Claire Billotey

Gadolinium Chelate Coated Gold Nanoparticles As Contrast Agents for Both X-ray Computed Tomography and Magnetic Resonance Imaging

Functionalized gold nanoparticles were applied as contrast agents for both in vivo X-ray and magnetic resonance imaging. These particles were obtained by encapsulating gold cores within a multilayered organic shell which is composed of gadolinium chelates bound to each other through disulfide bonds. The contrast enhancement in MRI stems from the presence of gadolinium ions which are entrapped in the organic shell, whereas the gold core provides a strong X-ray absorption. This study revealed that these particles suited for dual modality imaging freely circulate in the blood vessels without undesirable accumulation in the lungs, spleen, and liver.

Toward an image-guided microbeam radiation therapy using gadolinium-based nanoparticles.

Ultrasmall gadolinium-based nanoparticles (GBNs) induce both a positive contrast for magnetic resonance imaging and a radiosentizing effect. The exploitation of these characteristics leads to a greater increase in lifespan of rats bearing brain tumors since the radiosensitizing effect of GBNs can be activated by X-ray microbeams when the gadolinium content is, at the same time, sufficiently high in the tumor and low in the surrounding healthy tissue. GBNs exhibit therefore an interesting potential for image-guided radiotherapy.

The role of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography in disseminated carcinoma of unknown primary site

The authors conducted a comprehensive review of the efficacy of 2‐deoxy‐2‐[F‐18]fluoro‐D‐glucose positron emission tomography (FDG‐PET) in the detection of primary tumors in patients with disseminated carcinoma of unknown primary site.

Biodistribution study of nanometric hybrid gadolinium oxide particles as a multimodal SPECT/MR/optical imaging and theragnostic agent.

Nanometric hybrid gadolinium oxide particles (Gado-6Si-NP) for diagnostic and therapeutic applications (mean diameter 3-4 nm) were obtained by encapsulating Gd(2)O(3) cores within a polysiloxane shell, which carries organic fluorophore (Cy 5) and is derivatized by a hydrophilic carboxylic layer. As residency time in the living body and methods of waste elimination are crucial to defining a good nanoparticle candidate and moving forward with steps for validation, this study was aimed at evaluating the biodistribution of these multimodal Gado-6Si-NP in rodents. Gado-6Si-NP were imaged following intravenous injection in control Wistar rats and mice using MRI (7 T), optical fluorescent imaging, and SPECT. A clear correlation was observed among MRI, optical imaging, and SPECT regarding the renal elimination. Quantitative biodistribution using gamma-counting of each sampled organ confirmed that these nanoparticles circulated freely in the blood pool and were rapidly cleared by renal excretion without accumulation in liver and RES uptake. These results demonstrate that Gado-6Si-NP display optimal biodistribution properties, enabling them to be developed as multimodal agents for in vivo imaging and theragnostics, especially in oncological applications.

Dendronized iron oxide nanoparticles for multimodal imaging

The synthesis of small-size dendrons and their grafting at the surface of iron oxide nanoparticles were achieved with the double objective to obtain a good colloidal stability with a mean hydrodynamic diameter smaller than 100 nm and to ensure the possibility of tuning the organic coating characteristics including morphology, functionalities, physico-chemical properties, grafting of fluorescent or targeting molecules. Magnetic resonance and fluorescence imaging are then demonstrated to be simultaneously possible using such versatile superparamagnetic iron oxide nanocrystals covered by a dendritic shell displaying either carboxylate or ammonium groups at their periphery which could be further labelled with a fluorescent dye. The grafting conditions of these functionalized dendrons at the surface of SPIO NPs synthesized by co-precipitation have been optimized as a function of the nature of the peripheral functional group. The colloidal stability has been investigated in water and osmolar media, and in vitro and in vivo MRI and optical imaging measurements have been performed showing encouraging biodistribution.

Hybrid gadolinium oxide nanoparticles combining imaging and therapy

The cytotoxicity of luminescent paramagnetic gadolinium oxide nanoparticles activated by harmless thermal neutron irradiation was evaluated on a luciferase coding gene transfected lymphome cells (EL4-Luc). Cellular uptake of nanoparticles was determined by fluorescence and magnetic resonance imaging and by ICP-MS analyses while the metabolic activity of irradiated EL4-Luc cells was monitored by bioluminescence. The alteration of the irradiated cells depends both on neutron irradiation dose and on gadolinium content within cells. In addition to their dual modality imaging ability, the application of these multifunctional particles for neutron capture therapy can be envisaged.

