A GSH‐Gated DNA Nanodevice for Tumor‐Specific Signal Amplification of microRNA and MR Imaging–Guided Theranostics

Developing tumor‐responsive diagnosis and therapy strategies for tumor theranostics is still a challenge owing to their high accuracy and specificity. Herein, an AND logic gated–DNA nanodevice, based on the fluorescence nucleic acid probe and polymer‐modified MnO₂ nanosheets, for glutathione (GSH)‐gated miRNA‐21 signal amplification and GSH‐activated magnetic resonance (MR) imaging–guided chemodynamic therapy (CDT) is reported. In the presence of overexpressed miRNA and GSH (tumor cells), the nanodevice can be in situ activated and release significantly amplified fluorescence signals and MR signals. Conversely, the fluorescence signal is quenched and MR signal remains at the background level with low miRNA and GSH (normal cells), efficiently reducing the false‐positive signals by more than 50%. Under the guide of miRNA profiling and MR imaging, the tumor‐responsive hydroxyl radical ( · OH) can effectively kill tumor cells. Furthermore, the nanodevice shows catalase‐like activity and glucose oxidase–like activity with the performance of O₂ production and glucose consumption. This is the first time to fabricate a tumor‐responsive theranostic DNA nanodevice with tumor‐specific signal amplification of microRNA and GSH‐activated MR imaging for CDT, potential hypoxia relief and starvation therapy, which provides a new insight for designing smart theranostic strategies.     

Enhancing Prostate‐Cancer‐Specific MRI by Genetic Amplified Nanoparticle Tumor Homing

Precise localization and visualization of early‐stage prostate cancer (PCa) is critical to improve the success of focal ablation and reduce cancer mortality. However, it remains challenging under the current imaging techniques due to the heterogeneous nature of PCa and the suboptimal sensitivity of the techniques themselves. Herein, a novel genetic amplified nanoparticle tumor‐homing strategy to enhance the MRI accuracy of ultrasmall PCa lesions is reported. This strategy could specifically drive TfR expressions in PCa under PCa‐specific DD3 promoter, and thus remarkably increase Tf‐USPIONs concentrations in a highly accurate manner while minimizing their non‐specific off‐target effects on normal tissues. Consequently, this strategy can pinpoint an ultrasmall PCa lesion, which is otherwise blurred in the current MRI, and thereby addresses the unmet key need in MRI imaging for focal therapy. With this proof‐of‐concept experiment, the synergistic gene–nano strategy holds great promise to boost the MRI effects of a wide variety of commonly used nanoscale and molecular probes that are otherwise limited. In addition, such a strategy may also be translated and applied to MR‐specific imaging of other types of cancers by using their respective tumor‐specific promoters.     

Tunable Ionic Transport Control inside a Bio‐Inspired Constructive Bi‐Channel Nanofluidic Device

Inspired by the cooperative functions of the asymmetrical ion channels in living cells, a constructive bi‐channel nanofluidic device that demonstrates the enhanced capability of multiple regulations over both the ion flux amount and the ionic rectification property is prepared. In this bi‐channel system, the construction routes of the two asymmetric conical nanochannels provide a way to efficiently transform the nanodevice into four different functional working modes. In addition, the variation of external pH conditions leads the nanodevice to the uncharged, semi‐charged and charged states, where the multistory ionic regulating function property is enhanced by the charged degree. This intelligent integration of the single functional nanochannels demonstrates a promising future for building more functional multi‐channel integrated nanodevices as well as expands the functionalities of the bio‐inspired smart nanochannels.     

Multi‐Responsive and Logic Controlled Release of DNA‐Gated Mesoporous Silica Vehicles Functionalized with Intercalators for Multiple Delivery

Novel DNA‐gated mesoporous silica nanoparticle (MSN) vehicles functionalized with disulfide‐linked acridinamine intercalators are constructed for multi‐responsive controlled release. The DNA‐gated MSN vehicles release cargo encapsulated in the MSN pores under different stimuli, including disulfide reducing agents, elevated temperature, and deoxyribonuclease I (DNase I), for codelivery of drugs and DNA/genes in different forms. Furthermore, the cascade release of encapsulated and intercalative drugs is controlled by AND logic gates in combination of dual stimuli. The ingeniously designed DNA‐gated MSN vehicles integrates multiple responses and AND logic gate operations into a single smart nanodevice not only for codelivery of drugs and DNA/genes but also for cascade release of two drugs and has promising biological applications to meet diverse requirements of controlled release.     

