Magnetic/Silica Nanocomposites as Dual‐Mode Contrast Agents for Combined Magnetic Resonance Imaging and Ultrasonography

A simple and efficient method for synthesizing a range of hybrid nanocomposites based on a core of silica nanospheres (160, 330, and 660 nm in diameter) covered by an outer shell of superparamagnetic nanoparticles, either iron oxide or heterodimeric FePt‐iron oxide nanocrystals, is presented. The magnetic and ultrasound characterization of the resulting nanocomposites shows that they have great potential as contrast agents for dual‐mode imaging purposes, combining magnetic resonance imaging (MRI) and ultrasonography (US).     

Superparamagnetic Hyperbranched Polyglycerol‐Grafted Fe3O4 Nanoparticles as a Novel Magnetic Resonance Imaging Contrast Agent: An In Vitro Assessment

Hyperbranched polyglycerol‐grafted, magnetic Fe₃O₄ nanoparticles (HPG‐grafted MNPs) are successfully synthesized by surface‐initiated ring‐opening multibranching polymerization of glycidol. Reactive hydroxyl groups are immobilized on the surface of 6–9 nm Fe₃O₄ nanoparticles via effective ligand exchange of oleic acid with 6‐hydroxy caproic acid. The surface hydroxyl groups are treated with aluminum isopropoxide to form the nanosized macroinitiators. The successful grafting of HPG onto the nanoparticles is confirmed by infrared and X‐ray photoelectron spectroscopy. The HPG‐grafted MNPs have a uniform hydrodynamic diameter of (24.0 ± 3.0) nm, and are very stable in aqueous solution, as well as in cell culture medium, for months. These nanoparticles have great potential for application as a new magnetic resonance imaging contrast agent, as evidenced by their lack of cytotoxicity towards mammalian cells, low uptake by macrophages, excellent stability in aqueous medium and magnetic fields, and favorable magnetic properties. Furthermore, the possibility of functionalizing the hydroxyl end‐groups of the HPG with cell‐specific targeting ligands will expand the range of applications of these MNPs.     

Superparamagnetic Nanostructures for Off‐Resonance Magnetic Resonance Spectroscopic Imaging

This study proposes a new method to generate positive contrast in magnetic resonance imaging (MRI) using superparamagnetic contrast agents. Superparamagnetic nanostructures consisting of octahedron manganese ferrite nanoparticles embedded in spherical nanogels are fabricated using a bottom‐up approach. The composite nanoparticles are strongly magnetized in an external magnetic field and produce a unique NMR frequency shift in water protons, which can be demonstrated in MR spectroscopy and imaging to be different from the bulk pool. Moreover, the particles exhibit excellent colloidal stability in aqueous media and good cell biocompatibility. Hence, these particles are potentially useful as biomarkers by taking advantage of the positive contrast effects produced in MRI.     

Synthesis of PEOlated Fe3O4@SiO2 Nanoparticles via Bioinspired Silification for Magnetic Resonance Imaging

Inspired by the biosilification process, a highly benign synthesis strategy is successfully developed to synthesize PEOlated Fe₃O₄@SiO₂ nanoparticles (PEOFSN) at room temperature and near‐neutral pH. The success of such a strategy lies in the simultaneous encapsulation of Fe₃O₄ nanocrystals and silica precursors into the core of PEO‐based polymeric micelles. The encapsulation results in the formation of a silica shell being confined to the interface between the core and corona of the Fe₃O₄‐nanocrystal‐loaded polymeric micelles. Consequently, the surface of the Fe₃O₄@SiO₂ nanoparticle is intrinsically covered by a layer of free PEO chains, which enable the PEOFSN to be colloidally stable not only at room temperature, but also upon incubation in the presence of proteins under physiological conditions. In addition, the silica shell formation does not cause any detrimental effects to the encapsulated Fe₃O₄ nanocrystals with respect to their size, morphology, crystallinity, and magnetic properties, as shown by their physicochemical behavior. The PEOFSN are shown to be good candidates for magnetic resonance imaging (MRI) contrast agents as demonstrated by the high r₂/r₁ ratio with long‐term stability under high magnetic field, as well as the lack of cytotoxicity.     

