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Ultrasmall nanoparticles (US-NPs

Microencapsulation is being investigated as a means to avoid rejection of transplanted pancreatic islets. Monitoring bead distribution and stability in vivo is an important step toward improving microencapsulated islet transplantation strategies. Islet co-encapsulation with gadolinium-labeled mesoporous silica nanoparticles (Gd-MSNs) could allow bead visualization while immobilizing and limiting the potential internalization of the contrast agent. The porous nature of the MSNs could also be used to locally release anti-inflammatory, angiogenic, or anti-apoptotic factors. Mouse insulinoma 6 (MIN6) beta cells were co-encapsulated with Gd-MSNs in alginate beads produced by emulsification and internal gelation. Gd-MSN alginate beads appeared brighter in T1-weighted imaging sequences (detection threshold of 0.016 mM Gd; relaxometric ratio r2/r1 = 1.45) than beads without Gd-MSNs. No leaching of Gd3+ from the hydrogels was detected over the course of 3 months. MIN6 cells co-encapsulated with Gd-MSNs were viable...

When combined with 1H MRI, 19F MRI has the potential to combine high-resolution anatomical information with quantitative diagnostic. In this study, we report on the development of fluorinated mesoporous silica nanoparticles (MSNs), as dual 1H and 19F MRI probes. For this, MSNs were synthesised and covalently functionalized either with fluorosilane (FMSNs) or polyfluorosiloxane (polyFMSNs). Gadolinium chelates were also grafted on the particles, in order to confer 1H-MRI contrast enhancement to the imaging probes. Thus-treated nanoparticles were fully characterized and their 1H/19F relaxometric performances were thoroughly measured and compared. The 19F relaxation properties were found to be dependent on the concentration of fluorine; they were also highly sensitive to the presence of gadolinium. Better relaxivities were obtained with polyFMSNs, in comparison with those of FMSNs, leading to better 19F MRI sensitivity. Strong 1H relaxometric properties were also obtained for both nanoparticle systems, at la...

The fabrication of semiconductor products for the microelectronic industry requires the deposition of thin noble metal layers (e.g. Au-Sn and Pd) by means of processes involving fluid baths that contain metal ions (e.g. electrowinning and electroless plating). After several cycles, the plating solutions are used up and must be replaced, generating large volumes of discarded solutions containing precious metals. The metals (Au and Pd) are recovered either by electrowinning, a slow batch process, or by the use of toxic molecules (e.g. cyanides). This study demonstrates the possibility of using an atmospheric plasma technology to recover Au and Pd from these solutions, which provides a faster and greener process. Plasma discharges are generated at the surface of the solutions, causing ions to precipitate as nanoparticles. The treatment (few minutes only) allows the recovery of >95% gold, and >60% palladium. The process separates Au (NPs) from Sn ions (remaining in solution), as confirmed by elemental analysis and XPS. Particle size distributions of the nanoparticles recovered through the process suggests that as-synthesized nanoparticles could integrate value-added products (e.g. catalyst industry). Overall, the use of plasma technology could open several possibilities for the recycling of metals contained in solutions discarded from the semiconductor industry.

Mesoporous silica nanoparticles (MSNs) are considered as one of the most promising nanovectors for controlled drug delivery. For the design of ideal drug nanocarriers, several factors have to be taken into account, such as size and surface chemistry. Here, we report how MSNs surface functionalization and particle size critically affect the drug release performances and therapeutic capabilities. We illustrate the size effect of these functionalized MSNs on in vitro, intracellular, and in vivo drug release efficiency, as well as on nanoparticle and drug diffusion into the targeted tissues (tumor). For this, dispersible MSNs with different particle sizes (from 500 down to 45 nm), similar physicochemical properties (e.g., structural and textural properties), and high colloidal stability (even in saline conditions), were synthesized. Their surface was specifically functionalized with a phosphonate-silane according to a novel postgrafting strategy, for better control over loading and release of positively charg...

