Inorganic Nanoparticles for MRI Contrast Agents

Various inorganic nanoparticles have been used as magnetic resonance imaging (MRI) contrast agents due to their unique properties, such as large surface area and efficient contrasting effect. Since the first use of superparamagnetic iron oxide (SPIO) as a liver contrast agent, nanoparticulate MRI contrast agents have attracted a lot of attention. Magnetic iron oxide nanoparticles have been extensively used as MRI contrast agents due to their ability to shorten T2* relaxation times in the liver, spleen, and bone marrow. More recently, uniform ferrite nanoparticles with high crystallinity have been successfully employed as new T2 MRI contrast agents with improved relaxation properties. Iron oxide nanoparticles functionalized with targeting agents have been used for targeted imaging via the site‐specific accumulation of nanoparticles at the targets of interest. Recently, extensive research has been conducted to develop nanoparticle‐based T1 contrast agents to overcome the drawbacks of iron oxide nanoparticle‐based negative T2 contrast agents. In this report, we summarize the recent progress in inorganic nanoparticle‐based MRI contrast agents.     

Synthesis,self-assembly,and characterization of PEG-coated iron oxide nanoparticles as potential MRI contrast agent

Aim: Investigated the self-assembly and characterization of novel antifouling polyethylene glycol (PEG)-coated iron oxide nanoparticles as nanoprobes for magnetic resonance imaging (MRI) contrast agent. Method: Monodisperse oleic acid-coated superparamagnetic iron oxide cores are synthesized by thermal decomposition of iron oleate. The self-assembly behavior between iron oxide cores and PEG-lipid conjugates in water and their characteristics are confirmed by transmission electron microscope, X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectroscopy, and vibrating sample magnetometer. Result: Dynamic light scattering shows superparamagnetic iron oxide nanoparticles coated with PEG are stable in water for pH of 3–10 and ionic strengths up to 0.3 M NaCl, and are protein resistant in physiological conditions. Additionally, in vitro MRI study demonstrates the efficient magnetic resonance imaging contrast characteristics of the iron oxide nanoparticles. Conclusion: The result indicates that the novel antifouling PEG-coated superparamagnetic iron oxide nanoparticles could potentially be used in a wide range of applications such as biotechnology, MRI, and magnetic fluid hyperthermia.     

Facile synthesis of magnetic iron oxide nanoparticles and their characterization

Magnetic iron oxide nanoparticles are synthesized by suitable modification of the standard synthetic procedure without use of inert atmosphere and at room temperature. The facile synthesis procedure can be easily scaled up and is of important from industrial point of view for the commercial large scale production of magnetic iron oxide nanoparticles. The synthesized nanoparticles were characterized by thermal, dynamic light scattering, scanning electron microscopy and transmission electron microscopy analyses.     

In vivo imaging and biodistribution of multimodal polymeric nanoparticles delivered to the optic nerve

The use of nanoparticles for targeted delivery of therapeutic agents to sites of injury or disease in the central nervous system (CNS) holds great promise. However, the biodistribution of nanoparticles following in vivo administration is often unknown, and concerns have been raised regarding potential toxicity. Using poly(glycidyl methacrylate) (PGMA) nanoparticles coated with polyethylenimine (PEI) and containing superparamagnetic iron oxide nanoparticles as a magnetic resonance imaging (MRI) contrast agent and rhodamine B as a fluorophore, whole animal MRI and fluorescence analyses are used to demonstrate that these nanoparticles (NP) remain close to the site of injection into a partial injury of the optic nerve, a CNS white matter tract. In addition, some of these NP enter axons and are transported to parent neuronal somata. NP also remain in the eye following intravitreal injection, a non-injury model. Considerable infiltration of activated microglia/macrophages occurs in both models. Using magnetic concentration and fluorescence visualization of tissue homogenates, no dissemination of the NP into peripheral tissues is observed. Histopathological analysis reveals no toxicity in organs other than at the injection sites. Multifunctional nanoparticles may be a useful mechanism to deliver therapeutic agents to the injury site and somata of injured CNS neurons and thus may be of therapeutic value following brain or spinal cord trauma.     

