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Recent advances in nanotechnology have attracted significant attention to nanodiamonds (NDs) in both industrial and research areas thanks to their remarkable intrinsic properties: large specific area, poor cytotoxicity, chemical resistance, magnetic and optical properties, ease of large-scale production, and surface reactivity make them suitable for numerous applications, including electronics, optics, sensors, polishing materials, and more recently, biological purposes. Growing interest in diamond platforms for bioimaging and chemotherapy is observed. Given the outstanding features of these particles and their ease of tuning, current and future applications in medicine have the potential to display innovative imaging applications and to be used as tools for monitoring and tracking drug delivery in vivo.

Bimodal sub-5 nm superparamagnetic iron oxide nanoparticles (SPIO-5) coated with polyethylene glycol of different chain lengths (i.e. PEG-800, -2000 and -5000) have been prepared and characterized. Fluorescence properties have been obtained by mean of the grafting of a near-infrared-emitting dye (NIR-dye) onto the surface of the oxide, thanks to the carboxylic acid functions introduced towards an organosilane coating. Such modification allowed us to follow in vivo their biodistribution and elimination pathways by T1-w and T2-w high-field magnetic resonance imaging (MRI), as well as by optical and optoacoustic imaging. Interestingly, it has been highlighted that for a given composition, the thickness of the coating strongly influences the pharmacokinetic properties of the administrated SPIO-5.

The preparation of an efficient bimodal single probe for magnetic resonance (MRI) and optical imaging (OI) is reported. Paramagnetic properties have been obtained by the non-covalent encapsulation of the clinically used Gd3+ chelate (i.e., Gd-HP-DO3A) within silica nanoparticles through a water-in-oil microemulsion process. To ensure colloidal stability, the surface of the particles was modified by means of treatment using PEG-silane, and further functionalized photochemically using a diazirine linker bearing carboxylic functions. Optical properties were obtained by the covalent grafting of a near-infrared emitting probe (NIR) on the resulting surface. The confinement of Gd complexes within the permeable matrix resulted in a significant increase in longitudinal relaxivities (>500% at 20 MHz) in comparison with the relaxivities of free chelate, while the post-functionalization process of PEG with fluorescent compounds appeared promising for the derivatization procedure. Several physico-chemical properties attested to the efficient surface modification and confirmed covalent grafting. Preliminary imaging experiments complete this study and confirm the potential of the presented system for preclinical imaging experiments.

The present study focuses on the effects of the physicochemical properties of superparamagnetic PEG-modified, positively charged, and negatively charged iron oxide nanoparticles (SPIONs) on their reactivity with hydrogen peroxide. Our hypothesis was that the reactivity of SPIONs in this reaction would depend on their surface properties. The comparative study of the nanoparticles with DLS and TEM revealed the average sizes of PEG-modified, positively charged, and negatively charged SPIONs. We observed that the reactivity of negatively charged SPIONs with hydrogen peroxide was less than that of positively charged SPIONs and that of these second nanoparticles was less than that of PEG-modified SPIONs. This difference in the reactivity of these SPIONs with hydrogen peroxide was attributed to the presence of carboxyl or amine groups on their surface. However, the values of the rate constants of the reactions of PEG-modified, positively charged, and negatively charged SPIONs with hydrogen peroxide showed that the reaction of negatively charged SPIONs with hydrogen peroxide was more rapid than that of PEG-modified SPIONs and the reaction of these second SPIONs with hydrogen peroxide was more rapid than that of positively charged SPIONs. The surface study of the SPIONs using XPS showed that the high-resolution spectra of these nanoparticles changed after reaction with hydrogen peroxide, which indicates their surface modifications. These investigations can help develop more appropriate nanoparticles with controlled physicochemical properties.