Multifunctional Peptide-Conjugated Hybrid Silica Nanoparticles for Photodynamic Therapy and MRI

Photodynamic therapy (PDT) is an emerging theranostic modality for various cancer as well as non-cancer diseases. Its efficiency is mainly based on a selective accumulation of PDT and imaging agents in tumor tissue. The vascular effect is widely accepted to play a major role in tumor eradication by PDT. To promote this vascular effect, we previously demonstrated the interest of using an active- targeting strategy targeting neuropilin-1 (NRP-1), mainly over-expressed by tumor angiogenic vessels. For an integrated vascular-targeted PDT with magnetic resonance imaging (MRI) of cancer, we developed multifunctional gadolinium-based nanoparticles consisting of a surface-localized tumor vasculature targeting NRP-1 peptide and polysiloxane nanoparticles with gadolinium chelated by DOTA derivatives on the surface and a chlorin as photosensitizer. The nanoparticles were surface-functionalized with hydrophilic DOTA chelates and also used as a scaffold for the targeting peptide grafting. In vitro investigations demonstrated the ability of multifunctional nanoparticles to preserve the photophysical properties of the encapsulated photosensitizer and to confer photosensitivity to MDA-MB-231 cancer cells related to photosensitizer concentration and light dose. Using binding test, we revealed the ability of peptide-functionalized nanoparticles to target NRP-1 recombinant protein. Importantly, after intravenous injection of the multifunctional nanoparticles in rats bearing intracranial U87 glioblastoma, a positive MRI contrast enhancement was specifically observed in tumor tissue. Real-time MRI analysis revealed the ability of the targeting peptide to confer specific intratumoral retention of the multifunctional nanoparticles.

Assembly of Double-Hydrophilic Block Copolymers Triggered by Gadolinium Ions: New Colloidal MRI Contrast Agents.

Mixing double-hydrophilic block copolymers containing a poly(acrylic acid) block with gadolinium ions in water leads to the spontaneous formation of polymeric nanoparticles. With an average diameter near 20 nm, the nanoparticles are exceptionally stable, even after dilution and over a large range of pH and ionic strength. High magnetic relaxivities were measured in vitro for these biocompatible colloids, and in vivo magnetic resonance imaging on rats demonstrates the potential utility of such polymeric assemblies.

Biodistribution of ultra small gadolinium-based nanoparticles as theranostic agent: Application to brain tumors

Gadolinium-based nanoparticles are novel objects with interesting physical properties, allowing their use for diagnostic and therapeutic applications. Gadolinium-based nanoparticles were imaged following intravenous injection in healthy rats and rats grafted with 9L gliosarcoma tumors using magnetic resonance imaging and scintigraphic imaging. Quantitative biodistribution using gamma-counting of each sampled organ confirmed that these nanoparticles were rapidly cleared essentially by renal excretion. Accumulation of these nanoparticles in 9L gliosarcoma tumors implanted in the rat brain was quantitated. This passive and long-duration accumulation of gadolinium-based nanoparticles in tumor, which is related to disruption of the blood–brain barrier, is in good agreement with the use of these nanoparticles as radiosensitizers for brain tumors.

Effect of the nanoparticle synthesis method on dendronized iron oxides as MRI contrast agents

Aqueous suspensions of dendronized iron oxide nanoparticles (NPs) have been obtained after functionalization, with two types of dendrons, of NPs synthesized either by coprecipitation (leading to naked NPs in water) or by thermal decomposition (NPs in situ coated by oleic acid in an organic solvent). Different grafting strategies have been optimized depending on the NPs synthetic method. The size distribution, the colloidal stability in isoosmolar media, the surface complex nature as well as the preliminary biokinetic studies performed with optical imaging, and the contrast enhancement properties evaluated through in vitro and in vivo MRI experiments, have been compared as a function of the nature of both dendrons and NPs. All functionalized NPs displayed good colloidal stability in water, however the ones bearing a peripheral carboxylic acid function gave the best results in isoosmolar media. Whereas the grafting rates were similar, the nature of the surface complex depended on the NPs synthetic method. The in vitro contrast enhancement properties were better than commercial products, with a better performance of the NPs synthesized by coprecipitation. On the other hand, the NPs synthesized by thermal decomposition were more efficient in vivo. Furthermore, they both displayed good biodistribution with renal and hepatobiliary elimination pathways and no consistent RES uptake.