Ultrasmall water-soluble metal-iron oxide nanoparticles as T1-weighted contrast agents for magnetic resonance imaging

Using an improved hydrolysis method of inorganic salts assisted with water-bath incubation, ultrasmall water-soluble metal-iron oxide nanoparticles (including Fe(3)O(4), ZnFe(2)O(4) and NiFe(2)O(4) nanoparticles) were synthesized in aqueous solutions, which were used as T(1)-weighted contrast agents for magnetic resonance imaging (MRI). The morphology, structure, MRI relaxation properties and cytotoxicity of the as-prepared metal-iron oxide nanoparticles were characterized, respectively. The results showed that the average sizes of nanoparticles were about 4 nm, 4 nm and 5 nm for Fe(3)O(4), ZnFe(2)O(4) and NiFe(2)O(4) nanoparticles, respectively. Moreover, the nanoparticles have good water dispersibility and low cytotoxicity. The MRI test showed the strong T(1)-weighted, but the weak T(2)-weighted MRI performance of metal-iron oxide nanoparticles. The high T(1)-weighted MRI performance can be attributed to the ultrasmall size of metal-iron oxide nanoparticles. Therefore, the as-prepared metal-iron oxide nanoparticles with good water dispersibility and ultrasmall size can have potential applications as T(1)-weighted contrast agent materials for MRI.     

Hot-injection synthesis of iron/iron oxide core/shell nanoparticles for T2 contrast enhancement in magnetic resonance imaging

Here we report a new, bench-top synthesis for iron/iron oxide core/shell nanoparticles via the thermal decomposition of Fe(η(5)-C(6)H(3)Me(4))(2). The iron/iron oxide core/shell nanoparticles are superparamagnetic at room temperature and show improved negative contrast in T(2)-weighted MR imaging compared to pure iron oxides nanoparticles, and have a transverse relaxivity (r(2)) of 332 mM(-1) s(-1).     

One-dimensional magnetic nanowires obtained by protein fibril biotemplating

Magnetic nanowires were obtained through the in situ synthesis of magnetic material by Fe-controlled nanoprecipitation in the presence of two different protein (human serum albumin (HSA) and lysozyme (Lys)) fibrils as biotemplating agents. The structural characteristics of the biotemplates were transferred to the hybrid magnetic wires. They exhibited excellent magnetic properties as a consequence of the 1D assembly and fusion of magnetite nanoparticles as ascertained by SQUID magnetometry. Prompted by these findings, we also checked their potential applicability as MRI contrast agents. The magnetic wires exhibited large r(2)* relaxivities and sufficient contrast resolution even in the presence of an extremely small amount of Fe in the magnetic hybrids, which would potentially enable their use as T(2) contrast imaging agents.     

Iron hydroxide nanoparticles coated with poly(ethylene glycol)-poly(aspartic acid) block copolymer as novel magnetic resonance contrast agents for in vivo cancer imaging

PEG-coated β-FeOOH nanoparticles were prepared through electrostatic complex formation of iron oxide nanoparticles with poly(ethylene glycol)-poly(aspartic acid) block copolymer [PEG-P(Asp)] in distilled water. By dynamic light scattering (DLS) measurement, the nanopaticle size was determined to be 70 nm with narrow distribution. The FT-IR and zeta potential experimental results proved that PEG-PAsp molecules bound to the surface of the iron oxide nanoparticles via the coordination between the carboxylic acid residues in the PAsp segment of the block copolymer and the surface Fe of the β-FeOOH nanoparticles. The PEG-coated nanoparticles revealed excellent solubility and stability in aqueous solution as well as in physiological saline. In vivo MRI experiments on tumor-bearing mice demonstrated that the PEG-coated nanoparticles prepared by the current approach achieved an appreciable accumulation into solid tumor, suggesting their potential utility as tumor-selective MRI contrast agents.     