Surface-modified superparamagnetic nanoparticles for drug delivery: preparation, characterization, and cytotoxicity studies

Superparamagnetic iron oxide nanoparticles have been used for many years as magnetic resonance imaging (MRI) contrast agents or in drug delivery applications. In this study, a novel approach to prepare magnetic polymeric nanoparticles with magnetic core and polymeric shell using inverse microemulsion polymerization process is reported. Poly(ethyleneglycol) (PEG)-modified superparamagnetic iron oxide nanoparticles with specific shape and size have been prepared inside the aqueous cores of AOT/n-Hexane reverse micelles and characterized by various physicochemical means such as transmission electron microscopy (TEM), infrared spectroscopy, atomic force microscopy (AFM), vibrating sample magnetometry (VSM), and ultraviolet/visible spectroscopy. The inverse microemulsion polymerization of a polymerizable derivative of PEG and a cross-linking agent resulted in a stable hydrophilic polymeric shell of the nanoparticles. The results taken together from TEM and AFM studies showed that the particles are spherical in shape with core-shell structure. The average size of the PEG-modified nanoparticles was found to be around 40-50 nm with narrow size distribution. The magnetic measurement studies revealed the superparamagnetic behavior of the nanoparticles with saturation magnetization values between 45-50 electromagnetic units per gram. The cytotoxicity profile of the nanoparticles on human dermal fibroblasts as measured by standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the particles are nontoxic and may be useful for various in vivo and in vitro biomedical applications.     

Image-guided prostate cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles

CG-rich duplex containing prostate-specific membrane antigen (PSMA) aptamer-conjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPIONs) is reported as prostate cancer-specific nanotheranostic agents. These agents are capable of prostate tumor detection in vivo by magnetic resonance imaging (MRI) and selective delivery of drugs to the tumor tissue, simultaneously. The prepared PSMA-functionalized TCL-SPION via a hybridization method (Apt-hybr-TCL-SPION) exhibited preferential binding towards target prostate-cancer cells (LNCaP, PSMA+) in both in vitro and in vivo when analyzed by T(2) -weighted MRI. After Dox molecules were loaded onto the Apt-hybr-TCL-SPION through the intercalation of Dox to the CG-rich duplex containing PSMA aptamer as well as electrostatic interaction between the Dox-and-polymer coating layer of the nanoparticles, the resulting Dox@Apt-hybr-TCL-SPION showed selective drug-delivery efficacy in the LNCaP xenograft mouse model. These results suggest that Dox@Apt-hybr-TCL-SPION has potential for use as novel prostate cancer-specific nanotheranostics.     

磁性氧化铁高效磁共振造影剂的制备及应用

采用高温热分解法, 以乙酰丙酮铁为铁源, 生物相容性良好的聚乙二醇(PEG1000)作为溶剂、还原剂及修饰剂制备PEG修饰的氧化铁纳米粒子(PEG-SPIONs), 并研究其在小鼠体内的造影效果。X射线衍射(XRD)分析表明样品中含有Fe₃O₄晶相。透射电镜(TEM)结果显示, 合成的PEG-SPIONs形貌均一, 主要为等轴晶形, 纳米粒度及电位分析表明其表面呈负电性, 分散在水中的动力学粒径为20 nm。磁性能结果表明合成的PEG-SPIONs室温下具有超顺磁性, 并且具有较高的r₂/r₁值。细胞活性研究表明PEG-SPIONs具有较低的生物毒性, 体内的磁共振成像结果显示出PEG-SPIONs优异的对比增强效果, 说明PEG-SPIONs可以作为高效的T₂磁共振成像造影剂。     

LHRH-functionalized superparamagnetic iron oxide nanoparticles for breast cancer targeting and contrast enhancement in MRI

This paper shows that superparamagnetic iron oxide nanoparticles (SPIONs) conjugated to luteinizing hormone releasing hormone (LHRH) (LHRH–SPIONs), can be used to target breast cancer cells. They also act as contrast enhancement agents during the magnetic resonance imaging of breast cancer xenografts. A combination of transmission electron microscopy (TEM) and spectrophotometric analysis was used in our experiments, to investigate the specific accumulation of the functionalized superparamagnetic iron oxide nanoparticles (SPIONs) in cancer cells. The contrast enhancement of conventional T2 images obtained from the tumor tissue and of breast cancer xenograft bearing mice is shown to be much greater than that in saline controls, when the tissues were injected with LHRH–SPIONs. Magnetic anisotropy multi-CRAZED images of tissues extracted from mice injected with SPIONs were also found to have enhanced MRI contrast in breast cancer xenografts and metastases in the lungs.     

