Cellular Association and Assembly of a Multistage Delivery System

The realization that blood‐borne delivery systems must overcome a multiplicity of biological barriers has led to the fabrication of a multistage delivery system (MDS) designed to temporally release successive stages of particles or agents to conquer sequential barriers, with the goal of enhancing delivery of therapeutic and diagnostic agents to the target site. In its simplest form, the MDS comprises stage‐one porous silicon microparticles that function as carriers of second‐stage nanoparticles. Cellular uptake of nontargeted discoidal silicon microparticles by macrophages is confirmed by electron and atomic force microscopy (AFM). Using superparamagnetic iron oxide nanoparticles (SPIONs) as a model of secondary nanoparticles, successful loading of the porous matrix of silicon microparticles is achieved, and retention of the nanoparticles is enhanced by aminosilylation of the loaded microparticles with 3‐aminopropyltriethoxysilane. The impact of silane concentration and reaction time on the nature of the silane polymer on porous silicon is investigated by AFM and X‐ray photoelectron microscopy. Tissue samples from mice intravenously administered the MDS support co‐localization of silicon microparticles and SPIONs across various tissues with enhanced SPION release in spleen, compared to liver and lungs, and enhanced retention of SPIONs following silane capping of the MDS. Phantom models of the SPION‐loaded MDS display negative contrast in magnetic resonance images. In addition to forming a cap over the silicon pores, the silane polymer provides free amines for antibody conjugation to the microparticles, with both VEGFR‐2‐ and PECAM‐specific antibodies leading to enhanced endothelial association. This study demonstrates the assembly and cellular association of a multiparticle delivery system that is biomolecularly targeted and has potential for applications in biological imaging.     

Amino‐polyvinyl Alcohol Coated Superparamagnetic Iron Oxide Nanoparticles are Suitable for Monitoring of Human Mesenchymal Stromal Cells In Vivo

Mesenchymal stromal cells (MSCs) are promising candidates in regenerative cell‐therapies. However, optimizing their number and route of delivery remains a critical issue, which can be addressed by monitoring the MSCs’ bio‐distribution in vivo using super‐paramagnetic iron‐oxide nanoparticles (SPIONs). In this study, amino‐polyvinyl alcohol coated (A‐PVA) SPIONs are introduced for cell‐labeling and visualization by magnetic resonance imaging (MRI) of human MSCs. Size and surface charge of A‐PVA‐SPIONs differ depending on their solvent. Under MSC‐labeling conditions, A‐PVA‐SPIONs have a hydrodynamic diameter of 42 ± 2 nm and a negative Zeta potential of 25 ± 5 mV, which enable efficient internalization by MSCs without the need to use transfection agents. Transmission X‐ray microscopy localizes A‐PVA‐SPIONs in intracellular vesicles and as cytosolic single particles. After identifying non‐interfering cell‐assays and determining the delivered and cellular dose, in addition to the administered dose, A‐PVA‐SPIONs are found to be non‐toxic to MSCs and non‐destructive towards their multi‐lineage differentiation potential. Surprisingly, MSC migration is increased. In MRI, A‐PVA‐SPION‐labeled MSCs are successfully visualized in vitro and in vivo. In conclusion, A‐PVA‐SPIONs have no unfavorable influences on MSCs, although it becomes evident how sensitive their functional behavior is towards SPION‐labeling. And A‐PVA‐SPIONs allow MSC‐monitoring in vivo.     