Design of water-based ferrofluids as contrast agents for magnetic resonance imaging

We report the synthesis, characterization and relaxometric study of ferrofluids based on iron oxide, with potential for use as magnetic resonance imaging (MRI) contrast agents (CAs). The effect of different cost-effective, water-based surface modification approaches which can be easily scaled-up for the large scale synthesis of the ferrofluids has been investigated. Surface modification was achieved by silanization, and/or coating with non-toxic commercial dispersants (a lauric polysorbate and a block copolymer with pigment affinic groups, namely Tween 20 and Disperbyk 190) which were added after or during iron oxide nanoparticle synthesis. It was observed that all the materials synthesized functioned as negative contrast agents at physiological temperature and at frequencies covered by clinical imagers. The relaxometric properties of the magnetic nanoparticles were significantly improved after surface coating with stabilizers compared to the original iron oxide nanoparticles, with particular reference to the silica-coated magnetic nanoparticles. The results indicate that the optimization of the preparation of colloidal magnetic ferrofluids by surface modification is effective in the design of novel contrast agents for MRI by enabling better or more effective interaction between the coated iron oxide nanoparticles and protons present in their aqueous environment.     

Magnetite nanocrystal clusters with ultra-high sensitivity in magnetic resonance imaging

Magnetic iron oxide particles are widely used as contrast agents to improve the sensitivity of magnetic resonance imaging (MRI). Their efficiency in MRI is usually quantified by transverse relaxivity (r(2)) in solution. Herein, we synthesized a series of magnetite nanocrystal clusters (MNCs) with ultra-high transverse relaxivity by a polyol process and studied the relationship between r(2) and size of the MNCs. The sizes of MNCs can be tuned over a wide range from 13 to 179 nm. The r(2) of MNC suspensions as a function of the size of the cluster was analyzed and compared with a theoretical model. We found that MNCs of 64 nm had an r(2) value of 650 mM(-1) s(-1), which was more than three times that of the commercial contrast agent and was among the highest reported for iron oxide materials. Compared with the theoretical model, the r(2) value of the MNC suspension is approximately 0.93 of the theoretical prediction. Imaging of the MNC suspensions was performed in a clinical 1.5 T MRI instrument and a comparison was made between MNCs and commercial contrast agents. MRI indicated that the decrease of signal intensity induced by MNCs was in proportion to the r(2) value, which was in accordance with theoretical predictions. These results demonstrate that MNCs with ultra-high transverse relaxivity and tunable size are promising candidates for molecular imaging and clinical diagnosis in MRI.     

两种新型的MRI造影剂两种新型的MRI造影剂

用动物活体核磁共振T2分布像和T1加权像分别观测了超顺磁性氧化铁造影剂和电中性大分子锰配合物造影剂的实验结果。大白鼠肝部的活体测量结果显示,上述两种造影剂能分别显著地改变生物活体组织的T2和T1值。该实验结果对于磁共振造影剂的研制和人体的临床试验具有参考价值。     

Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents

Various magnetic nanoparticles have been extensively investigated as novel magnetic resonance imaging (MRI) contrast agents owing to their unique characteristics, including efficient contrast effects, biocompatibility, and versatile surface functionalization capability. Nanoparticles with high relaxivity are very desirable because they would increase the accuracy of MRI. Recent progress in nanotechnology enables fine control of the size, crystal structure, and surface properties of iron oxide nanoparticles. In this tutorial review, we discuss how MRI contrast effects can be improved by controlling the size, composition, doping, assembly, and surface properties of iron-oxide-based nanoparticles.     

Paramagnetic nanoparticle T(1) and T(2) MRI contrast agents

There is no doubt that magnetic resonance imaging contrast agents (MRI CAs) can play a vital role in diagnosing diseases. Therefore, demand for new MRI CAs with an enhanced sensitivity and advanced functionalities is very high. Here, paramagnetic nanoparticles (NPs) are reviewed as new potential candidates for either T(1) or T(2) MRI CAs or both. These include surface coated lanthanide (Ln) oxide NPs (Ln = Gd, Dy, and Ho) and manganese oxide NPs. Surface coating materials should be biocompatible and hydrophilic. Compared to conventional large NPs, these surface coated paramagnetic NPs can be made ultrasmall with core particle diameter ranging from 1 to 3 nm, but their magnetic properties are still sufficient for MRI CAs. At this particle diameter, they can be easily excreted from the body through the renal system, which is prerequisite for in vivo applications. Mixed lanthanide oxide NPs into which a fluorescent Ln material is incorporated will be valuable as multiple imaging agents for both MRI-fluorescent imaging (FI) and MRI-cellular imaging (CL). These paramagnetic NPs can be further functionalized towards target-specific imaging, multiplex imaging, and drug delivery.     

