Real‐Time In Vivo Quantitative Monitoring of Drug Release by Dual‐Mode Magnetic Resonance and Upconverted Luminescence Imaging

Insufficient or excess drug doses, due to unknown actual drug concentrations at the focus, are one of the main causes of chemotherapy failure for cancers. In this regard, the real‐time monitoring of the release of anticancer drugs from nanoparticle drug delivery systems is of crucial importance, but it remains a critical and unsolved challenge. Herein, we report the proposal and development of a novel concept of real‐time monitoring of NIR‐triggered drug release in vitro and in vivo by using simultaneous upconverted luminescence (UCL) and magnetic resonance (MR) imaging. Such a monitoring strategy features the high sensitivity of UCL and the high‐resolution, noninvasiveness, and tissue‐depth‐independence of MR imaging. The dual‐mode real‐time and quantitative monitoring of drug release can be applied to determine online the drug concentrations in vivo in the tissue regions of interest and, therefore, to avoid insufficient or excess drug dosings.     

Semi‐Interpenetrated Hydrogels‐Microfibers Electroactive Assemblies for Release and Real‐Time Monitoring of Drugs

Simultaneous drug release and monitoring using a single polymeric platform represents a significant advance in the utilization of biomaterials for therapeutic use. Tracking drug release by real‐time electrochemical detection using the same platform is a simple way to guide the dosage of the drug, improve the desired therapeutic effect, and reduce the adverse side effects. The platform developed in this work takes advantage of the flexibility and loading capacity of hydrogels, the mechanical strength of microfibers, and the capacity of conducting polymers to detect the redox properties of drugs. The engineered platform is prepared by assembling two spin‐coated layers of poly‐γ‐glutamic acid hydrogel, loaded with poly(3,4‐ethylenedioxythiophene) (PEDOT) microparticles, and separated by a electrospun layer of poly‐ε‐caprolactone microfibers. Loaded PEDOT microparticles are used as reaction nuclei for the polymerization of poly(hydroxymethyl‐3,4‐ethylenedioxythiophene) (PHMeDOT), that semi‐interpenetrate the whole three layered system while forming a dense network of electrical conduction paths. After demonstrating its properties, the platform is loaded with levofloxacin and its release monitored externally by UV–vis spectroscopy and in situ by using the PHMeDOT network. In situ real‐time electrochemical monitoring of the drug release from the engineered platform holds great promise for the development of multi‐functional devices for advanced biomedical applications.     

Ile‐Lys‐Val‐ala‐Val (IKVAV) peptide for neuronal tissue engineering

Despite the great advances in microsurgery, some neural injuries cannot be treated surgically. Stem cell therapy is a potential approach for treating neuroinjuries and neurodegenerative disease. Researchers have developed various bioactive scaffolds for tissue engineering, exhibiting enhanced cell viability, attachment, migration, neurite elongation, and neuronal differentiation, with the aim of developing functional tissue grafts that can be incorporated in vivo. Facilitating the appropriate interactions between the cells and extracellular matrix is crucial in scaffold design. Modification of scaffolds with biofunctional motifs such as growth factors, drugs, or peptides can improve this interaction. In this review, we focus on the laminin‐derived Ile‐Lys‐Val‐Ala‐Val peptide as a biofunctional epitope for neuronal tissue engineering. Inclusion of this bioactive peptide within a scaffold is known to enhance cell adhesion as well as neuronal differentiation in both 2‐dimensional and 3‐dimensional environments. The in vivo application of this peptide is also briefly described.     