Silica‐Coated Manganese Oxide Nanoparticles as a Platform for Targeted Magnetic Resonance and Fluorescence Imaging of Cancer Cells

Monodisperse silica‐coated manganese oxide nanoparticles (NPs) with a diameter of ～35 nm are synthesized and are aminated through silanization. The amine‐functionalized core–shell NPs enable the covalent conjugation of a fluorescent dye, Rhodamine B isothiocyanate (RBITC), and folate (FA) onto their surface. The formed Mn₃O₄@SiO₂(RBITC)–FA core–shell nanocomposites are water‐dispersible, stable, and biocompatible when the Mn concentration is below 50 µg mL^?1 as confirmed by a cytotoxicity assay. Relaxivity measurements show that the core–shell NPs have a T₁ relaxivity (r₁) of 0.50 mM ^?1 s^?1 on the 0.5 T scanner and 0.47 mM ^?1 s^?1 on the 3.0 T scanner, suggesting the possibility of using the particles as a T₁ contrast agent. Combined flow cytometry, confocal microscopy, and magnetic resonance imaging studies show that the Mn₃O₄@SiO₂(RBITC)–FA nanocomposites can specifically target cancer cells overexpressing FA receptors (FARs). Findings from this study suggest that the silica‐coated Mn₃O₄ core–shell NPs could be used as a platform for bimodal imaging (both magnetic resonance and fluorescence) in various biological systems.     

Hybrids of Magnetic Nanoparticles with Double‐Hydrophilic Core/Shell Cylindrical Polymer Brushes and Their Alignment in a Magnetic Field

The synthesis of double‐hydrophilic core/shell cylindrical polymer brushes (CPBs), their hybrids with magnetite nanoparticles, and the directed alignment of these magnetic hybrid cylinders by a magnetic field are demonstrated. Consecutive grafting from a polyinitiator poly(2‐(2‐bromoisobutyryloxy)ethyl methacrylate) (PBIEM) of tert‐butyl methacrylate (tBMA) and oligo(ethylene glycol) methacrylate (OEGMA) using atom‐transfer radical polymerization (ATRP) and further de‐protection yields core/shell CPBs with poly(methacrylic acid) (PMAA) as the core and POEGMA as the shell, which is evidenced by ¹H NMR, gel permeation chromatography (GPC), and dynamic and static light scattering (DLS and SLS). The resulting core/shell brush is well soluble in water and shows a pH responsiveness because of its weak polyelectrolyte core. Pearl‐necklace structures are observed by cryogenic transmission electron microscopy (cryo‐TEM) at pH 4, while at pH 7, these structures disappear owing to the ionization of the core. A similar morphology is also found for the polychelate of the core/shell CPBs with Fe³⁺ ions. Superparamagnetic magnetite nanoparticles have also been prepared and introduced into the core of the brushes. The hybrid material retains the superparamagnetic property of the magnetite nanoparticles, which is verified by superconducting quantum interference device (SQUID) magnetization measurements. Large‐scale alignment of the hybrid cylinders in relatively low magnetic fields (40–300 mT) can easily be performed when deposited on a surface. which is clearly revealed by the atomic force microscopy (AFM) and TEM measurements.     

