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The membrane translocation of hydrophilic substances constitutes a challenge for their application as therapeutic compounds and labelling probes1–4. To remedy this, charged amphiphilic molecules have been classically used as carriers3,5. However, such amphiphilic carriers may cause aggregation and non-specific membrane lysis6,7. Here we show that globular dodecaborate clusters, and prominently B12Br122−, can function as anionic inorganic membrane carriers for a broad range of hydrophilic cargo molecules (with molecular mass of 146–4,500 Da). We show that cationic and neutral peptides, amino acids, neurotransmitters, vitamins, antibiotics and drugs can be carried across liposomal membranes. Mechanistic transport studies reveal that the carrier activity is related to the superchaotropic nature of these cluster anions8–12. We demonstrate that B12Br122− affects cytosolic uptake of different small bioactive molecules, including the antineoplastic monomethyl auristatin F, the proteolysis targeting chimera dBET1 and the phalloidin toxin, which has been successfully delivered in living cells for cytoskeleton labelling. We anticipate the broad and distinct delivery spectrum of our superchaotropic carriers to be the starting point of conceptually distinct cell-biological, neurobiological, physiological and pharmaceutical studies.

This review comprehensively summarizes the state of the art in label-free supramolecular tandem enzyme assays using supramolecular chemosensors and includes prospective applications in inhibitor screening, optical sensor arrays, and MRI biosensing.

An overarching challenge in the development of supramolecular sensor systems is to enhance their sensitivity, which commonly involves the synthesis of refined receptors with increased affinity to the analyte. We show that a dramatic sensitivity increase by 1-2 orders of magnitude can be achieved by encapsulating supramolecular chemosensors inside liposomes and exposing them to a pH gradient across the lipid bilayer membrane. This causes an imbalance of the influx and efflux rates of basic and acidic analytes leading to a significantly increased concentration of the analyte in the liposome interior. The utility of our liposome-enhanced sensors was demonstrated with various host-dye reporter pairs and sensing mechanisms, and we could easily increase the sensitivity towards multiple biologically relevant analytes, including the neurotransmitters serotonin and tryptamine.

The accurate determination of ultra-high binding affinities in supramolecular host-guest chemistry is a challenging endeavour because direct binding titrations are generally limited to affinities

Our purpose was to investigate whether liver stereotactic body radiation therapy treatment planning can be harmonized across different treatment planning systems, delivery techniques, and institutions by using a specific prescription method and to minimize the knowledge gap concerning intersystem and interuser differences. We provide best practice guidelines for all used techniques.A multiparametric specification of target dose (gross target volume [GTV]GTVThis study showed the feasibility of harmonizing liver stereotactic body radiation therapy treatment plans across different treatment planning systems and delivery techniques when a sufficient set of clinical goals is given.

The membrane transport mechanisms of cell-penetrating peptides (CPPs) are still controversial, and reliable assays to report on their internalization in model membranes are required. Herein, we introduce a label-free, fluorescence-based method to monitor membrane transport of peptides in real time. For this purpose, a macrocyclic host and a fluorescent dye forming a host-dye reporter pair are encapsulated inside phospholipid vesicles. Internalization of peptides, which can bind to the supramolecular host, leads to displacement of the dye from the host, resulting in a fluorescence change that signals the peptide uptake and, thus, provides unambiguous evidence for their transport through the membrane. The method was successfully validated with various established CPPs, including the elusive peptide TP2, in the presence of counterion activators of CPPs, and with a calixarene-based supramolecular membrane transport system. In addition, transport experiments with encapsulated host-dye reporter pairs are not limited to large unilamellar vesicles (LUVs) but can also be used with giant unilamellar vesicles (GUVs) and fluorescence microscopy imaging.

