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.     

超顺磁性纳米氧化铁的制备、表面修饰及其在磁共振成像造影剂方面的应用

介绍了磁共振成像技术(MRI)和MRI造影剂的应用原理,综述了近年来超顺磁性纳米氧化铁(SPIO)的制备方法,包括化学沉淀法、水热法、微乳液法、溶胶-凝胶法和高温分解法等,以及SPIO在造影剂方面的应用,并展望了其今后的发展方向。     

Multiple emulsion microbubbles for ultrasound imaging

In order to improve the sensitivity of ultrasound imaging, the contrast agents, a powerful non-invasive and real-time medical imaging technique, are used. However, air or N₂ or perfluorocarbon only encapsulated microbubbles which are currently used have lower efficiency and short imaging time. So the novel contrast agents with a higher efficiency are required. To achieve this objective, the strategy that we have explored involves the use of superparamagnetic iron oxide (SPIO) Fe₃O₄ nanoparticles multilayer emulsion microbubbles. This multilayer structure consists of three layers. The core is poly-d, l-lactide (PLA) encapsulated N₂ nanobubble with the SPIO nanoparticles forming oil-in-water (W/O) layer. The outermost is water-in-oil-in-water ((W/O)/W) emulsion layer with PVA solution. Herein we describe the synthesis and characterization of ultrasound imaging microstructure with an overall diameter of around 2μm-8μm. On the one hand, the stable gas encapsulated microstructure can provide a high scattering intensity resulting in high echogenicity, On the other hand, SPIO nanoparticles have shown the potential of high-resolution sonography. So the multiple emulsion microbubbles with SPIO can have double action to enhance the ultrasound imaging. Besides, because SPIO can also serve as magnetic resonance imaging (MRI) contrast agents, such microstructure may be useful for multimodality imaging studies in ultrasound imaging and MRI.     

天然多酚单宁酸构建的铁基超灵敏磁共振造影剂及其肿瘤诊疗应用

Gd(Ⅲ)配合物和超顺磁性氧化铁(SPION)是目前常见的T1MRI造影剂,然而由于Gd(Ⅲ)的毒性和SPION较差的对比度,需要开发出新的稳定、无毒的高效造影剂.本论文基于减慢分子自旋的策略,利用生物安全的天然多酚单宁酸和牛血清白蛋白来构建无毒的Fe(Ⅲ)复合物TA-Fe@BSA.该复合物具有良好的增强弛豫性能,在溶...     

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。     

Detection of magnetic nanoparticles in tissue using magneto-motive ultrasound

The purpose of this study was to demonstrate the magneto-motive ultrasonic detection of superparamagnetic iron oxide (SPIO) nanoparticles as a marker of macrophage recruitment in tissue. The capability of ultrasound to detect SPIO nanoparticles (core diameter ～20?nm) taken up by murine liver macrophages was investigated. Eight mice were sacrificed two days after the intravenous administration of four SPIO doses (1.5, 1.0, 0.5, and 0.1?mmol Fe/kg body weight). In the iron-laden livers, ultrasound Doppler measurements showed a frequency shift in response to an applied time-varying magnetic field. M-mode scan and colour power Doppler images of the iron-laden livers also demonstrated nanoparticle movement under focused magnetic field excitation. In the livers of two saline injected control mice, no movement was observed using any ultrasound imaging modes. The results of our experiments indicate that ultrasound imaging of magneto-motive excitation is a candidate imaging modality to identify tissue-based macrophages containing SPIO nanoparticles.     

Impact of agglomeration on the relaxometric properties of paramagnetic ultra-small gadolinium oxide nanoparticles

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.     

Multiwall carbon nanotubes as MRI contrast agents for tracking stem cells

In this study we investigate the potential of multiwall carbon nanotubes (MWCNTs) with low metal impurities (2.57% iron) as magnetic resonance imaging (MRI) contrast agents. Taking into account probable aggregation at high MWCNTs concentration analysis shows that the r(2) relaxivity of MWCNTs in 1% agarose gels at 19?°C is 564 ± 41 s(-1) mM(-1); this is attributed to both the presence of iron oxide impurities and also to the carbon MWCNT structure itself. Stem cells were labelled with MWCNTs to demonstrate the effectiveness of MWCNTs as MRI contrast agents for cellular MRI. The MWCNTs did not impair cell viability or proliferation. These results suggest that the MRI contrast agent properties of the MWCNTs could be used in vivo for stem cell tracking/imaging and during MWCNT-mediated targeted electro-chemotherapy of tumours.     