Magneto‐Plasmonic Au‐Fe Alloy Nanoparticles Designed for Multimodal SERS‐MRI‐CT Imaging

Diagnostic approaches based on multimodal imaging are needed for accurate selection of the therapeutic regimens in several diseases, although the dose of administered contrast drugs must be reduced to minimize side effects. Therefore, large efforts are deployed in the development of multimodal contrast agents (MCAs) that permit the complementary visualization of the same diseased area with different sensitivity and different spatial resolution by applying multiple diagnostic techniques. Ideally, MCAs should also allow imaging of diseased tissues with high spatial resolution during surgical interventions. Here a new system based on multifunctional Au‐Fe alloy nanoparticles designed to satisfy the main requirements of an ideal MCA is reported and their biocompatibility and imaging capability are described. The MCAs show easy and versatile surface conjugation with thiolated molecules, magnetic resonance imaging (MRI) and computed X‐ray tomography (CT) signals for anatomical and physiological information (i.e., diagnostic and prognostic imaging), large Raman signals amplified by surface enhanced Raman scattering (SERS) for high sensitivity and high resolution intrasurgical imaging, biocompatibility, exploitability for in vivo use and capability of selective accumulation in tumors by enhanced permeability and retention effect. Taken together, these results show that Au‐Fe nanoalloys are excellent candidates as multimodal MRI‐CT‐SERS imaging agents.     

Characterizing Physical Properties of Superparamagnetic Nanoparticles in Liquid Phase Using Brownian Relaxation

Superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively used as bioimaging contrast agents, heating sources for tumor therapy, and carriers for controlled drug delivery and release to target organs and tissues. These applications require elaborate tuning of the physical and magnetic properties of the SPIONs. The authors present here a search‐coil‐based method to characterize these properties. The nonlinear magnetic response of SPIONs to alternating current magnetic fields induces harmonic signals that contain information of these nanoparticles. By analyzing the phase lag and harmonic ratios in the SPIONs, the authors can predict the saturation magnetization, the average hydrodynamic size, the dominating relaxation processes of SPIONs, and the distinction between single‐ and multicore particles. The numerical simulations reveal that the harmonic ratios are inversely proportional to saturation magnetizations and core diameters of SPIONs, and that the phase lag is dependent on the hydrodynamic volumes of SPIONs, which corroborate the experimental results. Herein, the authors stress the feasibility of using search coils as a method to characterize physical and magnetic properties of SPIONs, which may be applied as building blocks in nanoparticle characterization devices.     

Synchrotron‐Based Micro‐CT and Refraction‐Enhanced Micro‐CT for Non‐Destructive Materials Characterisation

X‐ray computed tomography is an important tool for non‐destructively evaluating the 3‐D microstructure of modern materials. To resolve material structures in the micrometer range and below, high brilliance synchrotron radiation has to be used. The Federal Institute for Materials Research and Testing (BAM) has built up an imaging setup for micro‐tomography and ‐radiography (BAMline) at the Berliner storage ring for synchrotron radiation (BESSY). In computed tomography, the contrast at interfaces within heterogeneous materials can be strongly amplified by effects related to X‐ray refraction. Such effects are especially useful for materials of low absorption or mixed phases showing similar X‐ray absorption properties that produce low contrast. The technique is based on ultra‐small‐angle scattering by microstructural elements causing phase‐related effects, such as refraction and total reflection. The extraordinary contrast of inner surfaces is far beyond absorption effects. Crack orientation and fibre/matrix debonding in plastics, polymers, ceramics and metal‐matrix‐composites after cyclic loading and hydro‐thermal aging can be visualized. In most cases, the investigated inner surface and interface structures correlate to mechanical properties. The technique is an alternative to other attempts on raising the spatial resolution of CT machines.     

Nano‐Sized CT Contrast Agents

Computed tomography (CT) is one of the most widely used clinical imaging modalities. In order to increase the sensitivity of CT, small iodinated compounds are used as injectable contrast agents. However, the iodinated contrast agents are excreted through the kidney and have short circulation times. This rapid renal clearance not only restricts in vivo applications that require long circulation times but also sometimes induces serious adverse effects related to the excretion pathway. In addition, the X‐ray attenuation of iodine is not efficient for clinical CT that uses high‐energy X‐ray. Due to these limitations, nano‐sized iodinated CT contrast agents have been developed that can increase the circulation time and decrease the adverse effects. In addition to iodine, nanoparticles based on heavy atoms such as gold, lanthanides, and tantalum are used as more efficient CT contrast agents. In this review, we summarize the recent progresses made in nano‐sized CT contrast agents.     