The combination of the macrocyclic hosts p‐sulfonatocalix[4]arene and cucurbit[7]uril with the fluorescent dyes lucigenin and berberine affords two label‐free enzyme assays for the detection of kinase and phosphatase activity by fluorescence monitoring. In contrast to established assays, no substrate labeling is required. Since phosphorylation is one of the most important regulatory mechanisms in biological signal transduction, the assays should be useful for identification of inhibitors and activators in high‐throughput screening (HTS) format for drug discovery., Monitoring enzyme activity: Reporter pairs composed of macrocyclic hosts and dyes afford kinase and phosphatase assays suitable for drug discovery

In this study, we investigate the influence of γ-cyclodextrin (γCD) or octakis-(2,3,6-tri-O-methyl)-γ-cyclodextrin (TMe-γCD) encapsulation on the solubility, thermal, optical, electrochemical, morphological, and electrical properties of an aromatic polyazomethine (PA). PA was prepared by oxidative C C coupling of pyrenyl groups from the monomer MA using FeCl3 as catalyst in DMF. After threading of γCD or TMe-γCD macrocycles onto the PA chains, the 1H NMR spectra were in line with the formation of the respective inclusion complexes, PA·γCD and PA·TMe-γCD, which showed distinct improvements of their solubility in common organic solvents, higher thermal stability, as well as better film-forming ability. Fluorescence spectroscopy revealed that the emission maximum shifted from 388 nm for PA to 425 nm and 428 nm for PA·γCD and PA·TMe-γCD, which is in good agreement with encapsulation of PA backbones into the hydrophobic cavities. Fluorescence lifetime measurements indicated multiexponential decays for all compounds, which is in accordance with different conformers in the excited state. Atomic force microscopy indicated that the surfaces of PA·γCD and PA·TMe-γCD in the solid state showed needle-shaped morphologies with widths of 105 ± 25 nm and 46 ± 13 nm, respectively, whereas the surface of the naked PA polymer displayed an irregular morphology with embedded particles and width of 158 ± 29 nm. The electrochemical band gaps (ΔEg) of PA·γCD and PA·TMe-γCD were lower than that of non-encapsulated PA. The electrical conductivities of the investigated compounds were about 10−11 S cm−1, which is in the range of insulating materials.

A putrescine derivative of aminomethyladamantane is established as a ditopic guest with two mutually exclusive binding sites for cucurbit[6]uril and cucurbit[7]uril. A mixture containing both hosts, the ditopic guest, and two fluorescent dyes affords a relay system with a ratiometric fluorescence response and enables a kinetic analysis of the switching mechanism.

We report herein two methods to characterize the surface of mixed-ligand shell gold nanoparticles, which was explored with gold nanoparticles containing varying molar ratios of 3-mercaptopropionic acid (MPA) and 3-mercapto-1-propanesulfonate (MPS) or 11-mercaptoundecanoic acid (MUA) and triethylene glycol mono-11-mercaptoundecyl ether (TEG) in their ligand shell. Incubation of gold nanoparticles with a solution containing the transition metal cation Ni2+ allows the extraction of Ni2+ depending on the number of negatively charged surface groups and the reaction of surface carboxylic acid groups with an aminomethyladamantane derivative allows the extraction of the supramolecular host molecule cucurbit[7]uril (CB7) depending on the number of reactive surface groups. In both the methods, the remaining surface probes in the supernatant could be conveniently quantified in a homogeneous solution after a simple centrifugation step. An excellent linear correlation between the amount of Ni2+ extracted and the ligand density of MPA and MPS in MPA/MPS gold nanoparticles or MUA in MUA/TEG gold nanoparticles afforded a simple and reliable assay method to determine the number of negatively charged surface groups. The supramolecular CB7 assay enabled the determination of the accessible ligand density of reactive surface carboxylic acid groups and revealed a striking difference in the number of surface groups that can be reacted with MPA/MPS gold nanoparticles or MUA/TEG gold nanoparticles, which suggests a simple method to probe the surface structure of mixed monolayer gold nanoparticles.

A supramolecular host-guest FRET pair based on a carboxyfluorescein-labelled cucurbit[7]uril (CB7-CF, as acceptor) and the fluorescent dye 4',6-diamidino-2-phenylindole (DAPI, as donor) is developed for sensing of DNA. In comparison to the commercial DNA staining dye SYBR Green I, the new chemosensing ensemble offers dual-emission signals, which allows a linear ratiometric response over a wide concentration range.

The use of sensor transponder systems inmedicine opens valuable possibilities in therapy and diagnostics. This chapter is about physical effects by the use of sensor transponder technology for medicine applications, especially for deeply implanted passive powered sensor transponders. This chapter will inform about present and future applications. The influence of human body on the energy transmission in a sensor transponder system is shown. The dielectrical properties of human tissue are discussed. A way how to estimate losses in an analytical way and with the use of a 3D FTDT method is presented. Finally, a design example of an energy transmission for a sensor transponder is shown with a calculation of the optimal frequency and experimental results.