This work describes the preparation, characterization and functionalization with magnetic nanoparticles of a bone tissue-mimetic scaffold composed of collagen and hydroxyapatite obtained through a biomineralization process. Bone remodeling takes place over several weeks and the possibility to follow it

International audience; One of the most widely used techniques to obtain anatomical information is magnetic resonance imaging (MRI). Despite its high resolution, it has a low sensitivity which could be enhanced by coupling MRI with a more sensitive technique such as photoacoustic imaging (PAI). The development of a bi-modal agent could thus lead to hybrid images with a high anatomical resolution provided by MRI and a precise localization of the contrast agent thanks to PAI. The probes used in this work

International audience; New pyridine containing triAza; 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA) ligands presenting pendant carboxylic acid or alcohol functions have been synthesized and used to form diaqua Gd(III) complexes, which have been immobilized onto dense silica nanoparticles. Cytotoxicity studies of these complexes (free or immobilized on the nanoparticles) on normal 1BR3G cells and cancerous HCT 116 cells indicated a dependence on the pendant chemical group for the free complexes. However, this effect disappeared once the complexes were immobilized on the surface of the nanoparticles, leading to non-toxic nanomaterials. The interest of these complexes (free or immobilized on dense silica nanoparticles) as contrast agents in magnetic resonance imaging (MRI) has been evaluated in comparison with DOTAREM® by recording their nuclear magnetic resonance dispersion (NMRD) profiles, measuring their transversal and longitudinal relaxivities as well as recording images on phantoms at 37 °C. This study has evidenced the high potential of these complexes: first it suggested the possibility to reduce the dose to be injected by a factor of 10, second it evidenced their high efficiency in high field T1-weighted MRI (9.4 T), the key towards images of higher resolution and shorter acquisition times.

This study reports the synthesis of stabilized ultrasmall iron oxide nanoparticles (USPIO) as bimodal probes for magnetic resonance and optical imaging. These nanosystems are based on small iron oxide cores surrounded by a thin polysiloxane shell exhibiting carboxylic acid functions. Thanks to these functions, hybrid particles were obtained by conjugating a fluorophore to the superparamagnetic contrastophore. Such modification allowed us to directly follow these USPIO in cellulo, which provided interesting information about their internalization pathway and cellular distribution upon mitosis. Finally, the efficiency of these systems as probes for bimodal imaging was emphasized by the observation of their in vivo behavior in mice using magnetic resonance and optical imaging.

For many years, the controlled delivery of therapeutic compounds has been a matter of great interest in the field of nanomedicine. Among the wide amount of drug nanocarriers, magnetic iron oxide nanoparticles (IONs) stand out from the crowd and constitute robust nanoplatforms since they can achieve high drug loading as well as targeting abilities stemming from their remarkable properties (magnetic and biological properties). These applications require precise design of the nanoparticles regarding several parameters which must be considered together in order to attain highest therapeutic efficacy.This short review presents recent developments in the field of cancer targeted drug delivery using magnetic nanocarriers as drug delivery systems.The design of nanocarriers enabling efficient delivery of therapeutic compounds toward targeted locations is one of the major area of research in the targeted drug delivery field. By precisely shaping the structural properties of the iron oxide nanoparticles, drugs loaded onto the nanoparticles can be efficiently guided and selectively delivered toward targeted locations. With these goals in mind, special attention should be given to the pharmacokinetics and in vivo behavior of the developed nanocarriers.

The diagnosis of Alzheimer's disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls'-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells.

