent fashion, resulting in a decrease in the hydration state, q, as pH is increased and a resultant decrease in relaxivity (r₁). In the absence of human serum albumin (HSA), r₁ increases from 2.0 to 6.0 mM ^?1 s^?1 for Gd‐glu and from 2.4 to 9.0 mM ^?1 s^?1 for Gd‐bbu from pH 5 to 8.5 at 37 °C, 0.47 T, respectively. These complexes (0.2 mM ) are bound (>98.9 %) to HSA (0.69 mM ) over the pH range 5–8.5. Binding to albumin increases the rotational correlation time and results in higher relaxivity. The r₁ increased 120 % (pH 5) and 550 % (pH 8.5) for Gd‐glu and 42 % (pH 5) and 260 % (pH 8.5) for Gd‐bbu . The increases in r₁ at pH 5 were unexpectedly low for a putative slow tumbling q=2 complex. The Gd‐bbu system was investigated further. At pH 5, it binds in a stepwise fashion to HSA with dissociation constants K_d1=0.65, K_d2=18, K_d3=1360 μM . The relaxivity at each binding site was constant. Luminescence lifetime titration experiments with the Eu^III analogue revealed that the inner‐sphere water ligands are displaced when the complex binds to HSA resulting in lower than expected r₁ at pH 5. Variable pH and temperature nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased r₁ of the albumin‐bound q=0 complexes is due to the presence of a nearby water molecule with a long residency time (1–2 ns). The distance between this water molecule and the Gd ion changes with pH resulting in albumin‐bound pH‐dependent relaxivity.     

Dysprosium Complexes and Their Micelles as Potential Bimodal Agents for Magnetic Resonance and Optical Imaging

Six diethylene triamine pentaacetic acid (DTPA) bisamide derivatives functionalized with p‐toluidine (DTPA‐BTolA), 6‐aminocoumarin (DTPA‐BCoumA), 1‐naphthalene methylamine (DTPA‐BNaphA), 4‐ethynylaniline (DTPA‐BEthA), p‐dodecylaniline (DTPA‐BC₁₂PheA) and p‐tetradecyl‐aniline (DTPA‐BC₁₄PheA) were coordinated to dysprosium(III) and the magnetic and optical properties of the complexes were examined in detail. The complexes consisting of amphiphilic ligands (DTPA‐BC₁₂PheA and DTPA‐BC₁₄PheA) were further assembled into mixed micelles. Upon excitation into the ligand levels, the complexes display characteristic Dy^III emission with quantum yields of 0.3–0.5 % despite the presence of one water molecule in the first coordination sphere. A deeper insight into the energy‐transfer processes has been obtained by studying the photophysical properties of the corresponding Gd^III complexes. Since the luminescence quenching effect is decreased by the intervention of non‐ionic surfactant, quantum yields up to 1 % are obtained for the micelles. The transverse relaxivity r₂ per Dy^III ion at 500 MHz and 310 K reaches a maximum value of 27.4 s^?1 mM ^?1 for Dy‐DTPA‐BEthA and 36.0 s^?1 mM ^?1 for the Dy‐DTPA‐BC₁₂PheA assemblies compared with a value of 0.8 s^?1 mM ^?1 for Dy‐DTPA. The efficient T₂ relaxation, especially at high magnetic field strengths, is sustained by the high magnetic moment of the dysprosium ion, the coordination of water molecules with slow water exchange kinetics and long rotational correlation times. These findings open the way to the further development of bimodal optical and magnetic resonance imaging probes starting from single lanthanide compounds.     