Time-resolved monitoring of the permeability of analytes is of utmost importance in membrane research. Existing methods are restricted to single-point determinations or flat synthetic membranes, limiting access to biologically relevant kinetic parameters (permeation rate constant, permeation coefficients). We now use the recently introduced fluorescent artificial receptor membrane assay (FARMA) as a method to monitor, in real time, the permeation of indole derivatives through liposomal membranes of different lipid compositions. This method is based on the liposomal encapsulation of a chemosensing ensemble or "fluorescent artificial receptor", consisting of 2,7-dimethyldiazapyrenium as a fluorescent dye and cucurbit[8]uril as the macrocyclic receptor, that responds to the complexation of a permeating aromatic analyte by fluorescence quenching. FARMA does not require a fluorescent labeling of the analytes and allows access to permeability coefficients in the range from 10-8 to 10-4 cm s-1. The effect of temperature on the permeation rate of a series of indole derivatives across the phospholipid membranes was studied. The activation energies for permeation through POPC/POPS phospholipid membranes were in the range of 28-96 kJ mol-1. To study the effect of different lipid phases on the membrane permeability, we performed experiments with DPPC/DOPS vesicles, which showed a phase transition from a gel phase to a liquid-crystalline phase, where the activation energies for the permeation process were expected to show a dramatic change. Accordingly, for the permeation of the indole derivatives into the DPPC/DOPS liposomes, discontinuities were observed in the Arrhenius plots, from which the permeation activation energies for the distinct phases could be determined, for example, for tryptamine 245 kJ mol-1 in the gel phase and 47 kJ mol-1 in the liquid-crystalline phase.

In view of the anticancer effect of nitrosoureas a set of four new N-(2-chloroethyl)-N-nitrosourea (CENU) derivatives was synthesized. An in silico absorption, distribution, metabolism, excretion and toxicity (ADME/Tox) prediction study revealed that the CENU derivatives satisfied all the required criteria for oral administration and introduced them as remarkable anticancer candidates in the central nervous system (CNS). A comparative solvatochromic study including the Kamlet-Taft, Catalan and Laurence models indicated that the solvatochromic behavior of the CENUs depended on both, unspecific and specific solvent–solute interactions. In detail, the solvatochromic effect of the solvent polarity on the absorption and emission maxima was significant for all CENUs, whereas the solvatochromic effect of the solvent’s ability to donate or accept hydrogen bonds on the absorption and emission maxima was critically dependent on the electron density of the N’-aryl group. From the solvatochromic comparison method, excellent correlations (r ≥ 0.890) were obtained between the ADME parameters and the solvatochromic regression coefficients obtained by the Catalan model. As potential stabilizers, inclusion complexes of the investigated CENU derivatives with β-cyclodextrin (β-CD) were also explored. The spectrofluorimetric host–guest experiments included double-reciprocal Benesi-Hildebrand plots as well as the molar ratio and continuous variation plots (Job’s plots), which established a 1:1 β-CD to CENU binding stoichiometry and relatively high affinities of β-CD for CENU derivatives.

Lysine (K) is an important target residue for protein and peptide delivery across membranes. K is the most frequently exposed residue in proteins, leading to high demand for the development of K-compatible transport activators. However, designing activators for K-rich peptides and proteins is more challenging than for arginine-rich species because of the kosmotropic nature of K and its recognition difficulty. In this study, we designed a new amphiphilic sulfonatocalix[5]arene (sCx5-6C) as a K-compatible transport activator. sCx5-6C was tailored with two key elements, recognition of K and the ability to embed into membranes. We measured the membrane transport efficiencies of α-poly-l-lysine, heptalysine, and histones across artificial membranes and of α-poly-l-lysine into live cells, activated by sCx5-6C. The results demonstrate that sCx5-6C acts as an efficient activator for translocating K-rich peptides and proteins, which cannot be achieved by known arginine-compatible activators.

Emerging smart sensor systems are the main driver of innovation in many fields of application. A prominent example is condition-based monitoring and especially its subdomain fault diagnosis. The integration of advanced machine and deep learning-based signal processing into sensor systems enables new intelligent condition monitoring solutions. However, the data-based nature of machine and deep learning methods still impedes their applicability in many cases, due to a severe lack of data. In this paper, we introduce a new hybrid physics- and data-based framework aiming to solve the issue of small datasets for vibration-based fault diagnosis applied to rolling-element bearings. The framework combines a vibration simulation model and a neural network with embedded physics-based knowledge into a physics-guided neural network. Our approach aims to generate physically consistent data for the training of fault classifiers without extensive data acquisition.