Anti‐Biofouling Polymer‐Decorated Lutetium‐Based Nanoparticulate Contrast Agents for In Vivo High‐Resolution Trimodal Imaging

Nanomaterials have gained considerable attention and interest in the development of novel and high‐resolution contrast agents for medical diagnosis and prognosis in clinic. A classical urea‐based homogeneous precipitation route that combines the merits of in situ thermal decomposition and surface modification is introduced to construct polyethylene glycol molecule (PEG)‐decorated hybrid lutetium oxide nanoparticles (PEG–UCNPs). By utilizing the admirable optical and magnetic properties of the yielded PEG–UCNPs, in vivo up‐conversion luminescence and T₁‐enhanced magnetic resonance imaging of small animals are conducted, revealing obvious signals after subcutaneous and intravenous injection, respectively. Due to the strong X‐ray absorption and high atomic number of lanthanide elements, X‐ray computed‐tomography imaging based on PEG–UCNPs is then designed and carried out, achieving excellent imaging outcome in animal experiments. This is the first example of the usage of hybrid lutetium oxide nanoparticles as effective nanoprobes. Furthermore, biodistribution, clearance route, as well as long‐term toxicity are investigated in detail after intravenous injection in a murine model, indicating the overall safety of PEG–UCNPs. Compared with previous lanthanide fluorides, our nanoprobes exhibit more advantages, such as facile construction process and nearly total excretion from the animal body within a month. Taken together, these results promise the use of PEG–UCNPs as a safe and efficient nanoparticulate contrast agent for potential application in multimodal imaging.     

Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application,Spatial Distribution,and Dosimetry

Targeted delivery of nanomedicine/nanoparticles (NM/NPs) to the site of disease (e.g., the tumor or lung injury) is of vital importance for improved therapeutic efficacy. Multimodal imaging platforms provide powerful tools for monitoring delivery and tissue distribution of drugs and NM/NPs. This study introduces a preclinical imaging platform combining X‐ray (two modes) and fluorescence imaging (three modes) techniques for time‐resolved in vivo and spatially resolved ex vivo visualization of mouse lungs during pulmonary NP delivery. Liquid mixtures of iodine (contrast agent for X‐ray) and/or (nano)particles (X‐ray absorbing and/or fluorescent) are delivered to different regions of the lung via intratracheal instillation, nasal aspiration, and ventilator‐assisted aerosol inhalation. It is demonstrated that in vivo propagation‐based phase‐contrast X‐ray imaging elucidates the dynamic process of pulmonary NP delivery, while ex vivo fluorescence imaging (e.g., tissue‐cleared light sheet fluorescence microscopy) reveals the quantitative 3D drug/particle distribution throughout the entire lung with cellular resolution. The novel and complementary information from this imaging platform unveils the dynamics and mechanisms of pulmonary NM/NP delivery and deposition for each of the delivery routes, which provides guidance on optimizing pulmonary delivery techniques and novel‐designed NM for targeting and efficacy.     

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.     

Controlled Deposition of Silver Nanoparticles in Mesoporous Single‐ or Multilayer Thin Films: From Tuned Pore Filling to Selective Spatial Location of Nanometric Objects

Silver nanoparticle assemblies are embedded within mesoporous oxide thin films by an in situ mild reduction leading to nanoparticle–mesoporous oxide thin‐film composites (NP@MOTF). A quantitative method based on X‐ray reflectivity is developed and validated with energy dispersive spectroscopy in order to assess pore filling. The use of dilute formaldehyde solutions leads to control over the formation of silver nanoparticles within mesoporous titania films. Inclusion of silver nanoparticles in mesoporous silica requires more drastic conditions. This difference in reactivity can be exploited to selectively synthesize nanoparticles in a predetermined layer of a multilayered mesoporous stack leading to complex 1D‐ordered multilayers with precise spatial location of nanometric objects. The metal oxide nanocomposites synthesized have potential applications in catalysis, optical devices, surface‐enhanced Raman scattering, and metal enhancement fluorescence.     