International audience; In this manuscript, we present a new strategy for the direct synthesis of functional nano-composite hybrid therapeutic vectors. The smart coupling of soft-chemistry and “ouzo effect” based emulsification processing allows us to create in a very simple way a Pickering stabilized emulsion from various prodrug modelling molecules used as a core, and subsequently embedded into a mesostructured silica shell. The resulting prodrug/Fe2O3/silica architecture offers a very good functionality/complexity ratio, realistic from a pharmaceutical development point of view at the industrial scale. While usual magnetic resonance imaging (MRI) contrast agent properties of maghemite nanoparticles are maintained, we proved for the first time that their smart localization at the organic/silica interface allows us to isolate them from phosphate anions of the surrounding environment, and thus to use their surface as a heterogeneous catalyst for controlled hydrolysis-mediated model drug delivery. This original hydrolysis-mediated release mechanism was investigated by grafting a model drug molecule via various covalent bonds. The release time can be tuned by this approach in between one hour and three days. In addition, magnetic radio frequency stimulation commonly used for hyperthermia treatment was able to accelerate the catalytic hydrolysis and release of the model drug by one order of magnitude, proving that drug release can be triggered on demand.

Colloidal ultrasmall superparamagnetic iron oxide nanoparticles (USNPs) with better control of their surface chemistry have been considered as a biocompatible alternative to clinically used gadolinium-based contrast agents for in vivo bright magnetic resonance imaging (MRI). Herein, we report a versatile mussel-inspired multidentate block copolymer strategy that allows for the stabilization of USNPs as promising MRI contrast agents with excellent colloidal stability. A well-controlled multidentate block copolymer with pendant multiple catechol groups (Cat-MDBC) is synthesized by a combination of controlled radical polymerization and postmodification methods. The Cat-MDBC proves to be effective to strongly anchor to USNP surfaces as well as provide optimal hydrophilic surfaces, thus enabling the fabrication of aqueous Cat-MDBC/USNP colloids at single layers with a diameter of ≈20 nm through a biphasic ligand exchange process. They exhibit excellent colloidal stability in broad pH range and physiological co...

Mesoporous silica nanoparticles (MSNs) are being developed as drug delivery vectors. Biomedical imaging (MRI and PET) enables their tracking in vivo, provided their surface is adequately grafted with imaging probes (metal chelates). However, MSNs are characterized by huge specific surfaces, and high-quality metal chelate anchoring procedures must be developed and validated, to demonstrate that their detection in vivo is associated to the presence of nanoparticles and not to detached metal chelates. MCM-48 nanospheres (M48SNs, 150 nm diam., 3-D pore geometry) were synthesized and functionalized with diethylenetriaminepentaacetic acid (DTPA). The strong grafting of DTPA was confirmed by 29Si MAS-NMR, XPS, FTIR and TGA. The particles were labeled with paramagnetic ions Gd3+ (for MRI) as well as radioactive ions 64Cu2+ (for PET; half-life: 12.7 h). Gd3+-DTPA-M48SNs formed a stable colloid in saline media for at least 6 months, without any sign of aggregation. The relaxometric properties were measured at various magnetic fields. The strength of DTPA binding at the surface of MSNs was also assessed in vivo, by injecting mice (i.v.) with Gd3+/64Cu2+-DTPA-M48SNs. Vascular retention and urinary clearance were monitored by MRI, whereas the PET modality provided dynamic and quantitative assessment of biodistribution and blood/organ clearance. No significant 64Cu activity was detectable in the bladder. The study confirmed the very limited detachment of DTPA from M48SNs cores once injected in vivo. The transit of MSNs through the liver and intestinal tract, does not lead to evidence of Gd3+/64Cu2+-DTPA in the urine. This physico-chemical and biodistribution study confirms the quality of DTPA attachment at the surface of the particles, necessary to allow further development of PET/MRI-assisted MSN-vectorized drug delivery procedures.