Synthesis of biocompatible, mesoporous Fe(3)O(4) nano/microspheres with large surface area for magnetic resonance imaging and therapeutic applications

This article reports the fabrication of mesoporous Fe(3)O(4) nano/microspheres with a high surface area value (163 m(2)/g, Brunauer-Emmett-Teller) and demonstrates their use for drug loading, release, and magnetic resonance imaging (MRI). These monodispersed, mesoporous Fe(3)O(4) nano/microspheres with controllable average sizes ranging from 50 to 200 nm were synthesized using a Fe(3)O(4)/poly(acrylic acid) hybrid sphere template and subsequent silica shell formation and removal. We found that the SiO(2) coating is a crucial step for the successful synthesis of uniform mesoporous Fe(3)O(4) nano/microspheres. The as-synthesized mesoporous Fe(3)O(4) nanospheres show a high magnetic saturation value (M(s) = 48.6 emu/g) and could be used as MRI contrast agents (r(2) = 36.3 s(-1) mM(-1)). Trypan blue exclusion and MTT assay (see Supporting Information ) cytotoxicity analyses of the nanospheres based on HepG2 and MDCK cells showed that the products were biocompatible, with a lower toxicity than lipofectamine (positive control). Hydrophilic ibuprofen and hydrophobic zinc(II) phthalocyanine drug loading into mesoporous Fe(3)O(4) nanospheres and selected release experiments were successfully achieved. The potential use of mesoporous Fe(3)O(4) nanospheres in biomedical applications, in light of the nano/microspheres' efficient drug loading and release, MRI, and low cytotoxicity, has been demonstrated. It is envisaged that mesoporous Fe(3)O(4) nanospheres can be used as drug carriers and MRI contrast agents for the reticuloendothelial system; they can also be delivered locally, such as via a selective catheter.     

N-alkyl-polyethylenimine stabilized iron oxide nanoparticles as MRI visible transfection agents

An amphiphilic polymer, alkylated branched polyethylenimine (N-Alkyl-PEI), is synthesized and used for stabilization of hydrophobic superparamagnetic iron oxide (SPIO) nanocrystals in aqueous phase. Such composite particles are monodisperse without aggregation in physiological buffer as verified by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The nanocomposite system is capable of binding and delivering plasmid DNA for gene transfection while maintaining magnetic properties and biocompatibility. Transfection of cells showed that N-Alkyl-PEI2k stabilized magnetite nanoparticles were most effective in gene transfection comparing to unmodified PEI2k and PEI25k agents. Obvious MR signal darkening of transfected cells was observed under a clinical 3T MRI scanner. This multifunctional nanocomposite system provides a safe and efficient method for gene delivery with non-invasive imaging monitoring capability.     

Giant vesicles containing superparamagnetic iron oxide as biodegradable cell-tracking MRI probes

A major breakthrough in in vivo cellular imaging has been the clinical/preclinical use of magnetic resonance imaging (MRI) with contrast agent. Superparamagnetic iron oxide (SPIO) is a promising candidate for the development of smart MRI probes for cell-tracking. In the present study, we describe biodegradable probes made of giant vesicles (GVs; closed lipid membranes with diameters >1 μm) that encapsulate SPIO for use as an MRI contrast agent. These SPIO-containing GVs (SPIO-GVs) exhibited excellent contrast enhancement in the single cell of medaka fish (Oryzias latipes) embryos immediately after their microinjection, and this enhancement disappeared when the GV membranes were destroyed. Our results demonstrate that SPIO-GVs are useful MRI probes for single cell-tracking that have minimum cytotoxicity and will greatly improve clinical/preclinical in vivo cellular imaging techniques.     

PAMAM树状大分子磁共振成像造影剂的研究进展

树状大分子磁共振成像造影剂与小分子造影剂相比具有很高的质子弛豫增强及摩尔弛豫率,成像清晰度更好,有更长的血液循环时间等,因而具有十分乐观的应用前景.着重介绍了聚酰胺-胺(PAMAM)树状大分子钆螯合物造影剂的性质及应用研究情况.低代数(PAMAM-G2、G3、G4)树状大分子钆螯合物造影剂分子尺寸较小(小于6nm),相对而言可以迅速从肾排泄,能够作为肾功能性造影剂.高代数(PAMAM-G7、G8)树状大分子钆螯合物造影剂分子尺寸较大(大于12nm),可静脉注射用于血池造影剂,而PAMAM-G6大分子试剂可用于淋巴成像造影剂.对PAMAM树状大分子钆螯合物进行化学或生物学修饰,还可以使其具有肿瘤靶向性,并能作为钆中子捕获治疗(Gd-NCT)试剂.     