Multifunctional Nanoprobe for MRI/Optical Dual‐Modality Imaging and Radical Scavenging

The development of novel nanomaterials for the diagnosis and/or treatment of human diseases has become an important issue. In this work, a multifunctional theranostic agent was designed by covalently binding hydroxyl‐ and amino‐bearing C₆₀ derivatives (C₆₀O_～10(OH)_～16(NH₂)_～6(NO₂)_～6 ? 24 H₂O) with gadolinium diethylenetriaminepentaacetic acid (Gd‐DTPA) to yield C₆₀O_～10(OH)_～16(NH₂)_～6(NO₂)_～6 ? 24 H₂O/(Gd‐DTPA)₃ ( DF₁Gd₃ ). The obtained DF₁Gd₃ shows more than fourfold contrast improvement over commercial Gd‐DTPA along with multiwavelength fluorescent emission for dual‐modality diagnosis. An inner‐ear magnetic resonance imaging (MRI) study was designed as a model of biological barriers, including the blood/brain barrier (BBB) for DF₁Gd₃ to investigate its in vivo behavior. This revealed that the fabricated contrast agent dramatically increases the local contrast but can not cross the middle ear/inner ear barrier and endolymph/perilymph barrier in the inner ear, and thus it is also BBB‐prohibited in normal individuals. In vivo biodistribution studies suggested that 1) DF₁Gd₃ could circulate in vessels for a relatively long time and is mainly eliminated through liver and kidney, 2) DF₁Gd₃ may potentially function as a liver‐specific MRI contrast agent. Interestingly, DF₁Gd₃ also shows an excellent quenching effect on hydroxyl radicals, as revealed by the DMPO spin trap/ESR method. The combination of enhanced MRI/FL imaging and local treatment of lesions is unique to DF₁Gd₃ and potentiates the medical paradigm of “detect and treat/prevent” in combating human diseases related to reactive oxygen.     

The Role of Equilibrium and Kinetic Properties in the Dissociation of Gd[DTPA‐bis(methylamide)] (Omniscan) at near to Physiological Conditions

[Gd(DTPA‐BMA)] is the principal constituent of Omniscan, a magnetic resonance imaging (MRI) contrast agent. In body fluids, endogenous ions (Zn²⁺, Cu²⁺, and Ca²⁺) may displace the Gd³⁺. To assess the extent of displacement at equilibrium, the stability constants of DTPA‐BMA^3? complexes of Gd³⁺, Ca²⁺, Zn²⁺, and Cu²⁺ have been determined at 37 °C in 0.15 M NaCl. The order of these stability constants is as follows: GdL≈CuL>ZnL?CaL. Applying a simplified blood plasma model, the extent of dissociation of Omniscan (0.35 mM [Gd(DTPA‐BMA)]) was found to be 17 % by the formation of Gd(PO₄), [Zn(DTPA‐BMA)]^? (2.4 %), [Cu(DTPA‐BMA)]^? (0.2 %), and [Ca(DTPA‐BMA)]^? (17.7 %). By capillary electrophoresis, the formation of [Ca(DTPA‐BMA)]^? has been detected in human serum spiked with [Gd(DTPA‐BMA)] (2.0 mM ) at pH 7.4. Transmetallation reactions between [Gd(DTPA‐BMA)] and Cu²⁺ at 37 °C in the presence of citrate, phosphate, and bicarbonate ions occur by dissociation of the complex assisted by the endogenous ligands. At physiological concentrations of citrate, phosphate, and bicarbonate ions, the half‐life of dissociation of [Gd(DTPA‐BMA)] was calculated to be 9.3 h at pH 7.4. Considering the rates of distribution and dissociation of [Gd(DTPA‐BMA)] in the extracellular space of the body, an open two‐compartment model has been developed, which allows prediction of the extent of dissociation of the Gd^III complex in body fluids depending on the rate of elimination of the contrast agent.     