High‐Content,Well‐Dispersed γ‐Fe2O3 Nanoparticles Encapsulated in Macroporous Silica with Superior Arsenic Removal Performance

Novel composites of iron oxide encapsulated in macroporous silica with excellent arsenic adsorption performance have been successfully developed. Macroporous silica foams with large pore sizes of ≈100 nm and a high pore volume of 1.6 cm³ g^?1 are chosen as the porous matrix. Electron tomography technique confirms that γ‐Fe₂O₃ nanoparticles with an average particle size of ≈6 nm are spatially well‐dispersed and anchored on the pore walls at even a high γ‐Fe₂O₃ content of 34.8 wt%, rather than forming aggregates inside the pores or on the external surface. The open large‐pore structure, high loading amount, and the non‐aggregated nature of γ‐Fe₂O₃ nanoparticles lead to increased adsorption sites and thus high adsorption capacities of both As (V) and As (III) without pre‐treatment (248 and 320 mg g^?1, respectively). Moreover, the composites can reduce the concentration of both As (V) and As (III) from 100 to 2 μg L^?1. It is also demonstrated that the composites can be applied in a household drinking water treatment device, which can continuously treat 20 L of wastewater containing As (V) with the effluent concentration lower than the World Health Organization standard.     

Ultrasmall Water‐Soluble and Biocompatible Magnetic Iron Oxide Nanoparticles as Positive and Negative Dual Contrast Agents

Monodispersed water‐soluble and biocompatible ultrasmall magnetic iron oxide nanoparticles (UMIONs, D = 3.3 ± 0.5 nm) generated from a high‐temperature coprecipitation route are successfully used as efficient positive and negative dual contrast agents of magnetic resonance imaging (MRI). Their longitudinal relaxivity at 4.7 T (r₁ = 8.3 mM^?1 s^?1) is larger than that of clinically used T₁‐positive agent Gd‐DTPA (r₁ = 4.8 mM^?1 s^?1), and three times that of commercial contrast agent SHU‐555C (r₁ = 2.9 mM^?1 s^?1). The transversal relaxivity (r₂ = 35.1 mM^?1 s^?1) is six times that of Gd‐DTPA (r₂ = 5.3 mM^?1 s^?1), half of SHU‐555C (r₂ = 69 mM^?1 s^?1). The in vivo results show that the liver signal from T₁‐weighted MRI is positively enhanced 26%, and then negatively decreased 20% after injection of the iron oxide nanoparticles, which is stronger than those obtained from Gd‐DTPA (<10%) using the same dosage. The kidney signal is positively enhanced up to 35%, similar to that obtained from Gd‐DTPA. Under T₂‐weighted conditions, the liver signal is negatively enhanced ?70%, which is significantly higher than that from Gd‐DTPA (?6%). These results demonstrate the great potential of the UMIONs in dual contrast agents, especially as an alternative to Gd‐based positive contrast agents, which have risks of inducing side effects in patients.     

Multifunctional Nanoparticles Composed of A Poly( dl‐lactide‐coglycolide) Core and A Paramagnetic Liposome Shell for Simultaneous Magnetic Resonance Imaging and Targeted Therapeutics

A multifunctional nanoscale platform that is self‐assembled from a hydrophobic poly( dl ‐lactide‐coglycolide)(PLGA) core and a hydrophilic paramagnetic‐folate‐coated PEGylated lipid shell (PFPL; PEG=polyethylene glycol) is designed for simultaneous magnetic resonance imaging (MRI) and targeted therapeutics. The nanocomplex has a well‐defined core‐shell structure which is studied using confocal laser scanning microscopy (CLSM). The paramagnetic diethylenetriaminepentaacetic acid‐gadolinium (DTPA‐Gd) chelated to the shell layer exhibits significantly higher spin–lattice relaxivity (r₁) than the clinically used small‐molecular‐weight MRI contrast agent Magnevist^®. The PLGA core serves as a nanocontainer to load and release the hydrophobic drugs. From a drug‐release study, it is found that the modification of the PLGA core with a polymeric liposome shell can be a useful tool for reducing the drug‐release rate. Cellular uptake of folate nanocomplex is found to be higher than that of non‐folate‐nanocomplex due to the folate‐binding effect on the cell membrane. This work indicates that the multifunctional platform with combined characteristics applicable to MRI and drug delivery may have great potential in cancer chemotherapy and diagnosis.     