The growing concern over the toxicity of Gd-based contrast agents used in magnetic resonance imaging (MRI) motivates the search for less toxic and more effective alternatives. Among these alternatives, iron&ndash, iron oxide (Fe@FeOx) core-shell architectures have been long recognized as promising MRI contrast agents while limited information on their engineering is available. Here we report the synthesis of 10 nm large Fe@FeOx nanoparticles, their coating with a 11 nm thick layer of dense silica and functionalization by 5 kDa PEG chains to improve their biocompatibility. The nanomaterials obtained have been characterized by a set of complementary techniques such as infra-red and nuclear magnetic resonance spectroscopies, transmission electron microscopy, dynamic light scattering and zetametry, and magnetometry. They display hydrodynamic diameters in the 100 nm range, zetapotential values around &minus, 30 mV, and magnetization values higher than the reference contrast agent RESOVIST&reg, They display no cytotoxicity against 1BR3G and HCT116 cell lines and no hemolytic activity against human red blood cells. Their nuclear magnetic relaxation dispersion (NMRD) profiles are typical for nanomaterials of this size and magnetization. They display high r2 relaxivity values and low r1 leading to enhanced r2/r1 ratios in comparison with RESOVIST&reg, All these data make them promising contrast agents to detect early stage tumors.

International audience; The present study reports the preparation of poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) polymer vesicles via a nanoprecipitation method and the loading of two different size hydrophobically coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles (magnetic core size of 4.2 nm and 7.6 nm) into the membrane of these nanovesicles, whose thickness was measured precisely by small angle neutron scattering (SANS). Spherical nano-assemblies with a high USPIO payload and a diameter close to 150 nm were obtained as confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM) and cryo-TEM. Vesicular structure of these hybrid nano-assemblies was confirmed by multi-angle light scattering (MALS) measurements. Their magnetic properties were evaluated by T1 and T2 measurements (20 and 60 MHz) and by nuclear magnetic relaxation dispersion (NMRD) profiles. The size of USPIO entrapped in the membranes of PEO-b-PCL vesicles has a strong impact on their magnetic properties. It affects both their longitudinal and their transverse relaxivities and thus their magnetic resonance imaging (MRI) sensitivity. Acid-catalyzed hydrolysis of PCL membrane also influences their relaxivities as shown by measurements carried out at pH 7 vs. pH 5. This property was used to monitor the membrane hydrolytic degradation in vitro, as a proof of concept of potential monitoring of a drug delivery by nanomedicines in vivo and non-invasively, by MRI.

The characterization of synthetic superparamagnetic iron oxide nanoparticle (SPION) surfaces prior to functionalization is an essential step in the prediction of their successful functionalization, and in uncovering issues that may influence their selection as magnetically targeted drug delivery vehicles (prodrugs). Here, three differently functionalized magnetite (Fe3O4) SPIONs are considered. All were identically prepared by the alkaline coprecipitation of Fe(2+) and Fe(3+) salts. We use X-ray photoelectron spectroscopy, electron microscopy, time-of-flight SIMS, FTIR spectroscopy and magnetic measurements to characterize their chemical, morphological and magnetic properties, in order to aid in determining how their surfaces differ from those prepared by Fe(CO)5 decomposition, which we have already studied, and in assessing their potential use as drug delivery carriers.

We demonstrate the successful functionalization of magnetite (Fe3O4) nanoparticles, using PEGdithiol and dimercaptosuccinic acid (DMSA). Following functionalization, TEM images show increased sizes, due to the presence of well-defined polymeric coatings. On subsequent nitrosation, X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectroscopy (TOF-SIMS) show the presence of S NO bonds.

Inorganic nanomaterials and their unique physical properties are the center of modern material science due to their potential technological importance. Among the existing structures, magnetic iron oxide nanoparticles (MNPs), including magnetite (Fe3O4) and maghemite (γ-Fe2O3), exhibit remarkable magnetic properties, called ‘superparamagnetism’, making these nanostructures suitable for a wide range of applications. Because their physico-chemical properties play an important role in major applications, our review focuses on the synthesis approaches giving rise to the best control of size and shape.