Real‐time Amyloid Aggregation Monitoring with a Photonic Crystal‐based Approach

We propose the application of a new label‐free optical technique based on photonic nanostructures to real‐time monitor the amyloid‐beta 1‐42 (Aβ(1‐42)) fibrillization, including the early stages of the aggregation process, which are related to the onset of the Alzheimer’s Disease (AD). The aggregation of Aβ peptides into amyloid fibrils has commonly been associated with neuronal death, which culminates in the clinical features of the incurable degenerative AD. Recent studies revealed that cell toxicity is determined by the formation of soluble oligomeric forms of Aβ peptides in the early stages of aggregation. At this phase, classical amyloid detection techniques lack in sensitivity. Upon a chemical passivation of the sensing surface by means of polyethylene glycol, the proposed approach allows an accurate, real‐time monitoring of the refractive index variation of the solution, wherein Aβ(1‐42) peptides are aggregating. This measurement is directly related to the aggregation state of the peptide throughout oligomerization and subsequent fibrillization. Our findings open new perspectives in the understanding of the dynamics of amyloid formation, and validate this approach as a new and powerful method to screen aggregation at early stages.     

Pd‐ Dithizone grafted onto magnetic nanoparticles and study of its catalyticactivity in C‐C and C‐N coupling reactions

In this paper, we report a simple, facile and efficient method for the synthesis of Fe₃O₄/SiO₂‐DTZ‐Pd. The immobilized palladium was an efficient catalyst without addition of phosphine ligands for Stille, Heck and N‐arylation reactions. This method has some advantages such as high yields and easy work up of products. In addition, the catalyst can be recovered using a magnet and reused several times without significant loss of its catalytic activity. This catalyst was characterized by various physico‐chemical techniques such as scanning electron microscopy (SEM), transmission electron microscopy (TEM), X‐ray diffraction (XRD) and inductively coupled plasma (ICP).     

A Chemistry for Incorporation of Selenium into DNA‐Encoded Libraries

Conventional direct C?H selenylation suffers from simple selenation with limited atom economy and complicated reaction system. In this work, we designed benzoselenazolone as a novel bifunctional selenide reagent for both off‐ and on‐DNA C?H selenylation under rhodium(III) catalysis. We show that using benzoselenazolone allowed production of a series of selenylation products containing an adjacent aminoacyl group in a fast and efficient way, with high atom economy. The synthetic application of this method was demonstrated by taking advantage of the amide functionality as a nucleophile, directing group, and amide coupling partner. This work shows great potential in facilitating rapid construction of selenium‐containing DNA‐encoded chemical libraries (SeDELs), and lays the foundation for the development of selenium‐containing drugs.     

Characterization of the surface of­bulk‐molded compounds

The automotive industry more and more frequently uses composite materials such as molded compounds (sheet‐molded compounds, SMC, or bulk‐molded compounds, BMC). Bonding is then the only way of assembling two pieces. Consequently, and in order tentatively to predict the adhesive behavior of such materials, it is necessary to have a good knowledge of their surface properties. Here, different complementary techniques of surface analysis allowed us, on the one hand, to reach this aim for BMCs prepared by compression molding and, on the other hand, to show the influence on the surface properties of the concentration and composition of the internal release agent added to the blend. The surface heterogeneity and the organic nature of the surface of the compounds are shown and no phase separation occurs there as in the bulk. Mold release agents remain in the surface layer and induce some acid–base character to the surface material which depends on the type of stearate introduced in the blend. Copyright © 1999 John Wiley & Sons, Ltd.     

In Vivo Solid‐Phase Microextraction for Sampling of Oxylipins in Brain of Awake,Moving Rats

Oxylipins are key lipid mediators of important brain processes, including pain, sleep, oxidative stress, and inflammation. For the first time, an in‐depth profile of up to 52 oxylipins can be obtained from the brains of awake moving animals using in vivo solid‐phase microextraction (SPME) chemical biopsy tool in combination with liquid chromatography–high resolution mass spectrometry. Among these, 23 oxylipins are detectable in the majority of healthy wildtype samples. This new approach successfully eliminates the changes in oxylipin concentrations routinely observed during the analysis of post‐mortem samples, allows time‐course monitoring of their concentrations with high spatial resolution in specific brain regions of interest, and can be performed using the same experimental set‐up as in vivo microdialysis (MD) thus providing a new and exciting tool in neuroscience and drug discovery.     