Designing Novel Contrast Agents for Magnetic Resonance Imaging. Synthesis and Relaxometric Characterization of three Gadolinium(III) Complexes Based on Functionalized Pyridine‐Containing Macrocyclic Ligands

The three novel pyridine‐containing 12‐membered macrocyclic ligands 1 – 3 were synthesized. The coordinating arms are represented by three acetate moieties in 1 and 3 and by one acetate and two phosphonate moieties in 2 . In all three ligands, the acetate arm in the distal position is substituted, with a benzyl group in 1 and 2 and with an arylmethyl moiety in 3 . The relaxivities r_1p (20 MHz, 25°) of Gd^III complexes are: GD?1 , r_1p=8.3 mM ^?1 s^?1; GD?2 , r_1p8.1 mM ^?1 s^?1; Gd?3 , r_1p10.5 mM ^?1 s^?1. ¹H‐NMRD and ¹⁷O‐NMR T₂ data show that Gd?1 and Gd?3 contain two H₂O molecules in the inner sphere, whereas the presence of two phosphonate arms allows the coordination of only one H₂O molecule in Gd?2 . Interestingly, the exchange lifetime of coordinated H₂O in the three complexes is similar in spite of the difference in the coordination number of the Gd^III ion (i.e., 9 in Gd?1 and Gd?3 , and 8 in Gd?2 ). ¹H‐Relaxometric measurements at different pH and in the presence of lactate and oxalate were carried out to get some insight into the formation of ternary complexes from Gd?1 and Gd?3 . Finally, it was found that binding to human‐serum albumin (HSA) of Gd?1 and Gd?2 , though weak, yields limited relaxivity enhancements, likely as a consequence of effects on the hydration sphere caused by donor atoms on the surface of the protein.     

Dual‐Modal Magnetic Resonance/Fluorescent Zinc Probes for Pancreatic β‐Cell Mass Imaging

Despite the contribution of changes in pancreatic β‐cell mass to the development of all forms of diabetes mellitus, few robust approaches currently exist to monitor these changes prospectively in vivo. Although magnetic‐resonance imaging (MRI) provides a potentially useful technique, targeting MRI‐active probes to the β cell has proved challenging. Zinc ions are highly concentrated in the secretory granule, but they are relatively less abundant in the exocrine pancreas and in other tissues. We have therefore developed functional dual‐modal probes based on transition‐metal chelates capable of binding zinc. The first of these, Gd ?1 , binds Zn^II directly by means of an amidoquinoline moiety (AQA), thus causing a large ratiometric Stokes shift in the fluorescence from λ_em=410 to 500 nm with an increase in relaxivity from r₁=4.2 up to 4.9 mM ^?1 s^?1. The probe is efficiently accumulated into secretory granules in β‐cell‐derived lines and isolated islets, but more poorly by non‐endocrine cells, and leads to a reduction in T₁ in human islets. In vivo murine studies of Gd ?1 have shown accumulation of the probe in the pancreas with increased signal intensity over 140 minutes.     

Platinum(II)–Gadolinium(III) Complexes as Potential Single‐Molecular Theranostic Agents for Cancer Treatment

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)–gadolinium(III) complexes with the formula [{Pt(NH₃)₂Cl}₂GdL](NO₃)₂ possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt–Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM ), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd–DTPA. T₁‐weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt–Gd complexes promising theranostic agents for cancer treatment.     

A Bis(pyridine N‐oxide) Analogue of DOTA: Relaxometric Properties of the GdIII Complex and Efficient Sensitization of Visible and NIR‐Emitting Lanthanide(III) Cations Including PrIII and HoIII