The radioisotope palladium (103Pd), encapsulated in millimetre-size seed implants, is widely used in prostate cancer brachytherapy. Gold nanoparticles (Au NPs) distributed in the vicinity of 103Pd radioactive implants, strongly enhance the therapeutic dose of radioactive implants (radiosensitisation effect). A new strategy under development to replace millimetre-size implants, consist in injecting radioactive NPs in the affected tissues. The development of 103Pd@Au NPs distributed in the diseased tissue, could increase the uniformity of treatment (compared with massive seeds), while enhancing the radiotherapeutic dose to the cancer cells (through Au-mediated radiosensitisation effect). To achieve this goal, it is necessary to develop a rapid, efficient, one-pot and easy-to-automatise procedure, allowing the synthesis of core-shell Pd@Au NPs. The novel synthesis route proposed here enables the production of Pd@Au NPs in not more than 4 h, in aqueous media, with minimal manipulations, and relying on biocompatible and non-toxic molecules. This rapid multi-step process consists of the preparation of ultra-small Pd NPs by chemical reduction of an aqueous solution of H2PdCl4 supplemented with ascorbic acid (AA) as reducing agent and 2,3-meso-dimercaptosuccinic acid (DMSA) as a capping agent. Pd conversion yields close to 87% were found, indicating the efficiency of the reaction process. Then Pd NPs were used as seeds for the growth of a gold shell (Pd@Au), followed by grafting with polyethylene glycol (PEG) to ensure colloidal stability. Pd@Au-PEG (TEM: 20.2 ± 12.1 nm) formed very stable colloids in saline solution as well as in cell culture medium. The physico-chemical properties of the particles were characterised by FTIR, XPS, and UV-vis. spectroscopies. The viability of PC3 human prostate cancer cells was not affected after a 24 h incubation cycle with Pd@Au-PEG NPs to concentrations up to 4.22 mM Au. Finally, suspensions of Pd@Au-PEG NPs measured in computed tomography (CT) are found to attenuate X-rays more efficiently than commercial Au NPs CT contrast media. A proof-of-concept was performed to demonstrate the possibility synthesise radioactive 103Pd:Pd@Au-PEG NPs. This study reveals the possibility to synthesise Pd@Au NPs rapidly (including radioactive 103Pd:Pd@Au-PEG NPs), and following a methodology that respects all the strict requirements underlying the production of NPs for radiotherapeutic use (rapidity, reaction yield, colloidal stability, NPs concentration, purification).

Mesoporous silica nanoparticles (MSNs) have emerged as promising bio- materials for drug delivery and cell tracking applications, for which MRI is the medical imaging modality of choice. In this contribution, MRI contrast agents (DTPA-Gd) and polyethylene glycol (PEG) are grafted selectively at the surface of MSNs, in order to achieve optimal relaxometric and drug loading performances. In fact, DTPA and PEG grafting procedures reported until now, have resulted in signifi cant pore obstruction, which is detrimental to the drug delivery function of MSNs. This usually induces a dramatic decrease in surface area and pore volume, thus limiting drug loading capacity. Therefore, these molecules must be selectively grafted at the outer surface of MSNs. In this study, 3D pore network MSNs (MCM-48-type) are synthesized and func- tionalized with a straightforward and effi cient grafting procedure in which DTPA and PEG are selectively grafted at the outer surface of MSNs. No pore blocking is observed, and more than 90% of surface area, pore volume and pore diameter are retained. The thus-treated particles are colloidally stable in SBF and cell culture media, they are not cytotoxic and they have high drug loading capacity. Upon labeling with Gd, the nanoparticle suspensions have strong relaxometric properties (r 2 /r 1 = 1.47, r 1 = 23.97 mM −1 s −1 ), which con- fers a remarkable positive contrast enhancement potential to the compound. The particles could serve as effi cient drug carriers, as demonstrated with a model of daunorubicin submitted to physiological conditions. The selective nanoparticle surface grafting procedures described in the present article represent a signifi cant advance in the design of high colloidal stability silica- based vectors with high drug loading capacity, which could provide novel theranostic nanocompounds.