The fast development of nanomedicines requires more and more reliable chemical tools in order to accurately design materials and control the surface properties of the nano-objects used in biomedical applications. In this study we describe a smooth and simple photografting technique, i.e., the clip photochemistry, that allows the introduction of molecules of interest in inert polymers or on stealth nanoparticles directly in aqueous solution. First we developed the methodology on polyethylene glycol (PEG) and looked for critical parameters of the process (irradiation times, concentrations, washings) by using several molecular probes and adapted analytical techniques ((19)F qNMR, EA, LSC). We found that the clip photochemistry in water is a robust and efficient method to functionalize PEG. Second we applied it on PEGylated USPIO (USPIO-PEG) magnetic resonance imaging agent and succeeded in introducing RGD peptide and homemade peptidomimetics on their PEG segments. The magnetic abilities of the conjugated nanoparticles were unchanged by the derivatization process as evidenced by their relaxometric properties and their NMRD profile. When tested on Jurkat lymphocyte T Cells, which express αvβ3 integrins, the USPIO conjugated with RGD ligands leads to an increase of the transverse relaxation rate (R2) by a factor 10 to 14 as compared to USPIO-PEG. Consequently, it makes them good candidates for targeted imaging technology in cancer therapy.

The incidence of papillary thyroid cancer has increased these last decades due to a better detection. High prevalence of nodules combined with the low incidence of thyroid cancers constitutes an important diagnostic challenge. We propose to develop an alternative diagnostic method to reduce the number of useless and painful thyroidectomies using a vectorized contrast agent for magnetic resonance imaging. Galectin-1 (gal-1), a protein overexpressed in well-differentiated thyroid cancer, has been targeted with a randomized linear 12-mer peptide library using the phage display technique. Selected peptides have been conjugated to ultrasmall superparamagnetic particles of iron oxide (USPIO). Peptides and their corresponding contrast agents have been tested in vitro for their specific binding and toxicity. Two peptides (P1 and P7) were selected according to their affinity toward gal-1. Their binding has been revealed by immunohistochemistry on human thyroid cancer biopsies, and they were co-localized with gal-1 by immunofluorescence on TPC-1 cell line. Both peptides induce a decrease in TPC-1 cells' adhesion to gal-1 immobilized on culture plates. After coupling to USPIO, the peptides preserved their affinity toward gal-1. Their specific binding has been corroborated by co-localization with gal-1 expressed by TPC-1 cells and by their ability to compete with anti-gal-1 antibody. The peptides and their USPIO derivatives produce no toxicity in HepaRG cells as determined by MTT assay. The vectorized contrast agents are potential imaging probes for thyroid cancer diagnosis. Moreover, the two gal-1-targeted peptides prevent cancer cell adhesion by interacting with the carbohydrate-recognition domain of gal-1.

Magnetic resonance imaging (MRI) offers the possibility of tracking cells labelled with a contrast agent and evaluating the progress of cell therapies. This requires efficient cell labelling with contrast agents. A basic incubation of cells with iron oxide nanoparticles (NPs) is a common method. This study reports the synthesis at the gram scale of iron oxide nanoparticles as MRI T2 contrast agents for cell labelling. These NPs are based on small iron oxide cores coated with a thin polysiloxane shell presenting carboxylic acid functions. The iron oxide cores produced have been characterized by transmission electron microscopy, X-ray diffraction, ζ-potential, infrared, photon correlation spectroscopy, atomic force microscopy, magnetometry and relaxometric measurements. These measurements confirmed the expected surface modification by carboxysilane. Carboxylic groups created electrostatic repulsion between NPs when they are deprotonated. Therefore, highly concentrated aqueous solutions of carboxysilane coated iron oxide NPs can be obtained, up to 70% (w/w). These NPs could be used for cell labelling owing to their aggregation and re-dispersion properties. NPs precipitated in Dulbecco's modified Eagle medium induced a rapid association with 3 T6 fibroblast cells and could easily be re-dispersed in phosphate buffer saline solution to obtain properly labelled cells. Copyright © 2013 John Wiley & Sons, Ltd.

This chapter discusses the synthesis, functionalization, characterization, and imaging applications of iron-oxide-nanoparticle-based contrast agents. By reducing the size from bulk to the nanometer scale (

This introduction highlights the importance of nanomaterials in biomedical applications. The use of different nanosystems in the medical field has conducted researchers to develop numerous synthetic ways.