We report the synthesis of a cyclen‐based ligand (4,10‐bis[(1‐oxidopyridin‐2‐yl)methyl]‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid= L1 ) containing two acetate and two 2‐methylpyridine N‐oxide arms anchored on the nitrogen atoms of the cyclen platform, which has been designed for stable complexation of lanthanide(III) ions in aqueous solution. Relaxometric studies suggest that the thermodynamic stability and kinetic inertness of the Gd^III complex may be sufficient for biological applications. A detailed structural study of the complexes by ¹H NMR spectroscopy and DFT calculations indicates that they adopt an anti‐Δ(λλλλ) conformation in aqueous solution, that is, an anti‐square antiprismatic (anti‐SAP) isomeric form, as demonstrated by analysis of the ¹H NMR paramagnetic shifts induced by Yb^III. The water‐exchange rate of the Gd^III complex is ${k{{298\hfill \atop {\rm ex}\hfill}}}$ =6.7×10⁶ s^?1, about a quarter of that for the mono‐oxidopyridine analogue, but still about 50 % higher than the ${k{{298\hfill \atop {\rm ex}\hfill}}}$ of GdDOTA (DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid). The 2‐methylpyridine N‐oxide chromophores can be used to sensitize a wide range of Ln^III ions emitting in both the visible (Eu^III and Tb^III) and NIR (Pr^III, Nd^III, Ho^III, Yb^III) spectral regions. The emission quantum yield determined for the Yb^III complex (${Q{{{\rm L}\hfill \atop {\rm Yb}\hfill}}}$ =7.3(1)×10^?3) is among the highest ever reported for complexes of this metal ion in aqueous solution. The sensitization ability of the ligand, together with the spectroscopic and relaxometric properties of its complexes, constitute a useful step forward on the way to efficient dual probes for optical imaging (OI) and MRI.     

Multifunctional Uniform Core–Shell Fe3O4@mSiO2 Mesoporous Nanoparticles for Bimodal Imaging and Photothermal Therapy

Multimodal imaging and simultaneous therapy is highly desirable because it can provide complementary information from each imaging modality for accurate diagnosis and, at the same time, afford an imaging‐guided focused tumor therapy. In this study, indocyanine green (ICG), a near‐infrared (NIR) imaging agent and perfect NIR light absorber for laser‐mediated photothermal therapy, was successfully incorporated into superparamagnetic Fe₃O₄@mSiO₂ core–shell nanoparticles to combine the merit of NIR/magnetic resonance (MR) bimodal imaging properties with NIR photothermal therapy. The resultant nanoparticles were homogenously coated with poly(allylamine hydrochloride) (PAH) to make the surface of the composite nanoparticles positively charged, which would enhance cellular uptake driven by electrostatic interactions between the positive surface of the nanoparticles and the negative surface of the cancer cell. A high biocompatibility of the achieved nanoparticles was demonstrated by using a cell cytotoxicity assay. Moreover, confocal laser scanning microscopy (CLSM) observations indicated excellent NIR fluorescent imaging properties of the ICG‐loaded nanoparticles. The relatively high r₂ value (171.6 mM ^?1 s^?1) of the nanoparticles implies its excellent capability as a contrast agent for MRI. More importantly, the ICG‐loaded nanoparticles showed perfect NIR photothermal therapy properties, thus indicating their potential for simultaneous cancer diagnosis as highly effective NIR/MR bimodal imaging probes and for NIR photothermal therapy of cancerous cells.     

Hexameric MnII Dendrimer as MRI Contrast Agent

A Mn^II chelating dendrimer was prepared as a contrast agent for MRI applications. The dendrimer comprises six tyrosine‐derived [Mn(EDTA)(H₂O)]^2? moieties coupled to a cyclotriphosphazene core. Variable temperature ¹⁷O NMR spectroscopy revealed a single water co‐ligand per Mn^II that undergoes fast water exchange (k_ex=(3.0±0.1)×10⁸ s^?1 at 37 °C). The 37 °C per Mn^II relaxivity ranged from 8.2 to 3.8 mM ^?1 s^?1 from 0.47 to 11.7 T, and is sixfold higher on a per molecule basis. From this field dependence a rotational correlation time was estimated as 0.45(±0.02) ns. The imaging and pharmacokinetic properties of the dendrimer were compared to clinically used [Gd(DTPA)(H₂O)]^2? in mice at 4.7 T. On first pass, the higher per ion relaxivity of the dendrimer resulted in twofold greater blood signal than for [Gd(DTPA)(H₂O)]^2?. Blood clearance was fast and elimination occurred through both the renal and hepatobiliary routes. This Mn^II containing dendrimer represents a potential alternative to Gd‐based contrast agents, especially in patients with chronic kidney disease where the use of current Gd‐based agents may be contraindicated.     