Local Tomography Study of the Fracture of an ERG Metal Foam

As one of the most important analysis techniques for non‐destructive imaging, X‐ray tomography has been widely used in materials science, medical science, and industry to evaluate the behavior of porous materials. By using this method, a three dimensional volume can be inspected in order to visualize in situ the progress of damage in materials and this can be analyzed qualitatively and quantitatively. In the present study, we have used X‐ray tomography to investigate the fracture behavior of an ERG open cell aluminum foam. The process of damage development of a sample undergoing tension and the relation between the inter‐metallics and the cracks can be observed totally by the X‐ray tomography set‐up. Local tomography has in particular been used to image the microstructure at high resolution. A finite element model has also been developed in order to simulate this process of the damage using the 3D data obtained by the tomography.     

Synthesis of BSA‐Coated BiOI@Bi2S3 Semiconductor Heterojunction Nanoparticles and Their Applications for Radio/Photodynamic/Photothermal Synergistic Therapy of Tumor

Developing an effective theranostic nanoplatform remains a great challenge for cancer diagnosis and treatment. Here, BiOI@Bi₂S₃@BSA (bovine serum albumin) semiconductor heterojunction nanoparticles (SHNPs) for triple‐combination radio/photodynamic/photothermal cancer therapy and multimodal computed tomography/photoacoustic (CT/PA) bioimaging are reported. On the one hand, SHNPs possess strong X‐ray attenuation capability since they contain high‐Z elements, and thus they are anticipated to be a very competent candidate as radio‐sensitizing materials for radiotherapy enhancement. On the other hand, as a semiconductor, the as‐prepared SHNPs offer an extra approach for reactive oxygen species generation based on electron–hole pair under the irradiation of X‐ray through the photodynamic therapy process. This X‐ray excited photodynamic therapy obviously has better penetration depth in bio‐tissue. What's more, the SHNPs also possess well photothermal conversion efficiency for photothermal therapy, because Bi₂S₃ is a thin band semiconductor with strong near‐infrared absorption that can cause local overheat. In vivo tumor ablation studies show that synergistic radio/photodynamic/photothermal therapy achieves more significant therapeutic effect than any single treatment. In addition, with the strong X‐ray attenuation and high near‐infrared absorption, the as‐obtained SHNPs can also be applied as a multimodal contrast agent in CT/PA imaging.     

Viewing the Early Stage of Metal Foam Formation by Computed Tomography using Synchrotron Radiation

Foamed aluminium alloy containing 7 wt.‐% of Si is investigated by μm‐resolved X‐ray computed tomography (CT) using synchrotron radiation. The foam is fabricated employing a powder metallurgical route. The evolution of foam microstructure is characterized by studying a series of samples representing different stages of foam expansion obtained by interrupting the foaming process for each sample at different foaming times. The computer tomographic reconstruction provides a 3D image of the pore structure as well as the spatial distribution of blowing agent particles. A statistical evaluation allows to determine the size distribution of the blowing agent and of the pores at different foaming stages.     

Anatomy of Skyrmionic Textures in Magnetic Multilayers

Room temperature magnetic skyrmions in magnetic multilayers are considered as information carriers for future spintronic applications. Currently, a detailed understanding of the skyrmion stabilization mechanisms is still lacking in these systems. To gain more insight, it is first and foremost essential to determine the full real‐space spin configuration. Here, two advanced X‐ray techniques are applied, based on magnetic circular dichroism, to investigate the spin textures of skyrmions in [Ta/CoFeB/MgO]_n multilayers. First, by using ptychography, a high‐resolution diffraction imaging technique, the 2D out‐of‐plane spin profile of skyrmions with a spatial resolution of 10 nm is determined. Second, by performing circular dichroism in resonant elastic X‐ray scattering, it is demonstrated that the chirality of the magnetic structure undergoes a depth‐dependent evolution. This suggests that the skyrmion structure is a complex 3D structure rather than an identical planar texture throughout the layer stack. The analyses of the spin textures confirm the theoretical predictions that the dipole–dipole interactions together with the external magnetic field play an important role in stabilizing sub‐100 nm diameter skyrmions and the hybrid structure of the skyrmion domain wall. This combined X‐ray‐based approach opens the door for in‐depth studies of magnetic skyrmion systems, which allows for precise engineering of optimized skyrmion heterostructures.     