Dual‐Locking Nanoparticles Disrupt the PD‐1/PD‐L1 Pathway for Efficient Cancer Immunotherapy

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR‐associated (Cas) enzyme, Cas13a, holds great promise in cancer treatment due to its potential for selective destruction of tumor cells via collateral effects after target recognition. However, these collateral effects do not specifically target tumor cells and may cause safety issues when administered systemically. Herein, a dual‐locking nanoparticle (DLNP) that can restrict CRISPR/Cas13a activation to tumor tissues is described. DLNP has a core–shell structure, in which the CRISPR/Cas13a system (plasmid DNA, pDNA) is encapsulated inside the core with a dual‐responsive polymer layer. This polymer layer endows the DLNP with enhanced stability during blood circulation or in normal tissues and facilitates cellular internalization of the CRISPR/Cas13a system and activation of gene editing upon entry into tumor tissue. After carefully screening and optimizing the CRISPR RNA (crRNA) sequence that targets programmed death‐ligand 1 (PD‐L1), DLNP demonstrates the effective activation of T‐cell‐mediated antitumor immunity and the reshaping of immunosuppressive tumor microenvironment (TME) in B16F10‐bearing mice, resulting in significantly enhanced antitumor effect and improved survival rate. Further development by replacing the specific crRNA of target genes can potentially make DLNP a universal platform for the rapid development of safe and efficient cancer immunotherapies.     

A contact detection algorithm for multi‐sphere particles by means of two‐level‐grid‐searching in DEM simulations

In discrete element method simulations, multi‐sphere particle is extensively employed for modeling the geometry shape of non‐spherical particle. A contact detection algorithm for multi‐sphere particles has been developed through two‐level‐grid‐searching. In the first‐level‐grid‐searching, each multi‐sphere particle is represented by a bounding sphere, and global space is partitioned into identical square or cubic cells of size D, the diameter of the greatest bounding sphere. The bounding spheres are mapped into the cells in global space. The candidate particles can be picked out by searching the bounding spheres in the neighbor cells of the bounding sphere for the target particle. In the second‐level‐grid‐searching, a square or cubic local space of size (D + d) is partitioned into identical cells of size d, the diameter of the greatest element sphere. If two bounding spheres of two multi‐sphere particles are overlapped, the contacts occurring between the element spheres in the target multi‐sphere particle and in the candidate multi‐sphere particle are checked. Theoretical analysis and numerical tests on the memory requirement and contact detection time of this algorithm have been performed to verify the efficiency of this algorithm. The results showed that this algorithm can effectively deal with the contact problem for multi‐sphere particles. Copyright © 2015 John Wiley & Sons, Ltd.     

Engineering of the Fluorescent‐Energy‐Conversion Arm of Phi29 DNA Packaging Motor for Single‐Molecule Studies

The bacteriophage phi29 DNA packaging motor contains a protein core with a central channel comprising twelve copies of re‐engineered gp10 protein geared by six copies of packaging RNA (pRNA) and a DNA packaging protein gp16 with unknown copies. Incorporation of this nanomotor into a nanodevice would be beneficial for many applications. To this end, extension and modification of the motor components are necessary for the linkage of this motor to other nanomachines. Here the re‐engineering of the motor DNA packaging protein gp16 by extending its length and doubling its size using a fusion protein technique is reported. The modified motor integrated with the eGFP‐gp16 maintains the ability to convert the chemical energy from adenosine triphosphate (ATP) hydrolysis to mechanical motion and package DNA. The resulting DNA‐filled capsid is subsequently converted into an infectious virion. The extended part of the gp16 arm is a fluorescent protein eGFP, which serves as a marker for tracking the motor in single‐molecule studies. The activity of the re‐engineered motor with eGFP‐gp16 is also observed directly with a bright‐field microscope via its ability to transport a 2‐µm‐sized cargo bound to the DNA.     

Preparation of a Mitochondria‐targeted and NO‐Releasing Nanoplatform and its Enhanced Pro‐Apoptotic Effect on Cancer Cells

The therapeutic applications of exogenous nitric oxide are usually limited by its short half‐life and its vulnerability to many biological substances, thus straightforward and precise spatiotemporal control of NO delivery may be critical to its therapeutic effects. Herein, the mitochondria‐targeted and photoresponsive NO‐releasing nanosystem is demonstrated as a new approach for cancer treatment. The nanosystem is fabricated by covalently incorporating a NO photo‐donor and a mitochondria targeting ligand onto carbon‐dots; accordingly, multi‐functionalities (mitochondria‐targeting, light‐enhanced efficient NO‐releasing, and cell imaging) are achieved. The in vitro NO release profiles for the nanosystem show that the duration of NO release from the present C‐dot‐based nanosystem containing immobilized SNO can be extended up to 8 hours or more. Upon cellular internalization, the nanosystem can target mitochondria and release NO. The action of the nanosystem on three cancer cell lines is evaluated; it is found that the targeted NO‐releasing system can cause high cytotoxicity towards the cancer cells by specifically damaging their mitochondria. Additionally, light irradiation can amplify the cell apoptosis by enhancing NO release. These observations demonstrate that incorporating mitochondria‐targeting ligand onto a NO‐releasing system can enhance its pro‐apoptosis action, thereby providing new insights for exploiting NO in cancer therapy.     