Highly Water‐Dispersible Surface‐Modified Gd2O3 Nanoparticles for Potential Dual‐Modal Bioimaging

Water‐dispersible and luminescent gadolinium oxide (GO) nanoparticles (NPs) were designed and synthesized for potential dual‐modal biological imaging. They were obtained by capping gadolinium oxide nanoparticles with a fluorescent glycol‐based conjugated carboxylate (H L ). The obtained nanoparticles (GO‐ L ) show long‐term colloidal stability and intense blue fluorescence. In addition, L can sensitize the luminescence of europium(III) through the so‐called antenna effect. Thus, to extend the spectral ranges of emission, europium was introduced into L‐ modified gadolinium oxide nanoparticles. The obtained Eu^III‐doped particles (Eu:GO‐ L ) can provide visible red emission, which is more intensive than that without L capping. The average diameter of the monodisperse modified oxide cores is about 4 nm. The average hydrodynamic diameter of the L ‐modified nanoparticles was estimated to be about 13 nm. The nanoparticles show effective longitudinal water proton relaxivity. The relaxivity values obtained for GO‐ L and Eu:GO‐ L were r₁=6.4 and 6.3 s^?1 mM ^?1 with r₂/r₁ ratios close to unity at 1.4 T. Longitudinal proton relaxivities of these nanoparticles are higher than those of positive contrast agents based on gadolinium complexes such as Gd‐DOTA, which are commonly used for clinical magnetic resonance imaging. Moreover, these particles are suitable for cellular imaging and show good biocompatibility.     

Improved Transversal Relaxivity for Highly Crystalline Nanoparticles of Pure γ‐Fe2O3 Phase

Pure and highly crystalline γ‐Fe₂O₃ nanocrystals (NCs) are obtained when hydrolysis and oxidation of a Fe^II organometallic precursor are performed in successive steps. Their synthesis in pure alkylamine leads to NCs of about 6 nm. In aqueous solutions of poly(vinyl)pyrrolidone, such pristine NCs form aggregates of about 150 nm that exhibit a high transversal relaxivity (r₂=466 mM ^?1 s^?1) about four times higher than that of a commercial Feridex magnetic resonance imaging (MRI) contrast agent. Consequently, they provide a significant decrease in the NMR signal at very short echo time (8 ms), which is of paramount importance in clinical practice because of the reduced duration of MRI measurements.     

Amphiphilic Ditopic Bis‐Aqua Gd‐AAZTA‐like Complexes Enhance Relaxivity of Lipidic MRI Nanoprobes

Two amphiphilic mono‐ and dimeric GdAAZTA‐like chelates composed of stable bis‐aquo Gd^III complexes (q=2) linked to one (for the monomer) or two dodecyl aliphatic chains (for the dimer) were synthesized. Both chelates showed high relaxivity when incorporated into the lipid bilayer of liposomes or after interaction with human serum albumin (HSA). The ditopic complex shows a significantly decreased internal motion relative to the monomeric complex, associated with an enhanced relaxivity (r₁≈60 mm ^?1 s^?1, at 30 MHz and 310 K). The presence of two metal‐bound water molecules in fast exchange and the restricted rotational freedom make the relaxivity of this system the highest measured for paramagnetic liposomes.     

Synthesis and Characterization of a Hypoxia‐Sensitive MRI Probe

Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with a 2‐nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia‐sensitive MRI agent. A control complex, Gd(DO3A‐monobutylamide), was also prepared in order to test whether the nitroimidazole side‐chain alters either the water proton T₁ relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)^? as expected for mono‐amide derivatives. The water proton T₁ relaxivity (r₁), bound water residence lifetime (τ_M) and rotational correlation time (τ_R) of both complexes was determined by relaxivity measurements, variable temperature ¹⁷O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r₁=6.38 mM ^?1 s^?1 at 20 MHz , τ_M=0.71 μs, τ_R=141 ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A‐monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N₂ as evidenced by an approximately twofold decrease in T₁ measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.