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.     

Supramolecular assembled nanostructure containing cubic silsesquioxane in aqueous solution

Micellization and aggregation behavior of amphiphilic cubic silsesquioxane-poly(ethylene oxide) (CSSQ-PEO) in aqueous solution was studied by Dynamic and Static Light Scattering (DLS and SLS), and Transmission Electron Microscopy (TEM). The effects of CSSQ-PEO concentration and temperature on particle size were also investigated. Above the critical aggregation concentration (CAC), a combination of unassociated single micelle and micellar aggregates is observed up to a certain level of CSSQ-PEO concentration as determined by DLS and TEM studies. The size of unassociated single micelles are found to be independent of CSSQ-PEO concentration while that of the micellar aggregates become larger at higher concentration due to the aggregation growth. Both studies revealed that a small CSSQ core is surrounded by PEO corona and found self-assembled nanostructure of CSSQ-PEO in aqueous solution. The molecular weight of micellar aggregates (Mw,agg), radius of gyration (Rg), and apparent aggregation number (Nagg) were evaluated by SLS measurement. The decrease in the particle size (described by hydrodynamic diameter: Dh) upon increasing temperature was observed because of the diminishing hydrophilicity of PEO. Surprisingly, Rg is also decreased at higher temperature assuming the dissociation of micellar aggregates by repulsive forces due to the crowding effect. The encapsulation property of CSSQ-PEO to model drug has also been studied. Our preliminary results from DLS and TEM studies showed the formation of CSSQ-PEO nanospheres containing drug in aqueous solution. The size of the drug loaded CSSQ-PEO nanospheres are found to be larger (250-300 nm) than that of the core-corona CSSQ-PEO micellar aggregates (approximatly 180 nm) in dilute aqueous solution.     

Polycatechol Nanoparticle MRI Contrast Agents

Amphiphilic triblock copolymers containing Fe^III‐catecholate complexes formulated as spherical‐ or cylindrical‐shaped micellar nanoparticles ( SMN and CMN , respectively) are described as new T ₁‐weighted agents with high relaxivity, low cytotoxicity, and long‐term stability in biological fluids. Relaxivities of both SMN and CMN exceed those of established gadolinium chelates across a wide range of magnetic field strengths. Interestingly, shape‐dependent behavior is observed in terms of the particles' interactions with HeLa cells, with CMN exhibiting enhanced uptake and contrast via magnetic resonance imaging (MRI) compared with SMN . These results suggest that control over soft nanoparticle shape will provide an avenue for optimization of particle‐based contrast agents as biodiagnostics. The polycatechol nanoparticles are proposed as suitable for preclinical investigations into their viability as gadolinium‐free, safe, and effective imaging agents for MRI contrast enhancement.     

Facile synthesis of ultrasmall PEGylated iron oxide nanoparticles for dual-contrast T1- and T2-weighted magnetic resonance imaging

The development of new types of high-performance nanoparticulate MR contrast agents with either positive (T(1)) or dual-contrast (both positive and negative, T(1) + T(2)) ability is of great importance. Here we report a facile synthesis of ultrasmall PEGylated iron oxide nanoparticles for dual-contrast T(1)- and T(2)-weighted MRI. The produced superparamagnetic iron oxide nanoparticles (SPIONs) are of high crystallinity and size uniformity with an average diameter of 5.4 nm, and can be individually dispersed in the physiological buffer with high stability. The SPIONs reveal an impressive saturation magnetization of 94 emu g(-1) Fe(3)O(4), the highest r(1) of 19.7 mM(-1) s(-1) and the lowest r(2)/r(1) ratio of 2.0 at 1.5 T reported so far for PEGylated iron oxide nanoparticles. T(1)- and T(2)-weighted MR images showed that the SPIONs could not only improve surrounding water proton signals in the T(1)-weighted image, but induce significant signal reduction in the T(2)-weighted image. The good contrast effect of the SPIONs as T(1) + T(2) dual-contrast agents might be due to its high magnetization, optimal nanoparticle size for T(1) + T(2) dual-contrast agents, high size monodispersity and excellent colloidal stability. In vitro cell experiments showed that the SPIONs have little effect on HeLa cell viability.     

