High-Relaxivity and Luminescent Silica Nanoparticles As Multimodal Agents for Molecular Imaging

The design and synthesis of a new bimodal contrast agent for magnetic resonance imaging and optical imaging is reported. Tunable-sized silica nanoparticles were synthesized by a microemulsion-mediated pathway and used as carriers for paramagnetic and luminescent probes. The near-infrared luminescent agent was a ruthenium complex that was directly entrapped in the silica shell to provide photoluminescence enhancement and to make it highly photostable as it was protected from the surrounding environment. The paramagnetic activity came from a Gd-DTPA derivative that was grafted on the silica surface. NMRD profiles showed a strong relaxivity enhancement (increase of 432% in the <i>r</i>₁ value at 20 MHz) when the paramagnetic complex was grafted at the nanoparticle surface, because of a reduction of its mobility. Polyethylene glycol was also grafted at the nanoparticle surface to enhance the nanoparticle residence time in the bloodstream. A thorough characterization of the material confirmed its potential as a very effective bimodal contrast agent

Controlled Synthesis of a Novel Heteropolymetallic Complex with Selectively Incorporated Lanthanide(III) Ions

A novel synthetic strategy toward a heteropolymetallic lanthanide complex with selectively incorporated gadolinium and europium ions is outlined. Luminescence and relaxometric measurements suggest possible applications in bimodal (magnetic resonance/optical) imaging

Tetranuclear d‑f Metallostars: Synthesis, Relaxometric, and Luminescent Properties

A novel ditopic ligand DTPA-ph-phen, based on 1,10-phenanthroline and diethylenetriaminepentaacetic acid (DTPA) units, has been designed and fully characterized by ¹H, ¹³C, and 2D-COSY NMR spectroscopy, IR and electrospray ionization mass spectrometry (ESI-MS) techniques. The DTPA core of the ligand specifically binds Ln­(III) ions (Ln = Eu, Gd) resulting in formation of the [Ln­{DTPA-ph-phen}­(H₂O)]⁻ complex. The photophysical properties of the Eu­(III) compound have been investigated, and the complex shows characteristic red luminescence with an overall quantum yield of 2.2%. Reaction of [Gd­{DTPA-ph-phen}­(H₂O)]⁻ with Ru­(II) leads to further self-assembly into a heterobimetallic metallostar complex containing Gd­(III) and Ru­(II) in a 3:1 ratio. This tetranuclear [(Gd­{DTPA-ph-phen})₃(H₂O)₃Ru]⁻ complex (Gd₃Ru), formed by the coordination of Ru­(II) to the 1,10-phenanthroline unit, has been characterized by a range of experimental techniques and evaluated toward its feasibility as a potential bimodal optical/MRI agent. The Gd₃Ru metallostar shows intense metal-to-ligand charge transfer (MLCT) transition resulting in intense light absorption in the visible spectral region. Upon irradiation into this MLCT band at 450 nm, the Gd₃Ru complex exhibits red broad-band luminescence in the range of 550–800 nm centered at 610 nm with a quantum yield of 4.8%. Proton nuclear magnetic relaxation dispersion (NMRD) measurements indicate that the Gd₃Ru complex exhibits an enhanced relaxivity value <i>r</i>₁ of 36.0 s^–1 mM^–1 per metallostar molecule at 20 MHz and 310 K. The ability of the complex to noncovalently bind to human serum albumin (HSA) was investigated, but no significant interaction was detected

A Tripodal Ruthenium–Gadolinium Metallostar as a Potential α_vβ₃ Integrin Specific Bimodal Imaging Contrast Agent

Gd^III-containing <i>metallostar</i> contrast agents are gaining increased attention, because their architecture allows for a slower tumbling rate, which, in turn, results in larger relaxivities. So far, these <i>metallostars</i> find possible applications as blood pool contrast agents. In this work, the first example of a tissue-selective <i>metallostar</i> contrast agent is described. This RGD-peptide decorated Ru^II(Gd^III)₃ <i>metallostar</i> is synthesized as an α_vβ₃-integrin specific contrast agent, with possible applications in the detection of atherosclerotic plaques and tumor angiogenesis. The contrast agent showed a relaxivity of 9.65 s^–1 mM^–1, which represents an increase of 170%, compared to a low-molecular-weight analogue, because of a decreased tumbling rate (τ_R = 470 ps). The presence of the MLCT band (absorption 375–500 nm, emission 525–850 nm) of the central Ru^II(Ph-Phen)₃-based complex grants the <i>metallostar</i> attractive luminescent properties. The ³MLCT emission is characterized by a quantum yield of 4.69% and a lifetime of 804 ns, which makes it an interesting candidate for time-gated luminescence imaging. The potential application as a selective MRI contrast agent for α_vβ₃-integrin expressing tissues is shown by an <i>in vitro</i> relaxometric analysis, as well as an <i>in vitro</i> <i>T</i>₁-weighted MR image