Variable‐Wavelength Quick Scanning Nanofocused X‐Ray Microscopy for In Situ Strain and Tilt Mapping

Compression of micropillars is followed in situ by a quick nanofocused X‐ray scanning microscopy technique combined with 3D reciprocal space mapping. Compared to other attempts using X‐ray nanobeams, it avoids any motion or vibration that would lead to a destruction of the sample. The technique consists of scanning both the energy of the incident nanofocused X‐ray beam and the in‐plane translations of the focusing optics along the X‐ray beam. Here, the approach by imaging the strain and lattice orientation of Si micropillars and their pedestals during in situ compression is demonstrated. Varying the energy of the incident beam instead of rocking the sample and mapping the focusing optics instead of moving the sample supplies a vibration‐free measurement of the reciprocal space maps without removal of the mechanical load. The maps of strain and lattice orientation are in good agreement with the ones recorded by ordinary rocking‐curve scans. Variable‐wavelength quick scanning X‐ray microscopy opens the route for in situ strain and tilt mapping toward more diverse and complex materials environments, especially where sample manipulation is difficult.     

Breaking the Depth Dependence by Nanotechnology‐Enhanced X‐Ray‐Excited Deep Cancer Theranostics

The advancements in nanotechnology have created multifunctional nanomaterials aimed at enhancing diagnostic accuracy and treatment efficacy for cancer. However, the ability to target deep‐seated tumors remains one of the most critical challenges for certain nanomedicine applications. To this end, X‐ray‐excited theranostic techniques provide a means of overcoming the limits of light penetration and tissue attenuation. Herein, a comprehensive overview of the recent advances in nanotechnology‐enhanced X‐ray‐excited imaging and therapeutic methodologies is presented, with an emphasis on the design of multifunctional nanomaterials for contrast‐enhanced computed tomography (CT) imaging, X‐ray‐excited optical luminescence (XEOL) imaging, and X‐ray‐excited multimodal synchronous/synergistic therapy. The latter is based on the concurrent use of radiotherapy with chemotherapy, gas therapy, photodynamic therapy, or immunotherapy. Moreover, the featured biomedical applications of X‐ray‐excited deep theranostics are discussed to highlight the advantages of X‐ray in high‐sensitivity detection and efficient elimination of malignant tumors. Finally, key issues and technical challenges associated with this deep theranostic technology are identified, with the intention of advancing its translation into the clinic.     

Magnetically responsive,sorafenib loaded alginate microspheres for hepatocellular carcinoma treatment

This study aimed to develop sorafenib loaded magnetic microspheres for the treatment of hepatocellular carcinoma. To achieve this goal, superparamagnetic iron oxide nanoparticles (SPIONs) were synthesised and encapsulated in alginate microspheres together with an antineoplastic agent, sorafenib. In the study, firstly SPIONs were synthesised and characterised by dynamic light scattering, energy‐dispersive X‐ray spectroscopy, and scanning electron microscopy. Then, alginate‐SPIONs microspheres were developed, and further characterised by electron spin resonance spectrometer and vibrating sample magnetometer. Besides the magnetic properties of SPIONs, alginate microspheres with SPIONs were also found to have magnetic properties. The potential use of microspheres in hyperthermia treatment was then investigated and an increase of about 4°C in the environment was found out. Drug release studies and cytotoxicity tests were performed after sorafenib was encapsulated into the magnetic microspheres. According to release studies, sorafenib has been released from microspheres for 8 h. Cytotoxicity tests showed that alginate‐SPION‐sorafenib microspheres were highly effective against cancerous cells and promising for cancer therapy.Inspec keywords: drug delivery systems, drugs, nanofabrication, magnetic particles, iron compounds, scanning electron microscopy, hyperthermia, biomedical materials, encapsulation, nanoparticles, light scattering, nanomagnetics, cellular biophysics, toxicology, cancer, nanomedicine, superparamagnetism, nanocomposites, magnetometry, paramagnetic resonance, X‐ray chemical analysisOther keywords: sorafenib loaded alginate microspheres, hepatocellular carcinoma treatment, sorafenib loaded magnetic microspheres, superparamagnetic iron oxide nanoparticles, dynamic light scattering, energy‐dispersive X‐ray spectroscopy, scanning electron microscopy, electron spin resonance spectrometer, vibrating sample magnetometer, hyperthermia treatment, drug release, alginate‐SPION‐sorafenib microspheres, antineoplastic agent, cytotoxicity tests, cancerous cells, time 8.0 hour, Fe₃ O₄      