Broad‐Spectrum Antibacterial Activity of Carbon Nanotubes to Human Gut Bacteria

Carbon nanotubes (CNTs) hold promise in manufacturing, environmental, and biomedical applications, as well as food and agricultural industries. Previous observations have shown that CNTs have antimicrobial activity; however, the impact of CNTs to human gut microbes has not been investigated. Here, the antibacterial activity of CNTs against the microbes commonly encountered in the human digestion system—L. acidophilus, B. adolescentis, E. coli, E. faecalis, and S. aureus—are evaluated. The bacteria studied include pathogenic and non‐pathogenic, gram‐positive and negative, and both sphere and rod strains. In this study, CNTs, including single‐walled CNTs (SWCNTs, 1–3 μm), short and long multi‐walled CNTs (s‐MWCNTs: 0.5–2 μm; l‐MWCNTs: >50 μm), and functionalized multi‐walled CNTs (hydroxyl‐ and carboxyl‐modification, 0.5–2 μm), all have broad‐spectrum antibacterial effects. Notably, CNTs may selectively lyse the walls and membranes of human gut microbes, depending on not only the length and surface functional groups of CNTs, but also the shapes of the bacteria. The mechanism of antibacterial activity is associated with their diameter‐dependent piercing and length‐dependent wrapping on the lysis of microbial walls and membranes, inducing release of intracellular components DNA and RNA and allowing a loss of bacterial membrane potential, demonstrating complete destruction of bacteria. Thin and rigid SWCNT show more effective wall/membrane piercing on spherical bacteria than MWCNTs. Long MWCNT may wrap around gut bacteria, increasing the area making contact with the bacterial wall. This work suggests that CNTs may be broad‐spectrum and efficient antibacterial agents in the gut, and selective application of CNTs could reduce the potential hazard to probiotic bacteria.     

MSN Anti‐Cancer Nanomedicines: Chemotherapy Enhancement,Overcoming of Drug Resistance,and Metastasis Inhibition

In the anti‐cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti‐cancer drugs to normal tissues due to the lack of tumor‐selectivity, the multi‐drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state‐of‐art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti‐cancer strategy, this review highlights the most recent advances of MSN anti‐cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs‐based anti‐cancer nanomedicines, and propose several innovative and forward‐looking anti‐cancer strategies, including tumor tissue?cell?nuclear successionally targeted drug delivery strategy, tumor cell‐selective nuclear‐targeted drug delivery strategy, multi‐targeting and multi‐drug strategy, chemo‐/radio‐/photodynamic‐/ultrasound‐/thermo‐combined multi‐modal therapy by virtue of functionalized hollow/rattle‐structured MSNs.     

The Brownian and Flow‐Driven Rotational Dynamics of a Multicomponent DNA Origami‐Based Rotor

Nanomechanical devices are becoming increasingly popular due to the very diverse field of potential applications, including nanocomputing, robotics, and drug delivery. DNA is one of the most promising building materials to realize complex 3D structures at the nanoscale level. Several mechanical DNA origami structures have already been designed capable of simple operations such as a DNA box with a controllable lid, bipedal walkers, and cargo sorting robots. However, the nanomechanical properties of mechanically interlinked DNA nanostructures that are in general highly deformable have yet to be extensively experimentally evaluated. In this work, a multicomponent DNA origami‐based rotor is created and fully characterized by electron microscopy under negative stain and cryo preparations. The nanodevice is further immobilized on a microfluidic chamber and its Brownian and flow‐driven rotational behaviors are analyzed in real time by single‐molecule fluorescence microscopy. The rotation in previous DNA rotors based either on strand displacement, electric field or Brownian motion. This study is the first to attempt to manipulate the dynamics of an artificial nanodevice with fluidic flow as a natural force.     