Magnetic‐Core/Porous‐Shell CoFe2O4/SiO2 Composite Nanoparticles as Immobilized Affinity Supports for Clinical Immunoassays

This study demonstrates a novel approach towards the development of advanced protein assay systems based on physically functionalized, magnetic‐core/porous‐shell CoFe₂O₄/SiO₂ composite nanoparticles. The preparation, characterization, and measurement of the relevant properties of the protein assay system is discussed, and the system is used for the detection of cancer antigen 15‐3 (CA 15‐3, used as a model here) in clinical immunoassays. The protein assay system, based on nanometer‐sized magnetic cores and silica shells, shows good adsorption properties for the selective attachment of CA 15‐3 antibodies specific to CA 15‐3. The core/shell nanostructures exhibit good magnetic properties, which enables their integration into a quartz crystal microbalance (QCM) detection cell with the help of a permanent magnet. Under optimal conditions, the resulting immunoassay system presents a good QCM response for the detection of CA 15‐3, and allows the detection of CA 15‐3 at concentrations as low as 1.5 U mL^–1 (U: units). Importantly, the proposed protein assay system can be extended to the detection of other antigens and biological compounds.     

Bifunctional Gd2O3/C Nanoshells for MR Imaging and NIR Therapeutic Applications

This paper reports dual function Gd₂O₃/C nanoshells for application in MR contrast images and NIR‐triggered killing cancer cells. The nanoshells are prepared using biological gelatin particles as core templates through a two‐step thermal treatment. The surfaces of the nanoshells can be readily modified by poly(styrene‐alt‐maleic acid) (PSMA) polymer to improve their water‐dispersible properties and increase their biocompatibility. The Gd₂O₃/C nanoshells show brightened images of kidney cortex and liver in mice, whereas the Gd₂O₃/C@PSMA nanoshells show a darkened liver signal. The biodistribution is measured as a function of time and shows that the nanoshells circulate in the vessels and are cleared out gradually from organs. The graphite carbon coated on the Gd₂O₃ nanoshells displays absorbance in the near‐IR (NIR) region. A large extinction coefficient is obtained, indicating the potential of the nanoshells as photothermal agents. The Gd₂O₃/C@PSMA nanoshells conjugated with anti‐epithermal growth factor receptor antibodies are used for targeting and destroying A549 lung cancer cells by means of NIR‐triggered killing capability. Both laser power density and material dose dependence are investigated to evaluate photothermolysis in cancer cells.     

Responsive Macroscopic Materials From Self‐Assembled Cross‐Linked SiO2‐PNIPAAm Core/Shell Structures

A way to obtain macroscopic responsive materials from silicon‐oxide polymer core/shell microstructures is presented. The microparticles are composed of a 60 nm SiO₂‐core with a random copolymer corona of the temperature responsive poly‐N‐isopropylacrylamide (PNIPAAm) and the UV‐cross‐linkable 2‐(dimethyl maleinimido)‐N‐ethyl‐acrylamide. The particles shrink upon heating and form a stable gel in both water and tetrahydrofuran (THF) at 3–5 wt% particle content. Cross‐linking the aqueous gel results in shrinkage when the temperature is increased above the lower critical solution temperature and it regains its original size upon cooling. By freeze drying with subsequent UV irradiation, thin stable layers are prepared. Stable fibers are produced by extruding a THF gel into water and subsequent UV irradiation, harnessing the cononsolvency effect of PNIPAAm in water/THF mixtures. The temperature responsiveness translates to the macroscopic materials as both films and fibers show the same collapsing behavior as the microcore/shell particle. The collapse and re‐swelling of the materials is related to the expelling and re‐uptake of water, which is used to incorporate gold nanoparticles into the materials by a simple heating/cooling cycle. This allows for future applications, as various functional particles (antibacterial, fluorescence, catalysis, etc.) can easily be incorporated in these systems.     