Iron hydroxide nanoparticles coated with poly(ethylene glycol)-poly(aspartic acid) block copolymer as novel magnetic resonance contrast agents for in vivo cancer imaging

PEG-coated β-FeOOH nanoparticles were prepared through electrostatic complex formation of iron oxide nanoparticles with poly(ethylene glycol)-poly(aspartic acid) block copolymer [PEG-P(Asp)] in distilled water. By dynamic light scattering (DLS) measurement, the nanopaticle size was determined to be 70 nm with narrow distribution. The FT-IR and zeta potential experimental results proved that PEG-PAsp molecules bound to the surface of the iron oxide nanoparticles via the coordination between the carboxylic acid residues in the PAsp segment of the block copolymer and the surface Fe of the β-FeOOH nanoparticles. The PEG-coated nanoparticles revealed excellent solubility and stability in aqueous solution as well as in physiological saline. In vivo MRI experiments on tumor-bearing mice demonstrated that the PEG-coated nanoparticles prepared by the current approach achieved an appreciable accumulation into solid tumor, suggesting their potential utility as tumor-selective MRI contrast agents.     

Innovative synthesis of citrate-coated superparamagnetic Fe3O4 nanoparticles and its preliminary applications

In this study, we describe the development of a facile and effective route for the synthesis of Fe(3)O(4)-based T(1) contrast agent, which can be useful for in vivo magnetic resonance (MR) imaging. Citrate-coated Fe(3)O(4) nanoparticles (6 nm) with a narrow size distribution were synthesized by "one-pot green chemistry route" in diethylene glycol (DEG) solvent. The synthesized nanoparticles were characterized by different analytical techniques including XRD, TEM, HRTEM, and FTIR. At room temperature, nanoparticles exhibited superparamagnetic nature with high saturation magnetization. The longitudinal (r(1)) and transverse (r(2)) relaxivities were found to be 35.45 and 51.81 mM(-1)s(-1), respectively. Contrast agent developed by this method showed a relatively higher longitudinal relaxivity (r(1)) and the lowest relaxivity ratio (r(2)/r(1)=1.46) at 3T MR field. The anionic nature of citric acid facilitated non-specific internalization without impairment of cell viability and functionality. The in vitro studies showed both phagocitic and non-phagocytic uptake of these NPs. In vivo MR imaging of swine showed both T(1) and T(2) contrast effect.     

Drug-loaded and superparamagnetic iron oxide nanoparticle surface-embedded amphiphilic block copolymer micelles for integrated chemotherapeutic drug delivery and MR imaging

We report on the fabrication of organic/inorganic hybrid micelles of amphiphilic block copolymers physically encapsulated with hydrophobic drugs within micellar cores and stably embedded with superparamagnetic iron oxide (SPIO) nanoparticles within hydrophilic coronas, which possess integrated functions of chemotherapeutic drug delivery and magnetic resonance (MR) imaging contrast enhancement. Poly(ε-caprolactone)-b-poly(glycerol monomethacrylate), PCL-b-PGMA, and PCL-b-P(OEGMA-co-FA) amphiphilic block copolymers were synthesized at first by combining ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP), and post- modification techniques, where OEGMA and FA are oligo(ethylene glycol) monomethyl ether methacrylate and folic acid-bearing moieties, respectively. A model hydrophobic anticancer drug, paclitaxel (PTX), and 4 nm SPIO nanoparticles were then loaded into micellar cores and hydrophilic coronas, respectively, of mixed micelles fabricated from PCL-b-PGMA and PCL-b-P(OEGMA-co-FA) diblock copolymers by taking advantage of the hydrophobicity of micellar cores and strong affinity between 1,2-diol moieties in PGMA and Fe atoms at the surface of SPIO nanoparticles. The controlled and sustained release of PTX from hybrid micelles was achieved, exhibiting a cumulative release of ~61% encapsulated drugs (loading content, 8.5 w/w%) over ~130 h. Compared to that of surfactant-stabilized single SPIO nanoparticles (r(2) = 28.3 s(-1) mM(-1) Fe), the clustering of SPIO nanoparticles within micellar coronas led to considerably enhanced T(2) relaxivity (r(2) = 121.1 s(-1) mM(-1) Fe), suggesting that hybrid micelles can serve as a T(2)-weighted MR imaging contrast enhancer with improved performance. Moreover, preliminary experiments of in vivo MR imaging were also conducted. These results indicate that amphiphilic block copolymer micelles surface embedded with SPIO nanoparticles at the hydrophilic corona can act as a new generation of nanoplatform integrating targeted drug delivery, controlled release, and disease diagnostic functions.     