Magnetic resonance imaging (MRI) has developed at an exponential rate over the last decades, and the development of contrast agents to enhance the visualization of organs has followed the same trend. Meanwhile, magnetic nanoparticles that generate either “positive” or “negative” contrast in MRI have become one of the most important biomedical applications of nanotechnology. Indeed, superparamagnetic iron oxide nanoparticles, as negative contrast agents for T 2/T 2 * -weighted imaging, have found numerous applications in preclinical and clinical MRI (cell labeling, vascular contrast, lymph node imaging, liver contrast). In addition to this, paramagnetic and antiferromagnetic nanoparticles based on the elements Gd3+ and Mn2+ have mainly been exploited in vascular procedures and targeted imaging, for their capacity to enhance the MR signal of blood and of molecular signatures of endovascular disease. They are commonly referred to as “positive” contrast agents for T 1-weighted imaging.

In recent years, pulsed laser ablation in liquids (PLAL) has emerged as a new green chemistry method to produce different types of nanoparticles (NPs). It does not require the use of reducing or stabilizing agents, therefore enabling the synthesis of NPs with highly-pure surfaces. In this study, pure Au NPs were produced by PLAL in aqueous solutions, sterically stabilized using minimal PEG excess, and functionalized with manganese chelates to produce a dual CT/MRI contrast agent. The small hydrodynamic size (36.5 nm), low polydispersity (0.2) and colloidal stability of Au NPs@PEG-Mn2+ were demonstrated by DLS. The particles were further characterized by TEM, XPS, FTIR and 1H NMR to confirm the purity of the Au surfaces (i.e. free from the common residual chemicals found after NP synthesis) and the presence of the different surface molecules. The potential of these particles as contrast agents for CT/MRI was assessed in vivo (e.g. chicken embryo). Au NPs@PEG-Mn2+ also demonstrated strong blood retention for at least 90 minutes following intravenous injection in mouse models. The promising performance of PEGylated PLAL-synthesized Au NPs containing manganese chelates could open new possibilities for the production of purer dual imaging contrast agents based on Au colloids.

International audience; Persistent luminescence and magnetic properties of Gd2O2S: Eu 3+ , Ti 4+ , Mg 2+ nanoparticles have been studied to attest the relevance of such nanoparticles as nanoprobes for multimodal imaging. The development of new imaging tools is required to improve the quality of medical images and then to diagnose some disorders as quickly as possible in order to ensure more effective treatment. Multimodal imaging agents here developed combine the high resolution abilities of Magnetic Resonance Imaging (MRI) with another more sensitive technique, like optical imaging, leading significant possibilities for early detection of diseases and a better understanding of pathologies. Recently, inorganic persistent luminescent nanoparticles (i-PLNPs) have been reported as suitable probes for in vivo imaging that meet the difficulties due to the biological environment. The i-PLNPs are first excited by a UV light for a few minutes outside the animal before injection and emit in the border of the red/NIR window for hours after the injection. In this paper, we explore a new chemical composition of host lattice doped with transition metal and lanthanide ions for persistent luminescence that contains a paramagnetic centre conferring additional magnetic properties for a use in MRI, and that can be obtained at the nanoscale. Thus, advanced Gd2O2S nanoparticles exhibiting both persistent luminescence and paramagnetic properties have been synthesized and fully characterized. Their luminescent properties were determined as well as their magnetic properties. One compound sample with composition Gd2O2S: Eu 3+ (5%), Ti 4+ (1%), Mg 2+ (8%) presents both optical and magnetic properties suitable for a bimodal imaging probe. Indeed, it shows an afterglow in the red range at 620 nm and a relaxivity corresponding to r2 / r1 ratio of 1.28.