Antibacterial Surface Coatings from Zinc Oxide Nanoparticles Embedded in Poly(N‐isopropylacrylamide) Hydrogel Surface Layers

Despite multiple research approaches to prevent bacterial colonization on surfaces, device‐associated infections are currently responsible for about 50% of nosocomial infections in Europe and significantly increase health care costs, which demands development of advanced antibacterial surface coatings. Here, novel antimicrobial composite materials incorporating zinc oxide nanoparticles (ZnO NP) into biocompatible poly(N‐isopropylacrylamide) (PNIPAAm) hydrogel layers are prepared by mixing the PNIPAAm prepolymer with ZnO NP, followed by spin‐coating and photocrosslinking. Scanning electron microscopy (SEM) characterization of the composite film morphology reveals a homogeneous distribution of the ZnO NP throughout the film for every applied NP/polymer ratio. The optical properties of the embedded NP are not affected by the matrix as confirmed by UV‐vis spectroscopy. The nanocomposite films exhibit bactericidal behavior towards Escherichia coli (E. coli) for a ZnO concentration as low as ≈0.74 μg cm^?2 (1.33 mmol cm^?3), which is determined by inductively coupled plasma optical emission spectrometry. In contrast, the coatings are found to be non‐cytotoxic towards a mammalian cell line (NIH/3T3) at bactericidal loadings of ZnO over an extended period of seven days. The differential toxicity of the ZnO/hydrogel nanocomposite thin films between bacterial and cellular species qualifies them as promising candidates for novel biomedical device coatings.     

p‐Si/SnO2/Fe2O3 Core/Shell/Shell Nanowire Photocathodes for Neutral pH Water Splitting

Silicon is one of the promising materials for solar water splitting and hydrogen production; however, it suffers from two key factors, including the large external potential required to drive water splitting reactions at its surface and its instability in the electrolyte. In this study, a successful fabrication of novel p‐Si/n‐SnO₂/n‐Fe₂O₃ core/shell/shell nanowire (css‐NW) arrays, consisting of vertical Si NW cores coated with a thin SnO₂ layer and a dense Fe₂O₃ nanocrystals (NCs) shell, and their application for significantly enhanced solar water reduction in a neutral medium is reported. The p‐Si/n‐SnO₂/n‐Fe₂O₃ css‐NW structure is characterized in detail using scanning, transmission, and scanning transmission electron microscopes. The p‐Si/n‐SnO₂/n‐Fe₂O₃ css‐NWs show considerably improved photocathodic performances, including higher photocurrent and lower photocathodic turn‐on potential, compared to the bare p‐Si NWs or p‐Si/n‐SnO₂ core/shell NWs (cs‐NWs), due to increased optical absorption, enhanced charge separation, and improved gas evolution. As a result, photoactivity at 0 V versus reversible hydrogen electrode and a low onset potential in the neutral solution are achieved. Moreover, p‐Si/n‐SnO₂/n‐Fe₂O₃ css‐NWs exhibit long‐term photoelectrochemical stability due to the Fe₂O₃ NCs shell well protection. These results reveal promising css‐NW photoelectrodes from cost‐effective materials by facile fabrication with simultaneously improved photocathodic performance and stability.     

Multifunctional Core/Shell Nanoparticles Self‐Assembled from pH‐Induced Thermosensitive Polymers for Targeted Intracellular Anticancer Drug Delivery

Core/shell nanoparticles that display a pH‐sensitive thermal response, self‐assembled from the amphiphilic tercopolymer, poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide‐co‐10‐undecenoic acid) (P(NIPAAm‐co‐DMAAm‐co‐UA)), have recently been reported. In this study, folic acid is conjugated to the hydrophilic segment of the polymer through the free amine group (for targeting cancer cells that overexpress folate receptors) and cholesterol is grafted to the hydrophobic segment of the polymer. This polymer also self‐assembles into core/shell nanoparticles that exhibit pH‐induced temperature sensitivity, but they possess a more stable hydrophobic core than the original polymer P(NIPAAm‐co‐DMAAm‐co‐UA) and a shell containing folate molecules. An anticancer drug, doxorubicin (DOX), is encapsulated into the nanoparticles. DOX release is also pH‐dependent. DOX molecules delivered by P(NIPAAm‐co‐DMAAm‐co‐UA) and folate‐conjugated P(NIPAAm‐co‐DMAAm‐co‐UA)‐g‐cholesterol nanoparticles enter the nucleus more rapidly than those transported by P(NIPAAm‐co‐DMAAm)‐b‐poly(lactide‐co‐glycolide) nanoparticles, which are not pH sensitive. More importantly, these nanoparticles can recognize folate‐receptor‐expressing cancer cells. Compared to the nanoparticles without folate, the DOX‐loaded nanoparticles with folate yield a greater cellular uptake because of the folate‐receptor‐mediated endocytosis process, and, thus, higher cytotoxicity results. These multifunctional polymer core/shell nanoparticles may make a promising carrier to target drugs to cancer cells and release the drug molecules to the cytoplasm inside the cells.     