Multifunctional yolk-shell nanoparticles: a potential MRI contrast and anticancer agent

We report a new type of multifunctional nanomaterials, FePt@Fe2O3 yolk-shell nanoparticles, that exhibit high cytotoxicity originated from the FePt yolks and strong MR contrast enhancement resulting from the Fe2O3 shells. Encouraged by the recently observed high cytotoxicity of FePt@CoS2 yolk-shell nanoparticles, we used Fe2O3 to replace CoS2 as the shells to further explore the applications of the yolk-shell nanostructures. The ultralow IC50 value (238 +/- 9 ng of Pt/mL) of FePt@Fe2O3 yolk-shell nanoparticles likely originates from the fact that the slow oxidation and release of FePt yolks increases the cytotoxicity. Moreover, compared with two commercial magnetic resonance imaging (MRI) contrast agents, MION and Sinerem, the FePt@Fe2O3 yolk-shell nanoparticle showed stronger contrast enhancement according to their apparent transverse relaxivity values (r2* = 3.462 (microg/mL)(-1) s(-1)). The bifunctional FePt@Fe2O3 yolk-shell nanoparticles may serve both as an MRI contrast agent and as a potent anticancer drug. This work indicates that these unique yolk-shell nanoparticles may ultimately lead to new designs of multifunctional nanostructures for nanomedicine.     

Ultrasmall Superparamagnetic Iron Oxide Nanoparticles with Europium(III) DO3A as a Bimodal Imaging Probe

A new prototype consisting of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles decorated with europium(III) ions encapsulated in a DO3A organic scaffold was designed as a platform for further development of bimodal contrast agents for MRI and optical imaging. The USPIO nanoparticles act as negative MRI contrast agents, whereas the europium(III) ion is a luminophore that is suitable for use in optical imaging detection. The functionalized USPIO nanoparticles were characterized by TEM, DLS, XRD, FTIR, and TXRF analysis, and a full investigation of the relaxometric and optical properties was conducted. The typical luminescence emission of europium(III) was observed and the main red emission wavelength was found at 614 nm. The relaxometric study of these ultrasmall nanoparticles showed r₂ values of 114.8 mm ^?1_Fes^?1 at 60 MHz, which is nearly double the r₂ relaxivity of Sinerem^®.     

Gold-Speckled SPION@SiO2 Nanoparticles Decorated with Thiocarbohydrates for ASGPR1 Targeting: Towards HCC Dual Mode Imaging Potential Applications

Efforts are made to perform an early and accurate detection of hepatocellular carcinoma (HCC) by simultaneous exploiting multiple clinically non-invasive imaging modalities. Original nanostructures derived from the combination of different inorganic domains can be used as efficient contrast agents in multimodal imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) and Au nanoparticles (NPs) possess well-established contrasting features in magnetic resonance imaging (MRI) and X-ray computed tomography (CT), respectively. HCC can be targeted by using specific carbohydrates able to recognize asialoglycoprotein receptor 1 (ASGPR1) overexpressed in hepatocytes. Here, two different thiocarbohydrate ligands were purposely designed and alternatively conjugated to the surface of Au-speckled silica-coated SPIONs NPs, to achieve two original nanostructures that could be potentially used for dual mode targeted imaging of HCC. The results indicated that the two thiocarbohydrate decorated nanostructures possess convenient plasmonic/superparamagnetic properties, well-controlled size and morphology and good selectivity for targeting ASGPR1 receptor.     

