Quantitative SERS sensor for mycotoxins with extraction and identification function.

The development of new sensors for on-site food toxin monitoring that combine extraction, analytes distinction and detection is important in resource-limited environments. Surface-enhanced Raman scattering (SERS)-based signal readout features fast response and high sensitivity, making it a powerful method for detecting mycotoxins. In this work, a SERS-based assay for the detection of multiple mycotoxins is presented that combines extraction and subsequent detection, achieving an analytically relevant detection limit (∼ 1 ng/mL), which is also tested in corn samples. This sensor consists of a magnetic-core and mycotoxin-absorbing polydopamine-shell, with SERS-active Au nanoparticles on the outer surface. The assay can concentrate multiple mycotoxins, which are identified through multiclass partite least squares analysis based on their SERS spectra. We developed a strategy for the analysis of multiple mycotoxins with minimal sample pretreatment, enabling in situ analytical extraction and subsequent detection, displaying the potential to rapidly identify lethal mycotoxin contamination on site.

Upconverting Nanoparticles Coated with Light-Breakable Mesoporous Silica for NIR-Triggered Release of Hydrophobic Molecules.

Upconverting nanoparticles (UCNPs) doped with Yb3+ and Tm3+ are near-infrared (NIR) to ultraviolet (UV) transducers that can be used for NIR-controlled drug delivery. However, due to the low quantum yield of upconversion, high laser powers and long irradiation times are required to trigger this drug release. In this work, we report the one-step synthesis of a nanocomposite consisting of a LiYbF4:Tm3+@LiYF4 UCNP coated with mesoporous UV-breakable organosilica shells of various thicknesses. We demonstrate that a thin shell accelerates the breakage of the shell at 1 W/cm2 NIR light exposure, a laser power up to 9 times lower than that of conventional systems. When the mesopores are loaded with hydrophobic vitamin D3 precursor 7-dehydrocholesterol (7-DH), shell breakage results in subsequent cargo release. Its minimal toxicity in HeLa cells and successful internalization into the cell cytoplasm demonstrate its biocompatibility and potential application in biological systems. The tunability of this system due to its simple, one-step synthesis process and its ability to operate at low laser powers opens up avenues in UCNP-powered NIR-triggered drug delivery toward a more scalable, flexible, and ultimately translational option.

Development of a new kappa-carrageenan hydrogel system to study benthic diatom vertical movements.

Benthic diatom vertical movement has been investigated mainly through indirect measurements based on chlorophyll a fluorescence and spectral reflectance signals. The presence of sediment hinders direct imaging and grazers activity renders the work under controlled conditions very difficult. This study provides a tool to study diatoms movement in a 3D hydrogel matrix. Synthetic and natural hydrogels were tested to find the best 3D transparent scaffold where diatoms could grow and freely move in all directions. Polyamidoamines (PAAm) hydrogels were no-cytocompatible and hyaluronic acid (HA) only allowed diatoms to survive for 2-days. Natural hydrogels made of gelatin/Na-alginate, Na-alginate and kappa-carrageenan (KC) were cytocompatible, with KC showing the best properties for diatom growth and movement on a long term (up to 2 months). Comparing Nitzschia spathulata, Gyrosigma limosum and Navicula phyllepta growth in liquid media vs in KC gels, we found that diatoms reached a significantly higher final biomass in the hydrogel condition. Hydrogels were also useful to isolate large size diatom species e.g., Nitzschia elongata, that did not survive in suspension. Finally, we showed three ways to study diatom species-specific movement in KC hydrogels: 1) controlled species mix; 2) natural diatom assemblages with grazers; and 3) natural diatom assemblages without grazers. With our system, single diatoms could be imaged, identified, and counted. In addition, different stimuli, e.g., light intensity and light composition can be applied and their effects on movement and physiology studied without being masked by sediment or impaired by meiofauna.

Supramolecular Nucleic Acid-Based Organosilica Nanoparticles Responsive to Physical and Biological Inputs.

Organosilica nanoparticles that contain responsive organic building blocks as constitutive components of the silica network offer promising opportunities for the development of innovative drug formulations, biomolecule delivery, and diagnostic tools. However, the synthetic challenges required to introduce dynamic and multifunctional building blocks have hindered the realization of biomimicking nanoparticles. In this study, capitalizing on our previous research on responsive nucleic acid-based organosilica nanoparticles, we combine the supramolecular programmability of nucleic acid (NA) interactions with sol-gel chemistry. This approach allows us to create dynamic supramolecular bridging units of nucleic acids in a silica-based scaffold. Two peptide nucleic acid-based monoalkoxysilane derivatives, which self-assemble into a supramolecular bis-alkoxysilane through direct base pairing, were chosen as the noncovalent units inserted into the silica network. In addition, a bridging functional NA aptamer leads to the specific recognition of ATP molecules. In a one-step bottom-up approach, the resulting supramolecular building blocks can be used to prepare responsive organosilica nanoparticles. The supramolecular Watson-Crick-Franklin interactions of the organosilica nanoparticles result in a programmable response to external physical (i.e., temperature) and biological (i.e., DNA and ATP) inputs and thus pave the way for the rational design of multifunctional silica materials with application from drug delivery to theranostics.