Effect of Synthesis Parameters on the Properties of Superparamagnetic Iron Oxide Nanoparticles

Iron oxide nanoparticles were coprecipitated in air medium using different sodium hydroxide (NaOH) concentrations, and their structural and magnetic properties were studied. It was observed that the precipitation of superparamagnetic iron oxide nanoparticles could be achieved above a critical NaOH concentration. This was followed by the investigation of the effect of the stirring rate on the structural and magnetic properties of the nanoparticles precipitated at 8.5?M NaOH and over. Morphological observation made by a transmission electron microscope (TEM) showed that the particle size of iron oxide nanoparticles was around 7.5?nm. Magnetization curves measured by a vibrating sample magnetometer showed zero coercivity indicating that the samples are superparamagnetic and the highest saturation magnetization (70.4?emu/g) was obtained at the stirring rate of 1100?rpm. The mean particle sizes of iron oxide nanoparticles calculated from the magnetization data are found to be consistent with the particle sizes obtained from the TEM images.     

Superparamagnetic nanohybrids with cross-linked polymers providing higher in vitro stability

A simple, rapid, reproducible, and scalable method for generating highly stable cross-linked superparamagnetic nanohybrids was developed. Pre-coating of superparamagnetic iron oxide nanoparticle surfaces with a biocompatible polymer, hydroxy polyvinyl alcohol (PVA-OH) prior to cross-linking with silica precursor resulted in improved stability, uniform morphologies and allows for further surface functionalization. The obtained magnetic nanohybrids contain a non-porous silica layer, are monodisperse (size 50.0 ± 3.7 nm), and show colloidal stability applicable for biomedical applications (pH 7.35–7.45) with long shelf life (>9 months). In vitro studies indicate that as-prepared nanohybrids are non-cytotoxic and highly robust toward endosomal/lysosomal conditions, with no particle dissolution evident for up to 42 days. As a demonstration of the potential utility of these nanohybrids in medical diagnostic applications (e.g., MRI), surface functionalization with folic acid resulted in particle recognition and affinity to folate receptor-positive cervix (HeLa) cells. Accordingly, the facile development of these non-toxic, stable cross-linked magnetic nanohybrids, with the added benefit of scalable preparation, should serve as an entry point for the further development of safer, target specific, MRI contrast agents for cancer diagnosis.     

Encapsulation of magnetic nanoparticles in a pH-sensitive poly(4-vinyl pyridine) polymer: a step forward to a multi-responsive system

A multiresponsive system that consists on pH-responsive polymer microspheres with encapsulated iron oxide magnetic nanoparticles that rendered the core magnetic to enable externally controlled actuation under magnetic induction has been developed. The inorganic nanoparticles were first prepared and, then, further encapsulated in a pH-sensitive poly(4-vinylpyridine). These spheres have been obtained by a modification of the simple, rapid and high-reproducible nanoprecipitation method. Magnetic measurements showed that the iron oxide nanoparticles are superparamagnetic and, therefore, able to undergo a local increase of the temperature when an oscillating magnetic field is applied. Magnetically triggered heating and pH sensitivity can be useful for biomedical applications.     

Manipulation and tracking of superparamagnetic nanoparticles using MRI

The use of magnetic fields in magnetic resonance imaging (MRI) for the tracking and delivery of chemotherapeutics bound to superparamagnetic nanoparticles offers a promising method for the non-invasive treatment of inoperable tumours. Here we demonstrate that superparamagnetic magnetite nanoparticles fabricated by an easily scalable method can be driven and tracked in real time at high velocities in vitro using MRI hardware. Force balance calculations are consistent with the magnetic properties of individual 10 nm diameter particles that move collectively as micron sized agglomerates with hydrodynamic diameter similar to that inferred from zero-magnetic-field dynamic light scattering measurements.     