An Ultra pH‐Sensitive and Aptamer‐Equipped Nanoscale Drug‐Delivery System for Selective Killing of Tumor Cells

Nanotechnology has often been applied in the development of targeted drug‐delivery systems for the treatment of cancer. An ideal nanoscale system for drug delivery should be able to selectively deliver and rapidly release the carried therapeutic drug(s) in cancer cells and, more importantly, not react to off‐target cells so as to eliminate unwanted toxicity on normal tissues. To reach this goal, a selective chemotherapeutic is formulated using a hollow gold nanosphere (HAuNS) equipped with a biomarker‐specific aptamer (Apt), and loaded with the chemotherapy drug doxorubicin (DOX). The formed Apt‐HAuNS‐Dox, approximately 42 nm in diameter, specifically binds to lymphoma tumor cells and does not react to control cells that do not express the biomarker. Through aptamer‐mediated selective cell binding, the Apt‐HAuNS‐Dox is internalized exclusively into the targeted tumor cells, and then released the DOX intracellularly. Of note, although the formed Apt‐HAuNS‐Dox is stable under normal biological conditions (pH 7.4), it appears ultrasensitive to pH change and rapidly releases 80% of the loaded DOX within 2 h at pH 5.0, a condition seen in cell lysosomes. Functional assays using cell mixtures show that the Apt‐HAuNS‐Dox selectively kills lymphoma tumor cells, but has no effect on the growth of the off‐target cells in the same cultures, indicating that this ultra pH‐sensitive Apt‐HAuNS‐Dox can selectively treat cancer through specific aptamer guidance, and will have minimal side effects on normal tissue.     

Gyrotron‐Forschung und ‐Entwicklung am KIT

Gyrotron Research and Development at KIT — An Important Contribution to the Fusion Research at Europe In future nuclear fusion power stations shall contribute to the continuous generation of environmentally friendly energy production. Electron cyclotron resonance heating is an important system to heating up the fusion plasma, the microwave source of which are gyrotrons. Together with its European partners, Karlsruhe Institute of Technology (KIT) has developed the series gyrotrons for the stellarator W7‐X and is developing EU gyrotrons for the tokamak ITER. Both are generating 1 MW CW of RF output power at 140 GHz and 170 GHz, respectively. Future fusion power plants will require multi‐megawatt gyrotrons operating at above 200 GHz. KIT is looking at new concepts, systematic design approaches and key components to achieve this target. In this paper the design approach for gyrotrons, the developments of key components and the modular test concept will be presented. Additionally, a brief introduction into the new test stand is given. Together with its European partners and with its industrial partner Thales Electron Devices, it is possible to develop and to produce a major key device, the gyrotron, for plasma experiments and future power plants.     

CMOS‐Compatible Silicon Nanowire Field‐Effect Transistors for Ultrasensitive and Label‐Free MicroRNAs Sensing

MicroRNAs (miRNAs) have been regarded as promising biomarkers for the diagnosis and prognosis of early‐stage cancer as their expression levels are associated with different types of human cancers. However, it is a challenge to produce low‐cost miRNA sensors, as well as retain a high sensitivity, both of which are essential factors that must be considered in fabricating nanoscale biosensors and in future biomedical applications. To address such challenges, we develop a complementary metal oxide semiconductor (CMOS)‐compatible SiNW‐FET biosensor fabricated by an anisotropic wet etching technology with self‐limitation which provides a much lower manufacturing cost and an ultrahigh sensitivity. This nanosensor shows a rapid (< 1 minute) detection of miR‐21 and miR‐205, with a low limit of detection (LOD) of 1 zeptomole (ca. 600 copies), as well as an excellent discrimination for single‐nucleotide mismatched sequences of tumor‐associated miRNAs. To investigate its applicability in real settings, we have detected miRNAs in total RNA extracted from lung cancer cells as well as human serum samples using the nanosensors, which demonstrates their potential use in identifying clinical samples for early diagnosis of cancer.     

Object‐oriented finite element analysis of thermo‐hydro‐mechanical (THM) problems in porous media

The design, implementation and application of a concept for object‐oriented in finite element analysis of multi‐field problems is presented in this paper. The basic idea of this concept is that the underlying governing equations of porous media mechanics can be classified into different types of partial differential equations (PDEs). In principle, similar types of PDEs for diverse physical problems differ only in material coefficients. Local element matrices and vectors arising from the finite element discretization of the PDEs are categorized into several types, regardless of which physical problem they belong to (i.e. fluid flow, mass and heat transport or deformation processes). Element (ELE) objects are introduced to carry out the local assembly of the algebraic equations. The object‐orientation includes a strict encapsulation of geometrical (GEO), topological (MSH), process‐related (FEM) data and methods of element objects. Geometric entities of an element such as nodes, edges, faces and neighbours are abstracted into corresponding geometric element objects (ELE–GEO). The relationships among these geometric entities form the topology of element meshes (ELE–MSH). Finite element objects (ELE–FEM) are presented for the local element calculations, in which each classification type of the matrices and vectors is computed by a unique function. These element functions are able to deal with different element types (lines, triangles, quadrilaterals, tetrahedra, prisms, hexahedra) by automatically choosing the related element interpolation functions. For each process of a multi‐field problem, only a single instance of the finite element object is required. The element objects provide a flexible coding environment for multi‐field problems with different element types. Here, the C++ implementations of the objects are given and described in detail. The efficiency of the new element objects is demonstrated by several test cases dealing with thermo‐hydro‐mechanical (THM) coupled problems for geotechnical applications. Copyright © 2006 John Wiley & Sons, Ltd.     