Synthesis and Characterization of PEGylated and Fluorinated Chitosans: Application to the Synthesis of Targeted Nanoparticles for Drug Delivery

To synthesize chitosan nanoparticles (CS NPs), ionic gelation is a very attractive method. It relies on the spontaneous supramolecular assembly of cationic CS with anionic compounds, which leads to nanohydrogels. To extend ionic gelation to functionalized CS, the assessment of CS degree of substitution (DS_CS) is a key step. In this paper, we have developed a hyphenated strategy for functionalized CS characterization, based upon ¹H, DOSY and, when relevant, 1D diffusion-filtered ¹⁹F NMR spectroscopies. For that, we have synthesized two series of water-soluble CS via amidation of CS amino groups with mPEG₂₀₀₀-COOH or fluorinated synthons (TFB-COOH). The aforementioned NMR techniques helped to discriminate between ungrafted and grafted synthons and finally to determine DS_CS. According to DS_CS values, the selection of CS–mPEG₂₀₀₀ or CS–TFB copolymers can be made to obtain, in the presence of hyaluronic acid (HA) and tripolyphosphate (TPP), CS–mPEG₂₀₀₀–TPP/HA or CS–TFB–TPP/HA nanohydrogels suitable for drug delivery

Mastering the Shape and Composition of Dendronized Iron Oxide Nanoparticles To Tailor Magnetic Resonance Imaging and Hyperthermia

The current challenge in the field of nanomedicine is the design of multifunctional nano-objects effective both for the diagnosis and treatment of diseases. Here, dendronized FeO_1–<i>x</i>@Fe_3–<i>x</i>O₄ nanoparticles with spherical, cubic, and octopode shapes and oxidized Fe_3–<i>x</i>O₄ nanocubes have been synthesized and structurally and magnetically characterized. Strong exchange bias properties are highlighted in core–shell nanoparticles (NPs) due to magnetic interactions between their antiferromagnetic core and ferrimagnetic shell. Both <i>in vitro</i> relaxivity measurements and nuclear magnetic resonance (NMR) distribution profiles have confirmed the very good <i>in vitro</i> magnetic resonance imaging (MRI) properties of core–shell and cubic shape NPs, especially at low concentration. This might be related to the supplementary anisotropy introduced by the exchange bias properties and the cubic shape. The high heating values of core–shell NPs and oxidized nanocubes at low concentration are attributed to dipolar interactions inducing different clustering states, as a function of concentration. <i>In vivo</i> MRI studies have also evidenced a clustering effect at the injection point, depending on the concentration, and confirmed the very good <i>in vivo</i> MRI properties of core–shell NPs and oxidized nanocubes in particular at low concentration. These results show that these core–shell and cubic shape dendronized nano-objects are very suitable to combine MRI and hyperthermia properties at low injected doses

Functionalization of Small Rigid Platforms with Cyclic RGD Peptides for Targeting Tumors Overexpressing α_vβ₃‑Integrins

Gadolinium based Small Rigid Plaforms (SRPs) have previously demonstrated their efficiency for multimodal imaging and radiosensitization. Since the RGD sequence is well-known to be highly selective for α_vβ₃ integrins, a cyclic pentapeptide containing the RGD motif (cRGDfK) has been grafted onto the SRP surface. An appropriate protocol led to the grafting of two targeting ligands per nano-object. The resulting nanoparticles have demonstrated a strong association with α_vβ₃ integrins in comparison with cRADfK grafted SRPs as negative control. Flow cytometry and fluorescence microscopy have also been used to highlight the ability of the nanoparticles to target efficiently HEK293­(β3) and U87MG cells. Finally the grafted radiosensitizing nanoparticles were intravenously injected into <i>Nude</i> mice bearing subcutaneous U87MG tumors and the signal observed by optical imaging was twice as high for SRP-cRGDfK compared to their negative analogue