A hybrid system: MnO-incorporated mesoporous silica nanoparticles for theranostic applications

The need for an alternative \({ T}_{1}\) contrast enhancer for magnetic resonance imaging (MRI) has been escalating owing to the toxicity profiles observed with the use of commercial contrast agents. Manganese oxide nanoparticles provide an optimal solution for the problem, as it is an endogenous co-factor for many enzymes in the biological system. In the present work, we have synthesized mesoporous silica nanoparticles encapsulated with manganese oxide nanoparticles as a positive contrast enhancer for MRI applications. Spherical magnetic MnO nanoparticles with divalent oxidation state were also synthesized and utilized as control to compare the efficiency of the nano-hybrid system. MRI showed higher contrast enhancement with the use of nano-hybrid and the relaxivity value for \({ T}_{1}\)-weighted imaging was calculated to be \(2.6~\hbox {mg ml}^{-1}~\hbox {s}^{-1}\). Also, the developed system was validated for its usefulness as a therapeutic system through adsorption studies. Therefore, the nano-hybrid has the potential to be a competent MRI contrast enhancer that could be used for theranostic applications.     

Multifunctional mesoporous silica nanospheres with cleavable Gd(III) chelates as MRI contrast agents: synthesis, characterization, target-specificity, and renal clearance

Mesoporous silica nanospheres (MSNs) are a promising material for magnetic resonance imaging (MRI) contrast agents. In this paper multifunctional MSNs with cleavable Gd(III) chelates are synthesized and characterized, and their applicability as MRI contrast agents is demonstrated both in vitro and in vivo. The MSNs contain Gd(III) chelates that are covalently linked via a redox-responsive disulfide moiety. The MSNs are further functionalized with polyethylene glycol (PEG) and an anisamide ligand to improve their biocompatibility and target specificity. The effectiveness of MSNs as an MRI imaging contrast agent and their targeting ability are successfully demonstrated in vitro using human colon adenocarcinoma and pancreatic cancer cells. Finally, the capability of this platform as an in vivo MRI contrast agent is tested using a 3T scanner. The Gd(III) chelate was quickly cleaved by the blood pool thiols and eliminated through the renal excretion pathway. Further tuning of the Gd(III) chelate release kinetics is needed before the MSN system can be used as target-specific MRI contrast agents in vivo.     

Magnetic resonance imaging probes for labeling of chondrocyte cells

Recent progress in cell therapy research has raised the need for non-invasive monitoring of transplanted cells. Magnetic resonance imaging (MRI) of superparamagnetic iron oxide (SPIO) labeled cells have been widely used for high resolution monitoring of the biodistribution of cells after transplantation. Here we report that self-assembly of amphiphilic polyethylenimine (PEI)/SPIO nanocomposites can lead to the formation of ultrasensitive MRI probes, which can be used to label chondrocyte cells with good biocompatibility. The labeled cells display strong signal contrast compared to unlabeled ones in a clinical MRI scanner. This probe may be useful for noninvasive MR tracking of implanted cells for tissue regeneration.     

Photoacoustic‐Guided Surgery with Indocyanine Green‐Coated Superparamagnetic Iron Oxide Nanoparticle Clusters

A common cause of local tumor recurrence in brain tumor surgery results from incomplete surgical resection. Adjunctive technologies meant to facilitate gross total resection have had limited efficacy to date. Contrast agents used to delineate tumors preoperatively cannot be easily or accurately used in the real‐time operative setting. Although multimodal imaging contrast agents are developed to help the surgeon discern tumor from normal tissue in the operating room, these contrast agents are not readily translatable. This study has developed a novel contrast agent comprised solely of two Food and Drug Administration approved components, indocyanine green (ICG) and superparamagnetic iron oxide (SPIO) nanoparticles—with no additional amphiphiles or carrier materials, to enable preoperative detection by magnetic resonance (MR) imaging and intraoperative photoacoustic (PA) imaging. The encapsulation efficiency of both ICG and SPIO within the formulated clusters is ≈100%, and the total ICG payload is 20–30% of the total weight (ICG + SPIO). The ICG–SPIO clusters are stable in physiologic conditions; can be taken up within tumors by enhanced permeability and retention; and are detectable by MR. In a preclinical surgical resection model in mice, following injection of ICG–SPIO clusters, animals undergoing PA‐guided surgery demonstrate increased progression‐free survival compared to animals undergoing microscopic surgery.