MRI contrast agents are known for about 30 years. Most of clinical compounds are extracellular agents without tissue specificity. They are excreted by the kidneys (Gd-DTPA, Gd-DOTA, Gd-DTPA-BMA or Gd-HP-DO3A for example). More recently, intracellular agents (Gd-EOB-DTPA, Gd-BOPTA, … undergoing hepatocyte uptake), and blood pool contrast agent (MS-325, binding albumin) have been developed. These Gd complexes have an extended clearance time and allow longer contrast-enhanced imaging sessions. These systems are called “T1 or positive” agents because they increase the water signal of the tissue areas where they are concentrated. A second kind of contrast agents is made of superparamagnetic iron oxide nanoparticles (USPIO or SPIO). These nanosystems have a high efficiency and are generally “T2 or negative” agents, inducing a darkening of the region where they accumulate. Such nanoparticles with a diameter of approximately 20–200 nm can be used as contrast agents for liver, lymphatic system (because of macrophage uptake, mainly as negative agent), or blood vessels (because of low extravasation, mainly as positive agent). The different kinds of mechanisms through which they affect the nuclear magnetic relaxation time of the water are briefly described. Nowadays, researches are focused on the development of molecular imaging contrast agents, to target receptors which are overexpressed in pathologies.

Thanks to their unique properties, inorganic nanostructures have become the center of modern material science. Among existing nanomaterials, magnetic iron oxide nanoparticles (IONP) have attracted a lot of interest. These nanoparticles are suitable for many technological applications such as contrast agent for magnetic resonance imaging. When comparing to molecular MRI probes (Gd-based organic complexes), IONP present many advantages such as a better sensitivity, a poor toxicity, and the possibility to easily modify their surface to develop some properties as multimodality, modulable half-life or specificity. However, one must stress that these properties are related to IONP’s composition, shape and stability (physical and chemical). In that paper, we will introduce some concepts related to IONP’s physico-chemical properties, the synthetic ways to obtain such structures and we will finish with some concepts governing their stability and surface modification.

The mechanism of action of the paramagnetic gadolinium complexes is briefly described, with an emphasis on the different parameters that can be tuned to increase their efficiency. An overview of the different classes of paramagnetic gadolinium chelates is then presented.

Recently, polymer vesicles called polymersomes have emerged as promising nanocarriers. Several studies have reported the formation of poly(ethylene oxide)-block-poly(e-caprolactone) (PEO-b-PCL) based vesicles due to their high potential for biomedical applications. However, to our knowledge, the incorporation of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) into these PEO-b-PCL vesicles has not yet been described. This work reports the self-assemby of PEO2000-b-PCL12650 copolymers with USPIO. PEO2000-b-PCL12650 was chosen as amphiphilic copolymer because PEO block is biocompatible and prolong the circulation time of nanoparticles in vivo whereas PCL block is biodegradable. Moreover, PEO2000-b-PCL12000 copolymers have been reported to form vesicles. USPIO were synthesized by the thermal decomposition method (magnetic core size of 4.2 nm and 7.5 nm) and self-assembly of PEO2000-b-PCL12650 with USPIO was performed by nanoprecipitation. Polymeric nanoparticles with diameters close to 100 nm and a high USPIO content were formed as shown by dynamic light scattering (DLS), transmission electron microscopy (TEM) and cryo-TEM. These nanoassemblies are characterized by very high r2/r1 ratios (at 20 and 60 MHz) which makes them highly promising canditates as T2-contrast agents for magnetic resonance imaging (MRI). The size of USPIO entrapped in PEO-b-PCL nanoassemblies has a strong impact on their magnetic properties. Indeed it affects both their longitudinal and their transverse relaxivities and thus their magnetic resonance imaging (MRI) sensitivity. The next steps in further studies will be the incorporation of an anti-cancer drug into these nanocarriers and the attachment of an active targeting group such as an RGD-containing peptide to their surfaces.