A p‐Hydroxyphenacyl–Benzothiazole–Chlorambucil Conjugate as a Real‐Time‐Monitoring Drug‐Delivery System Assisted by Excited‐State Intramolecular Proton Transfer

Among the well‐known phototriggers, the p‐hydroxyphenacyl (pHP) group has consistently enabled the very fast, efficient, and high‐conversion release of active molecules. Despite this unique behavior, the pHP group has been ignored as a delivery agent, particularly in the area of theranostics, because of two major limitations: Its excitation wavelength is below 400 nm, and it is nonfluorescent. We have overcome these limitations by incorporating a 2‐(2′‐hydroxyphenyl)benzothiazole (HBT) appendage capable of rapid excited‐state intramolecular proton transfer (ESIPT). The ESIPT effect also provided two unique advantages: It assisted the deprotonation of the pHP group for faster release, and it was accompanied by a distinct fluorescence color change upon photorelease. In vitro studies showed that the p‐hydroxyphenacyl–benzothiazole–chlorambucil conjugate presents excellent properties, such as real‐time monitoring, photoregulated drug delivery, and biocompatibility.     

One‐Step Synthesis of Silver Nanoparticle‐Decorated Hydroxyapatite Nanowires for the Construction of Highly Flexible Free‐Standing Paper with High Antibacterial Activity

A highly flexible and free‐standing paper with high antibacterial activity made from silver nanoparticle (AgNP)‐decorated ultralong hydroxyapatite nanowires (HAPNWs) is reported. The HAPNWs@AgNPs nanocomposites were obtained from a facile one‐step solvothermal process and utilized for the construction of highly flexible and free‐standing inorganic paper through a simple vacuum‐filtration procedure. The structure and properties of the HAPNWs@AgNPs paper were characterized in detail. Scanning electron microscope (SEM) and transmission electron microscope (TEM) micrographs show that AgNPs are highly dispersed and stabilized in the nanocomposite and exhibit a narrow particle size distribution. The effects of the concentration of silver nitrate, solvothermal temperature and time on the product were systematically investigated. This method is simple, convenient and reproducible. The as‐prepared HAPNWs@AgNPs paper shows long‐time sustained silver‐ion release, high antibacterial activity against both Gram‐negative and Gram‐positive bacteria, and good biocompatibility. Overall, this work provides a novel pathway for the preparation of a new type of highly flexible, free‐standing and antibacterial inorganic paper made from silver nanoparticle‐decorated hydroxyapatite nanowires for various applications, as a promising functional biomaterial.     

Ultrathin Cell‐Membrane‐Mimic Phosphorylcholine Polymer Film Coating Enables Large Improvements for In Vivo Electrochemical Detection

Resisting biomolecule adsorption onto the surface of brain‐implanted microelectrodes is a key issue for in vivo monitoring of neurochemicals. Herein, we demonstrate that an ultrathin cell‐membrane‐mimic film of ethylenedioxythiophene tailored with zwitterionic phosphorylcholine (EDOT‐PC) electropolymerized onto the surface of a carbon fiber microelectrode (CFE) not only resists protein adsorption but also maintains the sensitivity and time response for in vivo monitoring of dopamine (DA). As a consequence, the as‐prepared PEDOT‐PC/CFEs could be used as a new reliable platform for tracking DA in vivo and would help understand the physiological and pathological functions of DA.     

H2S‐Activable MOF Nanoparticle Photosensitizer for Effective Photodynamic Therapy against Cancer with Controllable Singlet‐Oxygen Release

Photodynamic therapy (PDT) has emerged as an important minimally invasive tumor treatment technology. The search for an effective photosensitizer to realize selective cancer treatment has become one of the major foci in recent developments of PDT technology. Controllable singlet‐oxygen release based on specific cancer‐associated events, as another major layer of selectivity mode, has attracted great attention in recent years. Here, for the first time, we demonstrated that a novel mixed‐metal metal–organic framework nanoparticle (MOF NP) photosensitizer can be activated by a hydrogen sulfide (H₂S) signaling molecule in a specific tumor microenvironment for PDT against cancer with controllable singlet‐oxygen release in living cells. The effective removal of tumors in vivo further confirmed the satisfactory treatment effect of the MOF NP photosensitizer.     