Morphological Evolution and Magnetic Property of Rare‐Earth‐Doped Hematite Nanoparticles: Promising Contrast Agents for T1‐Weighted Magnetic Resonance Imaging

A series of uniform rare‐earth‐doped hematite (α‐Fe₂O₃) nanoparticles are synthesized by a facile hydrothermal strategy. In a typical case of gadolinium (Gd)‐doped α‐Fe₂O₃, the morphology and chemical composition can be readily tailored by tuning the initial proportion of Gd³⁺/Fe³⁺ sources. As a result, the products are observed to be stretched into more elongated shapes with an increasing dopant ratio. As a benefit of such an elongated morphological feature and Gd³⁺ ions of larger effective magnetic moment than Fe³⁺, the doped product with the highest ratio of Gd³⁺ at 5.7% shows abnormal ferromagnetic features with a remnant magnetization of 0.605 emu g^?1 and a coercivity value of 430 Oe at 4 K. Density of states calculations also reveal the increase of total magnetic moment induced by Gd³⁺ dopant in α‐Fe₂O₃ hosts, as well as possible change of magnetic arrangement. As‐synthesized Gd‐doped α‐Fe₂O₃ nanoparticles are probed as contrast agents for T1‐weighted magnetic resonance imaging, achieving a remarkable enhancement effect for both in vitro and in vivo tests.     

Luminescent Core/Shell Nanoparticles with a Rhabdophane LnPO4‐xH2O Structure: Stabilization of Ce3+‐Doped Compositions

The core/shell strategy has been successfully developed for rhabdophane lanthanide phosphate aqueous colloids. The growth of a LaPO₄‐xH₂O shell around Ce,Tb‐doped core nanoparticles increases their stability against oxidation. A bright green luminescence is thus preserved in sol–gel films whose fabrication requires silica coating and thermal treatment of the core/shell nanoparticles.     

Protoporphyrin IX (PpIX)‐Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters for Magnetic Resonance Imaging and Photodynamic Therapy

The ability to produce nanotherapeutics at large‐scale with high drug loading efficiency, high drug loading capacity, high stability, and high potency is critical for clinical translation. However, many nanoparticle‐based therapeutics under investigation suffer from complicated synthesis, poor reproducibility, low stability, and high cost. In this work, a simple method for preparing multifunctional nanoparticles is utilized that act as both a contrast agent for magnetic resonance imaging and a photosensitizer for photodynamic therapy for the treatment of cancer. In particular, the photosensitizer protoporphyrin IX (PpIX) is used to solubilize small nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs) without the use of any additional carrier materials. These nanoclusters are characterized with a high PpIX loading efficiency; a high loading capacity, stable behavior; high potency; and a synthetic approach that is amenable to large‐scale production. In vivo studies of photodynamic therapy (PDT) efficacy show that the PpIX‐coated SPION nanoclusters lead to a significant reduction in the growth rate of tumors in a syngeneic murine tumor model compared to both free PpIX and PpIX‐loaded poly(ethylene glycol)‐polycaprolactone micelles, even when injected at 1/8th the dose. These results suggest that the nanoclusters developed in this work can be a promising nanotherapeutic for clinical translation.