Ultrasmall paramagnetic Gd(2)O(3) nanoparticles have been developed as contrast agents for molecular and cellular preclinical MRI procedures. These small particles (mean diameter

Thin films made of mesoporous silica nanoparticles (MSNs) are finding new applications in catalysis, optics, as well as in biomedicine. The fabrication of MSNs thin films requires a precise control over the deposition and sintering of MSNs on flat substrates. In this study, MSNs of narrow size distribution (150 nm) are synthesized, and then assembled onto flat silicon substrates, by means of a dip-coating process. Using concentrated MSN colloidal solutions (19.5 mg mL(-1) SiO2), withdrawal speed of 0.01 mm s(-1), and well-controlled atmospheric conditions (ambient temperature, ∼ 70% of relative humidity), monolayers are assembled under well-structured compact patterns. The thin films are sintered up to 900 °C, and the evolution of the MSNs size distributions are compared to those of their pore volumes and densities. Particle size distributions of the sintered thin films were precisely fitted using a model specifically developed for asymmetric particle size distributions. With increasing temperature, there is first evidence of intraparticle reorganization/relaxation followed by intraparticle sintering followed by interparticle sintering. This study is the first to quantify the impact of sintering on MSNs assembled as thin films.

Mesoporous silica nanoparticles (MSNs) are of growing interest for the development of novel probes enabling efficient tracking of cells in vivo using magnetic resonance imaging (MRI). The incorporation of Gd3+ paramagnetic ions into highly porous MSNs is a powerful strategy to synthesize “positive” MRI contrast agents for more quantitative T1-weighted MR imaging. Within this context, different strategies have been reported to integrate Gd chelates to 2D pore network MSNs. As an alternative, we report on the modulation of the pore network topology through the preparation of a 3D pore network hybrid GdSixOy MSN system. In this study, 2D GdSixOy-MSNs with similar porosity and particle size were also prepared and the relaxometric performances of both materials, directly compared. Both syntheses lead to water-dispersible MSNs suspensions (particle size < 200 nm), which were stable for at least 48h. 3D GdSixOy-MSNs provided a significant increase in 1H longitudinal relaxivity (18.5 s−1mM−1; 4.6 times higher than Gd-DTPA) and low r2/r1 ratios (1.56) compatible with the requirements of “positive” contrast agents for MRI. These results demonstrate the superiority of a 3D pore network to host paramagnetic atoms for MRI signal enhancement using T1-weighted imaging. Such an approach minimizes the total amount of paramagnetic element per particle.

Ultrasmall gadolinium oxide nanoparticles doped with terbium ions were synthesized by the polyol route and characterized as a potentially bifunctional material with both fluorescent and magnetic co ...

Progresses in cold atmospheric plasma technologies have made possible the synthesis of nanoparticles in aqueous solutions using plasma electrochemistry principles. In this contribution, a reactor based on microhollow cathodes and operating at atmospheric pressure was developed to synthesize iron-based nanoclusters (nanoparticles). Argon plasma discharges are generated at the tip of the microhollow cathodes, which are placed near the surface of an aqueous solution containing iron salts (FeCl2 and FeCl3) and surfactants (biocompatible dextran). Upon reaction at the plasma-liquid interface, reduction processes occur and lead to the nucleation of ultrasmall iron-based nanoclusters (IONCs). The purified IONCs were investigated by XPS and FTIR, which confirmed that the nucleated clusters contain a highly hydrated form of iron oxide, close to the stoichiometric constituents of α-FeOOH (goethite) or Fe5O3(OH)9 (ferrihydrite). Relaxivity values of r1 = 0.40 mM(-1) s(-1) and r2/r1 = 1.35 were measured (at 1.41 T); these are intermediate values between the relaxometric properties of superparamagnetic iron oxide nanoparticles used in medicine (USPIO) and those of ferritin, an endogenous contrast agent. Plasma-synthesized IONCs were injected into the mouse model and provided positive vascular signal enhancement in T1-w. MRI for a period of 10-20 min. Indications of rapid and strong elimination through the urinary and gastrointestinal tracts were also found. This study is the first to report on the development of a compact reactor suitable for the synthesis of MRI iron-based contrast media solutions, on site and upon demand.