Tuning salicylate‐based polymers to overcome lag time and extend release via copolymers and polymer blends

This work describes how physicochemical properties of salicylate‐based poly(anhydride‐esters) (PAEs) can be tuned for drug delivery and optimized by comparing copolymerization with polymer blending. These alterations reduced the lag time of drug release, while still maintaining a long‐term drug release profile. The chemical composition of the copolymers and polymer blends was determined by proton nuclear magnetic resonance and additional properties such as molecular weight, glass transition temperature and contact angle measurements were obtained. In vitro salicylic acid release from the copolymers and blends is studied in an environment mimicking physiological conditions. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 685–689     

Synthesis and characterization of new trifluoromethyl substituted 3‐ethoxycarbonyl‐ and 3‐pyrimidin‐2‐yl)‐(1,2,3)‐oxathiazinane‐S‐oxides

This paper describes the synthesis and characterization of a new series of 4‐substituted‐3‐ethoxycarbonyl‐6‐trifluoromethyl‐(1,2,3)‐oxathiazinane‐S‐oxides and 3‐(4,6‐diphenyl‐pyrimidin‐2‐yl)‐6‐trifluoromethyl‐(1,2,3)oxathiazinane‐S‐oxides from the cyclization reaction of 4,4,4‐trifluoro‐3‐hydroxybutylcarbamates and 4‐(4,6‐diphenyl‐pyrimidin‐2‐ylamino)‐1,1,1‐trifluoro‐butan‐2‐ols with thionyl chloride. The analysis of the NMR data allowed us to define important features of the molecular structure. Significant chemical and structural differences were observed between the trifluoromethylated oxathiazinanes obtained in this work from other analogue compounds reported in the literature.     

Rapid discovery of absorbed constituents and metabolites in rat plasma after the oral administration of Zi Shen Wan using high‐throughput UHPLC–MS with a multivariate analysis approach

Zi Shen Wan is a typical formula consisting of three herbs, Phellodendri Amurensis Cortex, Rhizoma Anemarrhenae, and Cortex Cinnamomi, and has been widely used for treating prostatitis and infection diseases. However, it lacks in‐depth research of the constituents of Zi Shen Wan in vivo and in vitro. In this work, ultra high performance liquid chromatography coupled with quadrupole‐time‐of‐flight mass spectrometry and MassLynx software was established to characterize the chemical compositions of Zi Shen Wan in vivo and in vitro. In total, 92 peaks were characterized in vitro and 33 peaks were characterized in vivo based on mass spectrometry and tandem mass spectrometry data. Among the 33 compounds characterized in rat plasma, 22 prototype components absorbed in rat serum and 11 metabolites were identified in vivo. This work was fully reports the chemical constituents of traditional Chinese formula of Zi Shen Wan, it demonstrated that ultra high performance liquid chromatography combined with quadrupole time‐of‐flight mass spectrometry coupled to MassLynx software and multivariate data processing approach could be successfully applied for rapid screening and comprehensive analysis of chemical constituents in vitro and prototype components or metabolites in vivo of traditional Chinese medicine.     

High‐throughput LC–MS method for the rapid characterization of multiple chemical constituents and metabolites of Da‐Bu‐Yin‐Wan