"Two-in-one" fabrication of Fe3O4/MePEG-PLA composite nanocapsules as a potential ultrasonic/MRI dual contrast agent

A new method for the fabrication of Fe(3)O(4) nanoparticles enveloped by polymeric nanocapsules is proposed. This method is characterized by combining a double emulsification with the interfacial coprecipitation of iron salts to form Fe(3)O(4)/polymer composite nanocapsules in a single step. To demonstrate the viability of this approach, methoxy poly(ethylene glycol)-poly(lactide) (MePLEG) was chosen as the shell material for Fe(3)O(4)/MePLEG nanocapsules. In addition to the versatility offered for fabricating nanocapsules with different shell materials, the method was found to be convenient for adjusting the magnetite content of the nanocapsules from 0 to 43%. In addition to their confirmed T(2)-weighted magnetic resonance imaging (MRI) enhancement, the resultant composite nanocapsules display much more obvious acoustic responses than MePLEG nanocapsules in an acoustic investigation. Furthermore, the low toxicity of these composite nanocapsules, as confirmed by our study, combined with their magnetic and acoustic properties ensure that these composite nanocapsules have great potential in acting as ultrasonic/MRI dual contrast agents.     

Bifunctional nanoparticles with fluorescence and magnetism via surface-initiated AGET ATRP mediated by an iron catalyst

Fluorescent/magnetic nanoparticles are of interest in many applications in biotechnology and nanomedicine for its living detection. In this study, a novel method of surface modification of nanoparticles was first used to modify a fluorescent monomer on the surfaces of magnetic nanoparticles directly. This was achieved via iron(III)-mediated atom-transfer radical polymerization with activators generated by electron transfer (AGET ATRP). Fluorescent monomer 9-(4-vinylbenzyl)-9H-carbazole (VBK) was synthesized and was grafted from magnetic nanoparticles (ferroferric oxide) via AGET ATRP using FeCl(3)·6H(2)O as the catalyst, tris(3,6-dioxaheptyl)amine (TDA-1) as the ligand, and ascorbic acid (AsAc) as the reducing agent. The initiator for ATRP was modified on magnetic nanoparticles with the reported method: ligand exchange with 3-aminopropyltriethoxysilane (APTES) and then esterification with 2-bromoisobutyryl bromide. After polymerization, a well-defined nanocomposite (Fe(3)O(4)@PVBK) was yielded with a magnetic core and a fluorescent shell (PVBK). Subsequently, well-dispersed bifunctional nanoparticles (Fe(3)O(4)@PVBK-b-P(PEGMA)) in water were obtained via consecutive AGET ATRP of hydrophilic monomer poly(ethylene glycol) methyl ether methacrylate (PEGMA). The chemical composition of the magnetic nanoparticles' surface at different surface modification stages was investigated with Fourier transform infrared (FT-IR) spectra. The magnetic and fluorescent properties were validated with a vibrating sample magnetometer (VSM) and a fluorophotometer. The Fe(3)O(4)@PVBK-b-P(PEGMA) nanoparticles showed an effective imaging ability in enhancing the negative contrast in magnetic resonance imaging (MRI).     

A Comparative Study of Receptor-Targeted Magnetosome and HSA-Coated Iron Oxide Nanoparticles as MRI Contrast-Enhancing Agent in Animal Cancer Model

Magnetosomes are specialized organelles arranged in intracellular chains in magnetotactic bacteria. The superparamagnetic property of these magnetite crystals provides potential applications as contrast-enhancing agents for magnetic resonance imaging. In this study, we compared two different nanoparticles that are bacterial magnetosome and HSA-coated iron oxide nanoparticles for targeting breast cancer. Both magnetosomes and HSA-coated iron oxide nanoparticles were chemically conjugated to fluorescent-labeled anti-EGFR antibodies. Antibody-conjugated nanoparticles were able to bind the MDA-MB-231 cell line, as assessed by flow cytometry. To compare the cytotoxic effect of nanoparticles, MTT assay was used, and according to the results, HSA-coated iron oxide nanoparticles were less cytotoxic to breast cancer cells than magnetosomes. Magnetosomes were bound with higher rate to breast cancer cells than HSA-coated iron oxide nanoparticles. While 250 μg/ml of magnetosomes was bound 92 ± 0.2%, 250 μg/ml of HSA-coated iron oxide nanoparticles was bound with a rate of 65 ± 5%. In vivo efficiencies of these nanoparticles on breast cancer generated in nude mice were assessed by MRI imaging. Anti-EGFR-modified nanoparticles provide higher resolution images than unmodified nanoparticles. Also, magnetosome with anti-EGFR produced darker image of the tumor tissue in T2-weighted MRI than HSA-coated iron oxide nanoparticles with anti-EGFR. In vivo MR imaging in a mouse breast cancer model shows effective intratumoral distribution of both nanoparticles in the tumor tissue. However, magnetosome demonstrated higher distribution than HSA-coated iron oxide nanoparticles according to fluorescence microscopy evaluation. According to the results of in vitro and in vivo study results, magnetosomes are promising for targeting and therapy applications of the breast cancer cells.     