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) with diameters5 nm hold great promise as T1-positive contrast agents for in vivo magnetic resonance imaging. However, control of the surface chemistry of USPIOs to ensure individual colloidal USPIOs with a ligand monolayer and to impart biocompatibility and enhanced colloidal stability is essential for successful clinical applications. Herein, an effective and versatile strategy enabling the development of aqueous colloidal USPIOs stabilized with well-defined multidentate block copolymers (MDBCs) is reported. The multifunctional MDBCs are designed to consist of an anchoring block possessing pendant carboxylates as multidentate anchoring groups strongly bound to USPIO surfaces and a hydrophilic block having pendant hydrophilic oligo(ethylene oxide) chains to confer water dispersibility and biocompatibility. The surface of USPIOs is saturated with multiple anchoring groups of MDBCs, thus exhibiting excellent long-term colloidal stability as well as enhanced colloidal stability at biologically relevant electrolyte, pH, and temperature conditions. Furthermore, relaxometric properties as well as in vitro and in vivo MR imaging results demonstrate that the MDBC-stabilized USPIO colloids hold great potential as an effective T1 contrast agent.

Tripositive gadolinium-ion doped NIR-to-NIR upconverting paramagnetic nanoparticles are efficiently detected are NIR imaging techniques but can also provide efficient "positive" contrast in MRI. On page 1478 John A. Capobianco, Marc-Andre Fortin, and co-workers show that citrate-coated nanoparticles present the lowest relaxometric ratios reported for NaGdF4 nanoparticle suspensions. IV-injected nanoparticles evidence long blood retention times in mice while biodistribution studies show elimination through the reticuloendothelial and urinary systems.

Mesoporous silica nanoparticles (MSNs) are used in drug delivery and cell tracking applications. As Mn(2+) is already implemented as a "positive" cell contrast agent in preclinical imaging procedures (in the form of MnCl2 for neurological studies), the introduction of Mn in the porous network of MSNs would allow labelling cells and tracking them using MRI. These particles are in general internalized in endosomes, an acidic environment with high saline concentration. In addition, the available MSN porosity could also serve as a carrier to deliver medical/therapeutic substances through the labelled cells. In the present study, manganese oxide was introduced in the porous network of MCM-48 silica nanoparticles (Mn-M48SNs). The particles exhibit a narrow size distribution (~140 nm diam.) and high porosity (~60% vol.), which was validated after insertion of Mn. The resulting Mn-M48SNs were characterized by TEM, N2 physisorption, and XRD. Evidence was found with H2-TPR, and XPS characterization, that Mn(II) is the main oxidation state of the paramagnetic species after suspension in water, most probably in the form of Mn-OOH. The colloidal stability as a function of time was confirmed by DLS in water, acetate buffer and cell culture medium. In NMR data, no significant evidence of Mn(2+) leaching was found in Mn-M48SNs in acidic water (pH 6), up to 96 hours after suspension. High longitudinal relaxivity values of r1 = 8.4 mM(-1) s(-1) were measured at 60 MHz and 37 °C, with the lowest relaxometric ratios (r2/r1 = 2) reported to date for a Mn-MSN system. Leukaemia cells (P388) were labelled with Mn-M48SNs and nanoparticle cell internalization was confirmed by TEM. Finally, MRI contrast enhancement provided by cell labelling with escalated incubation concentrations of Mn-M48SNs was quantified at 1 T. This study confirmed the possibility of efficiently confining Mn into M48SNs using incipient wetness, while maintaining an open porosity and relatively high pore volume. Because these Mn-labelled M48SNs express strong "positive" contrast media properties at low concentrations, they are potentially applicable for cell tracking and drug delivery methodologies.