The Shortening of MWNT‐SPION Hybrids by Steam Treatment Improves Their Magnetic Resonance Imaging Properties In Vitro and In Vivo

Carbon nanotubes (CNTs) have been advocated as promising nanocarriers in the biomedical field. Their high surface area and needle‐like shape make these systems especially attractive for diagnostic and therapeutic applications. Biocompatibility, cell internalization, biodistribution, and pharmacokinetic profile have all been reported to be length dependent. In this study, further insights are gotten on the role that the length of CNTs plays when developing novel contrast agents for magnetic resonance imaging (MRI). Two samples of CNTs with different length distribution have been decorated with radio‐labeled iron oxide nanoparticles. Despite characterization of the prepared hybrids reveals a similar degree of loading and size of the nanoparticles for both samples, the use of short CNTs is found to enhance the MRI properties of the developed contrast agents both in vitro and in vivo compared to their long counterparts.     

肿瘤靶向纳米四氧化三铁造影剂的制备及其磁共振成像应用

环氧氯丙烷交联法制备交联葡聚糖与多肽偶联的肿瘤新生血管靶向的纳米Fe3O4造影剂,考察其体内肿瘤靶向性并进行磁共振成像试验。以共沉淀法制备6～8nm的Fe3O4粒子,采用油酸钠和葡聚糖二次包覆,用环氧氯丙烷使葡聚糖交联并与靶向多肽偶联,进行了肿瘤细胞结合实验和荷瘤动物磁共振成像实验。结果表明,包覆后纳米Fe3O4复合粒子为20～30nm,水动力学粒径小于80nm,仍表现为超顺磁性;葡聚糖交联的时间4～8h,造影剂在体内血浆半衰期从2.8h延长到6.2h;主要通过肝脏和肾脏代谢。与无靶的比较,靶向多肽偶联后与肿瘤细胞特异性结合能力提高了10～30倍,MR成像信号密度是无靶的3.68倍。     

Characterization of the biocompatible magnetic colloid on the basis of Fe3O4 nanoparticles coated with dextran, used as contrast agent in magnetic resonance imaging

The magnetic resonance imaging contrast agent, the so-called Endorem colloidal suspension on the basis of superparamagnetic iron oxide nanoparticles (mean diameter of 5.5 nm) coated with dextran, were characterized on the basis of several measurement techniques to determine the parameters of their most important physical and chemical properties. It is assumed that each nanoparticle is consisted of Fe3O4 monodomain and it was observed that its oxidation to gamma-Fe2O3 occurs at 253.1 degrees C. The M?ssbauer spectroscopy have shown a superparamagnetic behavior of the magnetic nanoparticles. The Magnetic Resonance results show an increase of the relaxation times T1, T2, and T2* with decreasing concentration of iron oxide nanoparticles. The relaxation effects of SPIONs contrast agents are influenced by their local concentration as well as the applied field strength and the environment in which these agents interact with surrounding protons. The proton relaxation rates presented a linear behavior with concentration. The measured values of thermo-optic coefficient dn/dT, thermal conductivity kappa, optical birefringence delta n0, nonlinear refractive index n2, nonlinear absorption beta' and third-order nonlinear susceptibility |chi(3)| are also reported.     

Mesoporous silica nanoparticles as a delivery system of gadolinium for effective human stem cell tracking

The progress of using gadolinium (Gd)-based nanoparticles in cellular tracking lags behind that of superparamagnetic iron oxide (SPIO) nanoparticles in magnetic resonance imaging (MRI). Here, dual functional Gd-fluorescein isothiocyanate mesoporous silica nanoparticles (Gd-Dye@MSN) that possess green fluorescence and paramagnetism are developed in order to evaluate their potential as effective T1-enhancing trackers for human mesenchymal stem cells (hMSCs). hMSCs are labeled efficiently with Gd-Dye@MSN via endocytosis. Labeled hMSCs are unaffected in their viability, proliferation, and differentiation capacities into adipocytes, osteocytes, and chondrocytes, which can still be readily MRI detected. Imaging, with a clinical 1.5-T MRI system and a low incubation dosage of Gd, low detection cell numbers, and short incubation times is demonstrated on both loaded cells and hMSC-injected mouse brains. This study shows that the advantages of biocompatibility, durability, high internalizing efficiency, and pore architecture make MSNs an ideal vector of T1-agent for stem-cell tracking with MRI.     