A Gd3+-based magnetic resonance imaging contrast agent sensitive to beta-galactosidase activity utilizing a receptor-induced magnetization enhancement (RIME) phenomenon

Magnetic resonance imaging (MRI) permits noninvasive three-dimensional imaging of opaque organisms. Gadolinium (Gd(3+)) complexes have become important imaging tools as MRI contrast agents for MRI studies, though most of them are nonspecific and report solely on anatomy. Recently, MRI contrast agents have been reported whose ability to relax water protons is triggered or greatly enhanced by recognition of a particular biomolecule. This new class of MRI contrast agents could open up the possibility of reporting on the physiological state or metabolic activity deep within living specimens. One possible strategy for this purpose is to utilize the increase in the longitudinal water proton r(1) relaxivity that occurs upon slowing the molecular rotation of a small paramagnetic complex, a phenomenon which is known as receptor-induced magnetization enhancement (RIME), by either binding to a macromolecule or polymerization of the agent itself. Here we describe the design and synthesis of a novel beta-galactosidase-activated MRI contrast agent, the Gd(3+) complex [Gd-5], by using the RIME approach. beta-Galactosidase is commonly used as a marker gene to monitor gene expression. This newly synthesized compound exhibited a 57% increase in the r(1) relaxivity in phosphate-buffered saline (PBS) with 4.5% w/v human serum albumin (HSA) in the presence of beta-galactosidase. Detailed investigations revealed that RIME is the dominant factor in this increase of the observed r(1) relaxivity, based on analysis of Gd(3+) complexes [Gd-5] and [Gd-8], which is generated from [Gd-5] by the activity of beta-galactosidase, and spectroscopic analysis of their corresponding Tb(3+) complexes, [Tb-5] and [Tb-8].     

Maghemite nanoparticles protectively coated with poly(ethylene imine) and poly(ethylene oxide)-block-poly(glutamic acid)

Superparamagnetic iron oxide particles (SPIO) of maghemite were prepared in aqueous solution and subsequently stabilized with polymers in two layer-by-layer deposition steps. The first layer around the maghemite core is formed by poly(ethylene imine) (PEI), and the second one is formed by poly(ethylene oxide)-block-poly(glutamic acid) (PEO-PGA). The hydrodynamic diameter of the particles increases stepwise from D(h) = 25 nm (parent) via 35 nm (PEI) to 46 nm (PEI plus PEO-PGA) due to stabilization. This is accompanied by a switching of their zeta-potentials from moderately positive (+28 mV) to highly positive (+50 mV) and finally slightly negative (-3 mV). By contrast, the polydispersity indexes of the particles remain constant (ca. 0.15). M?ssbauer spectroscopy revealed that the iron oxide, which forms the core of the particles, is only present as Fe(III) in the form of superparamagnetic maghemite nanocrystals. The magnetic domains and the maghemite crystallites were found to be identical with a size of 12.0 +/- 0.5 nm. The coated maghemite nanoparticles were tested to be stable in water and in physiological salt solution for longer than 6 months. In contrast to novel methods for magnetic nanoparticle production, where organic solvents are necessary, the procedure proposed here can dispense with organic solvents. Magnetic resonance imaging (MRI) experiments on living rats indicate that the nanoparticles are useful as an MRI contrast agent.