Study of X‐Ray Imaging with Toroidally Bent Crystal

We developed a focusing imager with a toroidally bent crystal imager. The imager can be used in X‐ray imaging of laser fusion experiments. This article discusses the focusing properties of toroidally bent crystal in Bragg geometry. Simulations of spatial resolution for toroidally bent crystals with different conditions including source size and detector position were done using the ray‐tracing method. The applicable conditions for optimized two‐dimensional (2D) imaging of X‐ray source are proposed. Toroidally bent crystal of mica with curvature radius 290 mm in the meridional plane and 190 mm in the sagittal plane is used as imaging element in the experiments. The high‐quality visible 2D X‐ray image was obtained with the imaging plate due to the high collection efficiency of the bent crystal imaging system. It is demonstrated that the toroidally bent mica crystal could be used in X‐ray imaging. By analyzing the image information of the sagittal direction, we find out that the toroidal crystal imager has spatial resolution about 34 µm.     

Well‐Defined Cobalt Catalyst with N‐Doped Carbon Layers Enwrapping: The Correlation between Surface Atomic Structure and Electrocatalytic Property

Admittedly, the surface atomic structure of heterogenous catalysts toward the electrochemical oxygen reduction reaction (ORR) are accepted as the important features that can tune catalytic activity and even catalytic pathway. Herein, a surface engineering strategy to controllably synthesize a carbon‐layer‐wrapped cobalt‐catalyst from 2D cobalt‐based metal–organic frameworks is elaborately demonstrated. Combined with synchrotron radiation X‐ray photoelectron spectroscopy, the soft X‐ray absorption near‐edge structure results confirmed that rich covalent interfacial Co? N? C bonds are efficiently formed between cobalt nanoparticles and wrapped carbon‐layers during the polydopamine‐assisted pyrolysis process. The X‐ray absorption fine structure and corresponding extended X‐ray absorption fine structure spectra further reveal that the wrapped cobalt with Co–N coordinations shows distinct surface distortion and atomic environmental change of Co‐based active sites. In contrast to the control sample without coating layers, the 800 °C‐annealed cobalt catalyst with N‐doped carbon layers enwrapping achieves significantly enhanced ORR activity with onset and half‐wave potentials of 0.923 and 0.816 V (vs reversible hydrogen electrode), highlighting the important correlation between surface atomic structure and catalytic property.     

Granzyme B Functionalized Nanoparticles Targeting Membrane Hsp70‐Positive Tumors for Multimodal Cancer Theranostics

Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. Membrane‐bound 70 kDa heat shock protein (mHsp70) is ubiquitously expressed on the cell membrane of various tumor types but not normal cells and therefore provides a tumor‐specific target. The serine protease granzyme B (GrB) that is produced as an effector molecule by activated T and NK cells has been shown to specifically target mHsp70 on tumor cells. Following binding to Hsp70, GrB is rapidly internalized into tumor cells. Herein, it is demonstrated that GrB functionalized SPIONs act as a contrast enhancement agent for magnetic resonance imaging and induce specific tumor cell apoptosis. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting are found to further enhance the therapeutic efficacy of GrB‐SPIONs in different tumor mouse models.