Highly water-dispersible PEG surface modified ultra small superparamagnetic iron oxide nanoparticles useful for target-specific biomedical applications

For the application of superparamagnetic iron oxide nanoparticles in biomedical fields for target-specific purposes, they should be ultra small in diameter. We developed a simple one-step synthesis of surface modified ultra small superparamagnetic iron oxide nanoparticles (USPIONs) with an average particle diameter of 1.7?nm in a polar organic solvent. Polyethylene glycol diacid (PEG) surface modified USPIONs synthesized in triethylene glycol were nearly monodisperse in diameter and highly water-dispersible. The PEG surface modified USPIONs were tested for use as magnetic resonance (MR) contrast agents. They had a low r(2)/r(1) relaxivity ratio of 3.4 (r(1) = 4.46 and r(2) = 15.01?mM(-1)?s(-1)) and showed clear dose-dependent T(1) and T(2) map images, indicating that they will be useful as both target-specific T(1) and T(2) MR contrast agents due to their ultra small size.     

Amphiphilic polymer-coated hybrid nanoparticles as CT/MRI dual contrast agents

We describe hybrid nanoparticles, composed of iron oxide and gold nanoparticles, as potential dual contrast agents for both computed tomography (CT) and magnetic resonance imaging (MRI). The hybrid nanoparticles are synthesized by thermal decomposition of mixtures of Fe-oleate and Au-oleylamine complexes. Using a nano-emulsion method, the nanoparticles are coated with amphiphilic poly(DMA-r-mPEGMA-r-MA) to impart water-dispersity and antibiofouling properties. An in?vitro phantom study shows that the hybrid nanoparticles have high CT attenuation, because of the constituent gold nanoparticles, and afford a good MR signal, attributable to the contained iron oxide nanoparticles. Intravenous injection of the hybrid nanoparticles into hepatoma-bearing mice results in high contrast between the hepatoma and normal hepatic parenchyma in both CT and MRI. These results suggest that the hybrid nanoparticles may be useful as CT/MRI dual contrast agents for in?vivo hepatoma imaging.     

Mesoporous silica nanoparticles improve magnetic labeling efficiency in human stem cells

Tumblerlike magnetic/fluorescein isothiocyanate (FITC)-labeled mesoporous silica nanoparticles, Mag-Dye@MSNs, have been developed, which are composed of silica-coated core-shell superparamagnetic iron oxide (SPIO@SiO(2)) nanoparticles co-condensed with FITC-incorporated mesoporous silica. Mag-Dye@MSNs can label human mesenchymal stem cells (hMSCs) through endocytosis efficiently for magnetic resonance imaging (MRI) in vitro and in vivo, as manifested by using a clinical 1.5-T MRI system with requirements of simultaneous low incubation dosage of iron, low detection cell numbers, and short incubation time. Labeled hMSCs are unaffected in their viability, proliferation, and differentiation capacities into adipocytes and osteocytes, which can still be readily detected by MRI. Moreover, a higher MRI signal intensity decrease is observed in Mag-Dye@MSN-treated cells than in SPIO@SiO(2)-treated cells. This is the first report that MCM-41-type MSNs are advantageous to cellular uptake, as manifested by a higher labeling efficiency of Mag-Dye@MSNs than SPIO@SiO(2).     

Design of iron oxide/silica/alginate hybrid magnetic carriers (HYMAC)

A large number of natural and synthetic polymers have already been evaluated for the design of nanomaterials incorporating magnetic nanoparticles for biomedical applications. The possibility to use hybrid (bio)-organic/inorganic nano-carriers have been much less studied. Here we describe the design of Hybrid MAgnetic Carriers (HYMAC) consisting of alginate/silica nanocomposites incorporating magnetite nanoparticles, based on a spray-drying approach. Transmission electron microscopy and X-ray energy dispersive spectrometry confirm the successful incorporation of magnetic colloids within homogeneous hybrid capsules. X-ray diffraction data suggest that surface iron ions are partially desorbed by the spray-drying process, leading to the formation of lepidocrocite and of an iron silicate phase. Magnetic measurements show that the resulting nanocomposites exhibit a superparamagnetic behaviour with a blocking temperature close to 225 K. Comparison with un-silicified capsules indicate that the mineral phase enhances the thermal stability of the polymer network and do not modify of the amount of incorporated iron oxide nanoparticles. Moreover, evaluation of nanocomposite up-take by fibroblasts indicates their possible internalization. A selective intracellular alginate degradation is observed, suggesting that these HYMAC nanomaterials may exhibit interesting properties for the design of drug delivery devices.