Near-infrared (NIR)-to-NIR upconverting NaY(Gd)F4 :Tm(3+) ,Yb(3+) paramagnetic nanoparticles (NPs) are efficiently detected by NIR imaging techniques. As they contain Gd(3+) ions, they also provide efficient "positive" contrast in magnetic resonance imaging (MRI). Water-dispersible small (≈25 nm, "S-") and ultrasmall (5 nm diam., "US-") NaY(Gd)F4 :Tm(3+) ,Yb(3+) NPs are synthesized by thermal decomposition and capped with citrate. The surface of citrate-coated US-NPs shows sodium depletion and high Gd elemental ratios, as confirmed by a comparative X-ray photoelectron spectroscopy (XPS)/neutron absorption analysis study. US-NaGd0.745 F4 :Tm0.005 ,Yb0.25 NPs have hydrodynamic diameters close to that measured by TEM, with the lowest relaxometric ratios (r2 /r1 = 1.18) reported for NaGdF4 nanoparticle suspensions (r1 = 3.37 mM(-1) s(-1) at 1.4 T and 37 °C). Strong relaxivity peaks in the range of 20 (0.47 T) - 300 MHz (7.05 T) are revealed in nuclear magnetic resonance dispersion profiles, with high r2 /r1 ratios at increasing field strengths for S-NPs. This indicates the superiority of US-NPs over S-NPs for achieving high positive contrast at clinical MRI field strengths. I.-v. injected citrate-coated US-NPs evidence long blood retention times (90 min) in mice. Biodistribution studies (48 h, 8 d) show elimination through the reticuloendothelial and urinary systems, similarly to other citrate-capped US-NP systems. In summary, upconverting NaY(Gd)F4 :Tm(3+) ,Yb(3+) nanoparticles have promising luminescent, relaxometric and blood-retention properties for dual MRI/optical imaging.

Manganese oxide (MnO) nanoparticles have been suggested as a promising "positive" MRI contrast agent for cellular and molecular studies. Mn-based contrast agents could enable T(1)-weighted quantitative cell tracking procedures in vivo based on signal enhancement. In this study, ultrasmall MnO particles were synthesized and coated with thiolated molecules (DMSA) and polyethylene glycol (PEG) to allow enhanced cell labeling properties and colloidal stability. This coating allowed the fabrication of individual ultrasmall nanoparticles of MnO (USPMnO) as well as of nanoaggregates of the same material (SPMnO). Particle size was measured by TEM and DLS. Physico-chemical properties were characterized by XPS and FTIR. The relaxometric properties of these aqueous suspensions were measured at various magnetic fields. The suspensions provided strong positive contrast enhancement in T(1)-weighted imaging due to high longitudinal relaxivities (r(1)) and low r(2)/r(1) ratios (USPMnO: r(1) = 3.4 ± 0.1 mM(-1)s(-1), r(2)/r(1) = 3.2; SPMnO: r(1) = 17.0 ± 0.5 mM(-1)s(-1), r(2)/r(1) = 4.0, at 1.41T). HT-1080 cancer cells incubated with the contrast agents were clearly visualized in MRI for Mn contents1.1 pg Mn/cell. The viability of cells was not affected, contrarily to cells labeled with an equivalent concentration of Mn(2+) ions. A higher signal per cell was found for SPMnO-labeled compared with USPMnO-labeled cells, due to the higher relaxometric properties of the agglomerates. As a result, the "positive" signal enhancement effect is not significantly affected upon agglomeration of MnO particles in endosomes. This is a major requirement in the development of reliable cell tracking procedures using T(1)-weighted imaging sequences. This study confirms the potential of SPMnO and USPMnO to establish more quantitative cell tracking procedures with MRI.