Despite progress in modern chemotherapy to combat tuberculosis, the causative pathogen Mycobacterium tuberculosis (M.tb.) is far from eradicated. Bacillary resistance to anti-mycobacterial agents, bacillary persistence and human immunodeficiency virus (HIV) co-infection hamper current drug treatment to completely cure the infection, generating a constant demand for novel drug candidates to tackle these problems. A small library of novel heterocyclic compounds was screened in a rapid luminometric in vitro assay against the laboratory M.tb. strain H37Rv. A group of amidines was found to have the highest potency and was further evaluated for acute toxicity against C3A hepatocytes. Next, the most promising compounds were evaluated for activity against a multi-drug resistant clinical isolate. The group of amidines was also tested for their ability to kill intracellular M.tb. residing in mouse J774A.1 macrophages. Finally, we report on a correlation between the structural differences of the compounds and their anti-mycobacterial activity.

Five bis-benzamidines were screened towards murine magnesium deficiency-dependent audiogenic seizures, unravelling two compounds with efficacious doses 50 (ED(50)) less than 10mg/kg. They were also screened against maximal electroshock and subcutaneous pentylenetetrazole-induced seizures, and explored for superoxide -scavenging activity. 1,2-Ethane bis-1-amino-4-benzamidine (EBAB) was selected and evaluated in 6 Hz seizure test (ED(50)=49 mg/kg) and at 4 microg/kg in focal cerebral ibotenate poisoning in pups (sizes of both white and grey matter wounds were halved). EBAB was further tested on NMDA-induced seizures in mice (ED(50)=6 mg/kg) and on (3)H-TC -binding to a rodent cerebral preparation (IC(50)=1.4 microM). Taken as a whole, present data emphasise the suitability of bis-benzamidines as templates for designing brain protective compounds.

Because of their outstanding magnetic properties, iron oxide nanoparticles have already been the subject of numerous studies in the biomedical field, in particular as a negative contrast agent for T2-weighted nuclear magnetic resonance imaging, or as therapeutic agents in hyperthermia experiments. Recent studies have shown that below a given particle size (i.e. 5 nm), iron oxide may be used to provide a significant positive (brightening) effect on T1-weighted MRI. In such an application, not only the size of the crystal, but also the control of the coating process is essential to ensure optimal properties, especially at a very high field (> 3 T). In this work, we focused on the development of very small iron oxide nanoparticles as a potential platform for high field T1 magnetic resonance angiography (MRA) applications. The feasibility has been evaluated in vivo at 9.4 T, demonstrating the usefulness of the developed system for MRA applications.

Diverse applications of superparamagnetic iron oxide nanoparticles (SPIONs) in the chemical and biomedical industry depend on their surface properties. In this paper, we investigate the effect of initial surface charge (bare, positively and negatively charged SPIONs) on the resulting physicochemical properties of the particles following treatment through photo-initiated chemical vapour deposition (PICVD). Transmission electron microscopy shows a nanometric polymer coating on the SPIONs and contact angle measurements with water demonstrate that their surface became non-polar following functionalization using PICVD. FTIR and XPS data confirm the change in the chemical composition of the treated SPIONs. Indeed, XPS data reveal an initial charge-dependent increase in the surface oxygen content in the case of treated SPIONs. The O/C percentage ratios of the bare SPIONs increase from 1.7 to 1.9 after PICVD treatment, and decrease from 1.7 to 0.7 in the case of negatively charged SPIONs. The ratio remains unchanged for positively charged SPIONs (1.7). This indicates that bare and negatively charged SPIONs showed opposite preference for the oxygen or carbon attachment to their surface during their surface treatment. These results reveal that both the surface charge and stereochemical effects have determinant roles in the polymeric coating of SPIONs with PICVD. Our findings suggest that this technique is appropriate for the treatment of nanoparticles.