Cancer‐Cell‐Specific Induction of Apoptosis Using Mesoporous Silica Nanoparticles as Drug‐Delivery Vectors

Targeted delivery of the chemotherapeutic agent methotrexate (MTX) to cancer cells using poly(ethyleneimine)‐functionalized mesoporous silica particles as drug‐delivery vectors is reported. Due to its high affinity for folate receptors, the expression of which is elevated in cancer cells, MTX serves as both a targeting ligand and a cytotoxic agent. Enhanced cancer‐cell apoptosis (programmed cell death) relative to free MTX is thus observed at particle concentrations where nonspecific MTX‐induced apoptosis is not observed in the nontargeted healthy cell line, while corresponding amounts of free drug affect both cell lines equally. The particles remain compartmentalized in endo‐/lysosomes during the time of observation (up to 72 h), while the drug is released from the particle only upon cell entry, thereby inducing selective apoptosis in the target cells. As MTX is mainly attached to the particle surface, an additional advantage is that the presented carrier design allows for adsorption (loading) of additional drugs into the pore network for therapies based on a combination of drugs.     

Short communication optimal replacement scheduling in multi‐state series–parallel systems

The paper generalizes a replacement schedule optimization problem to multi‐state systems, where the system and its components have a range of performance levels—from perfect functioning to complete failure. The multi‐state system reliability is defined as the ability to satisfy a demand which is represented as a required system performance level. The reliability of system elements is characterized by their lifetime distributions with hazard rates increasing in time and is specified as expected number of failures during different time intervals. The optimal number of element replacements during the study period is defined as that which provides the desired level of the system reliability by minimum sum of maintenance cost and cost of unsupplied demand caused by failures. To evaluate multi‐state system reliability, a universal generating function technique is applied. A genetic algorithm (GA) is used as an optimization technique. Examples of the optimal replacement schedule determination are demonstrated. Copyright © 2000 John Wiley & Sons, Ltd.     

A High‐Throughput Automated Confocal Microscopy Platform for Quantitative Phenotyping of Nanoparticle Uptake and Transport in Spheroids

There is a high demand for advanced, image‐based, automated high‐content screening (HCS) approaches to facilitate phenotypic screening in 3D cell culture models. A major challenge lies in retaining the resolution of fine cellular detail but at the same time imaging multicellular structures at a large scale. In this study, a confocal microscopy‐based HCS platform in optical multiwell plates that enables the quantitative morphological profiling of populations of nonuniform spheroids obtained from HT‐29 human colorectal cancer cells is described. This platform is then utilized to demonstrate a quantitative dissection of the penetration of synthetic nanoparticles (NP) in multicellular 3D spheroids at multiple levels of scale. A pilot RNA interference‐based screening validates this methodology and identifies a subset of RAB GTPases that regulate NP trafficking in these spheroids. This technology is suitable for high‐content phenotyping in 3D cell‐based screening, providing a framework for nanomedicine drug development as applied to translational oncology.     

Sequence‐Specific HCV RNA Quantification Using the Size‐Dependent Nonlinear Optical Properties of Gold Nanoparticles

The hepatitis C virus (HCV) is a single‐stranded (ss) RNA virus that is responsible for chronic liver diseases, such as cirrhosis, end‐stage liver disease, and hepatocellular carcinoma. Driven by the need to detect the presence of the HCV viral sequence, herein it is demonstrated for the first time that the nonlinear optical (NLO) properties of gold nanoparticles can be used for screening and quantifying HCV RNA without any modification, with excellent detection limit (80 pM ) and selectivity (single base‐pair mismatch). The hyper‐Rayleigh scattering (HRS) intensity increases 25 times when label‐free, 145‐mer, HCV ss‐RNA is hybridized with 400 pM target RNA. The mechanism of HRS intensity change is discussed with experimental evidence for a higher multipolar contribution to the NLO response of gold nanoparticles.