The performance of nanomaterials for biomedical applications is highly dependent on the nature and the quality of surface coatings. In particular, the development of functionalized nanoparticles for magnetic resonance imaging (MRI) requires the grafting of hydrophilic, nonimmunogenic, and biocompatible polymers such as poly(ethylene glycol) (PEG). Attached at the surface of nanoparticles, this polymer enhances the steric repulsion and therefore the stability of the colloids. In this study, phosphate molecules were used as an alternative to silanes or carboxylic acids, to graft PEG at the surface of ultrasmall gadolinium oxide nanoparticles (US-Gd(2)O(3), 2-3 nm diameter). This emerging, high-sensitivity "positive" contrast agent is used for signal enhancement in T(1)-weighted molecular and cellular MRI. Comparative grafting assays were performed on Gd(2)O(3) thin films, which demonstrated the strong reaction of phosphate with Gd(2)O(3) compared to silane and carboxyl groups. Therefore, PEG-phosphate was preferentially used to coat US-Gd(2)O(3) nanoparticles. The grafting of this polymer on the particles was confirmed by XPS and FTIR. These analyses also demonstrated the strong attachment of PEG-phosphate at the surface of Gd(2)O(3), forming a protective layer on the nanoparticles. The stability in aqueous solution, the relaxometric properties, and the MRI signal of PEG-phosphate-covered Gd(2)O(3) particles were also better than those from non-PEGylated nanoparticles. As a result, reacting PEG-phosphate with Gd(2)O(3) particles is a promising, rapid, one-step procedure to PEGylate US-Gd(2)O(3) nanoparticles, an emerging "positive" contrast agent for preclinical molecular and cellular applications.

Ultra-small gadolinium oxide nanoparticles (US-Gd(2)O(3)) are used to provide 'positive' contrast effects in magnetic resonance imaging (MRI), and are being considered for molecular and cellular imaging applications. However, these nanoparticles can aggregate over time in aqueous medium, as well as when internalized into cells. This study is aimed at measuring in vitro, in aqueous medium, the impact of aggregation on the relaxometric properties of paramagnetic US-Gd(2)O(3) particles. First, the nanoparticle core size as well as aggregation behaviour was assessed by HRTEM. DLS (hydrodynamic diameter) was used to measure the hydrodynamic diameter of nanoparticles and nanoaggregates. The relaxometric properties were measured by NMRD profiling, as well as with (1)H NMR relaxometers. Then, the positive contrast enhancement effect was assessed by using magnetic resonance scanners (at 1.5 and 7 T). At every magnetic field, the longitudinal relaxivity (r(1)) decreased upon agglomeration, while remaining high enough to provide positive contrast. On the other hand, the transverse relaxivity (r(2)) slightly decreased at 0.47 and 1.41 T, but it was enhanced at higher fields (7 and 11.7 T) upon agglomeration. All NMRD profiles revealed a characteristic relaxivity peak in the range 60-100 MHz, suggesting the possibility to use US-Gd(2)O(3) as an efficient 'positive-T(1)' contrast agent at clinical magnetic fields (1-3 T), in spite of aggregation.

The majority of contrast agents used in magnetic resonance imaging (MRI) is based on the rare-earth element gadolinium. Gadolinium-based nanoparticles could find promising applications in pre-clinical diagnostic procedures of certain types of cancer, such as glioblastoma multiforme. This is one of the most malignant, lethal and poorly accessible forms of cancer. Recent advances in colloidal nanocrystal synthesis have led to the development of ultra-small crystals of gadolinium oxide (US-Gd(2)O(3), 2-3 nm diameter). As of today, this is the smallest and the densest of all Gd-containing nanoparticles. Cancer cells labeled with a sufficient quantity of this compound appear bright in T(1)-weighted MRI images. Here we demonstrate that US-Gd(2)O(3) can be used to label GL-261 glioblastoma multiforme cells, followed by localization and visualization in vivo using MRI. Very high amounts of Gd are efficiently internalized and retained in cells, as confirmed with TEM and ICP-MS. Labeled cells were visualized in vivo at 1.5 T using the chicken embryo model. This is one more step toward the development of "positively contrasted" cell tracking procedures with MRI.

The size distribution and magnetic properties of ultra-small gadolinium oxide crystals (US-Gd2O3) were studied, and the impact of polyethylene glycol capping on the relaxivity constants (r1, r2) an ...