Traditional Chinese medicine is the clinical experience accumulated by Chinese people against diseases. Da‐Bu‐Yin‐Wan is a famous traditional Chinese medicine formula consisting of Phellodendri amurensis Rupr., Anemarrhenae asphodeloides Bge., Radix Rehmanniae Preparata and Chinemys reevesii . In this study, ultra high performance liquid chromatography with electrospray ionization quadrupole time‐of‐flight high‐definition mass spectrometry with the control software of Masslynx (V4.1) was established for comprehensive screening and identification of the chemical constituents and serum metabolites of Da‐Bu‐Yin‐Wan in vivo and in vitro. Consequently, 70 peaks in the methanol extract from Da‐Bu‐Yin‐Wan and 38 peaks absorbed into rat blood were characterized. The 70 constituents in vitro included alkaloids, flavonoids, polysaccharide, limonoids, flavonoid, etc. And the 38 constituents consist of 22 absorbed prototypes and 16 metabolites of Da‐Bu‐Yin‐Wan absorbed in vivo. We fully clarified the chemical constituents of Da‐Bu‐Yin‐Wan and provided a scientific strategy for the screening and characterization of the chemical constituents and metabolites of traditional Chinese medicine in vitro and in vivo.     

“Two‐Step” Raman Imaging Technique To Guide Chemo‐Photothermal Cancer Therapy

Graphene oxide‐wrapped gold nanorods (GO@AuNRs) offer efficient drug delivery as well as NIR laser photothermal therapy (PTT) in vitro and in vivo. However, no real‐time observation of drug release has been reported to better understand the synergy of chemotherapy and PTT. Herein, surface‐enhance Raman spectroscopy (SERS) is employed to guide chemo‐photothermal cancer therapy by a two‐step mechanism. In the presence of GO as an internal standard, SERS signals of DOX (doxorubicin) loaded onto GO@AuNRs are found to be pH‐responsive. Both DOX and GO show strong SERS signals before the DOX@GO@AuNRs are endocytic. However, when the DOX@GO@AuNRs enter acidic microenvironments such as endosomes and/or lysosomes, the DOX signals start decreasing while the GO signals remain the same. This plasmonic antenna could be used to identify the appropriate time to apply the PTT laser during chemo‐photothermal therapy.     

Mechanism‐Guided Improvements to the Single Molecule Oxidation of Carbon Nanotube Sidewalls

Real‐time monitoring of carbon nanotube conductance during electrochemical and chemical etching reveals the electronic signatures of individual bond alteration events on the nanotube sidewall. Tracking the conductance of multiple single‐molecule experiments through different synthetic protocols supports putative mechanisms for sidewall derivatization. Insights gained from these mechanistic observations imply the formation of sidewall carboxylates, which are useful as handles for bioconjugation. We describe an electronic state required for efficacious chemical treatment. Such real‐time monitoring can improve carboxylate yields to 45 % or more. The experiments illustrate the power of molecular nanocircuits to uncover and direct the mechanisms of chemical reactions.     

Biomimetic Peptide‐Gated Nanoporous Membrane for On‐Demand Molecule Transport

The controllable molecule transport is crucial to realize many highly valuable applications both in vivo and in vitro. Nanoporous membranes, with nanoscopic pores, high porosity, uniform pore dimensions, and controllable surface chemical properties, hold tremendous potential to achieve this function. Herein, we report a nano‐gating system for on‐demand molecule transport based on a peptide‐gated nanoporous membrane. Acting as gatekeeper, the peptides introduced to the nanoporous membrane provide an opportunity to realize on‐demand on–off states via reversible conformational switching of the peptides. This nano‐gating system offers sustained release and can be used as a sophisticated molecule transport platform for localized drug delivery with a feedback function.     

Square‐Wave Voltammetry as Analytical Tool for Real‐Time Study of Controlled Naproxen Releasing from Cellulose Derivative Materials

This work reports the successful use of square‐wave voltammetry (SWV) to directly assess the controlled releasing profile of naproxen from lab‐made cellulose derivative materials (membranes and microparticles) in phosphate buffer (pH 7.4) at 36 °C. Particular advantage of SWV refers to the direct real‐time monitoring of released drug from cellulose derivative microparticles, which cannot be easily assessed by UV‐spectrophotometry. Moreover, SWV was able to detect modifications in the naproxen releasing profile due to morphology and processing of membranes and microparticles. The possible miniaturization and versatility of SWV suggest the promising application on the study of several drug delivery systems, including in vivo studies.