In recent years drones have proven their ability to solve complex tasks autonomously and effectively. Drones have not been present as a ubiquitous technology for solving these tasks yet. The reason is mainly due to their limited flying time. The technology has great market potential in many areas if flight time could be increased. However, only a few solutions for recharging are available, but none for recharging on power lines. This remains a research topic for now. Through this paper a novel energy harvesting design is presented based on inductive coupling, allowing a drone to grasp and perch onto an overhead power line to recharge its batteries. The overall electronic design was based on analyzing and simulating different current transformers in simulation before testing in the laboratory. The split-core including windings was integrated into a gripping mechanism, verified by analytical and numerical analysis as well as non-destructive and destructive testing. The results indicate that enough power can be harvested from the powerline to recharge the drone batteries. The theoretically achievable power was also found to be within the expected range. With this design, drones can solve time-consuming and complex tasks in the future.

We introduce herein boron-dipyrromethene (BODIPY) dyes as a new class of fluorophores for the design of reporter dyes for supramolecular host–guest complex formation with cucurbit[7]uril (CB7). The BODIPYs contain a protonatable aniline nitrogen in the meso-position of the BODIPY chromophore, which was functionalized with known binding motifs for CB7. The unprotonated dyes show low fluorescence due to photoinduced electron transfer (PET), whereas the protonated dyes are highly fluorescent. Encapsulation of the binding motif inside CB7 positions the aniline nitrogen at the carbonyl rim of CB7, which affects the pKa value, and leads to a host-induced protonation and thus to a fluorescence increase. The possibility to tune binding affinities and pKa values is demonstrated and it is shown that, in combination with the beneficial photophysical properties of BODIPYs, several new applications of host–dye reporter pairs can be implemented. This includes indicator displacement assays with favourable absorption and emission wavelengths in the visible spectral region, fluorescence correlation spectroscopy, and noncovalent surface functionalization with fluorophores.

We propose a method to dynamically monitor the progress of an enzymatic reaction using NMR of hyperpolarized ^(129)Xe in a host-guest system. It is based on a displacement assay originally designed for fluorescence experiments that exploits the competitive binding of the enzymatic product on the one hand and a reporter dye on the other hand to a supramolecular host. Recently, this assay has been successfully transferred to NMR, using xenon as a reporter, cucurbit[6]uril as supramolecular host, and Hyper-CEST as detection technique. Its advantage is that the enzyme acts on the unmodified substrate and only the product is detected through immediate inclusion into the host. We here apply a method that drastically accelerates the acquisition of Hyper-CEST spectra in vitro using magnetic field gradients. This allows monitoring the dynamic progress of the conversion of lysine to cadaverine with a temporal resolution of ~30 s. Moreover, the method only requires to sample the very early onset of the reaction (

Die Phosphorylierung und Dephosphorylierung von Peptiden durch Kinasen und Phosphatasen ist ein allgegenwartiger Mechanismus der Signaltransduktion in biologischen Systemen. Eine unnaturlich hohe oder niedrige Aktivitat dieser Enzyme steht im Zusammenhang mit vielen Krankheiten. Hier fuhren wir amphiphile Calixarene als supramolekulare Schlusselkomponenten fur einen Membrantransport von Peptiden ein, der sich durch Phosphorylierung regulieren lasst. Mithilfe von farbstoffbeladenen Liposomen zeigen wir, dass diese Calixarene als Gegenionen fur etablierte zellpenetrierende Peptide fungieren und deren Transport effizient aktivieren konnen. Die ermittelten EC50-Werte liegen im niedrigen nanomolaren Bereich. Die Calixarene aktivieren sogar den Membrantransport von kurzen Peptiden, die Substrate fur Kinasen in Signaltransduktionskaskaden sind. Dadurch dass das phosphorylierte Produkt viel weniger effektiv transportiert wird, ermoglicht dies die Regulierung des Membrantransports durch Proteinkinase A (PKA) und Proteinkinase C (PKC). Daraus folgt auch eine markierungsfreie Methode, um die Aktivitat dieser Enzyme mittels Fluoreszenz nachzuweisen.