Responsive Nucleic Acid-Based Organosilica Nanoparticles.

The development of smart nanoparticles (NPs) that encode responsive features in the structural framework promises to extend the applications of NP-based drugs, vaccines, and diagnostic tools. New nanocarriers would ideally consist of a minimal number of biocompatible components and exhibit multiresponsive behavior to specific biomolecules, but progress is limited by the difficulty of synthesizing suitable building blocks. Through a nature-inspired approach that combines the programmability of nucleic acid interactions and sol-gel chemistry, we report the incorporation of synthetic nucleic acids and analogs, as constitutive components, into organosilica NPs. We prepared different nanomaterials containing single-stranded nucleic acids that are covalently embedded in the silica network. Through the incorporation of functional nucleic acids into the organosilica framework, the particles respond to various biological, physical, and chemical inputs, resulting in detectable physicochemical changes. The one-step bottom-up approach used to prepare organosilica NPs provides multifunctional systems that combine the tunability of oligonucleotides with the stiffness, low cost, and biocompatibility of silica for different applications ranging from drug delivery to sensing.

Cargo-loaded lipid-shielded breakable organosilica nanocages for enhanced drug delivery.

The recent nanomedicine advancements have introduced a variety of smart nanoparticles in cancer treatment and diagnostics. However, their application to the clinic is still hindered by several challenges related to their biocompatibility, elimination and biodistribution. Here we propose breakable organosilica mesoporous nanoparticles, i.e. nanocages, able to efficiently incorporate cargo molecules and be coated, with different lipid compositions, to enhance their biomimetic behaviour. We exploit the electrostatic interactions between the organosilica surface and the opposite charge of the lipid mixtures in order to obtain an efficient organosilica coverage. The lipid-coated nanocages are proved to have an incredibly high hemocompatibility, significantly increased with respect to pristine nanocages, and excellent colloidal stability and biocompatibility. The cargo-loaded and lipid-coated nanocages are tested and compared in vitro on two different cancer cell lines, demonstrating the key role played by the lipid coating in mediating the internalization of the nanocages, evaluated by the enhanced and rapid cellular uptake. The efficient intracellular delivery of the therapeutic agents is then assured by the destruction of the organosilica, due to the disulfide bridges, introduced into the silica framework, that in reducing media, like the intracellular one, are reduced to thiols causing the breaking of the nanoparticles. The possibility to image and effectively kill cancer cells demonstrates the potentiality of the lipid-coated nanocages as a powerful tool in anticancer research and as a promising smart theranostic platform.

Tryptophan-PNA gc Conjugates Self-Assemble to Form Fibers.

Peptide nucleic acids and their conjugates to peptides can self-assemble and generate complex architectures. In this work, we explored the self-assembly of PNA dimers conjugated to the dipeptide WW. Our studies suggest that the indole ring of tryptophan promotes aggregation of the conjugates. The onset of fluorescence is observed upon self-assembly. The structure of self-assembled WWgc is concentration-dependent, being spherical at low concentrations and fibrous at high concentrations. As suggested by molecular modeling studies, fibers are stabilized by stacking interactions between tryptophans and Watson-Crick hydrogen bonds between nucleobases.

Enhancing Pt(IV) Complexes' Anticancer Activity upon Encapsulation in Stimuli-Responsive Nanocages.

Platinum-based chemotherapy is the first-line treatment for different cancer types, and in particular, for malignant pleural mesothelioma patients (a tumor histotype with urgent medical needs). Herein, a strategy is presented to stabilize, transport, and intracellularly release a platinumIV (PtIV ) prodrug using a breakable nanocarrier. Its reduction, and therefore activation as an anticancer drug, is promoted by the presence of glutathione in neoplastic cells that also causes the destruction of the carrier. The nanocage presents a single internal cavity in which the hydrophobic complex (Pt(dach)Cl2 (OH)2 ), (dach = R,R-diaminocyclohexane) is encapsulated. The in vitro uptake and the internalization kinetics in cancer model cells are evaluated and, using flow cytometry analysis, the successful release and activation of the Pt-based drug inside cancer cells are demonstrated. The in vitro findings are confirmed by the in vivo experiments on a mice model obtained by xenografting MPM487, a patient-derived malignant pleural mesothelioma. MPM487 confirms the well-known resistance of malignant pleural mesothelioma to cisplatin treatment while an interesting 50% reduction of tumor growth is observed when mice are treated with the PtIV , entrapped in the nanocages, at an equivalent dose of the platinum complex.

The Role of a Confined Space on the Reactivity and Emission Properties of Copper(I) Clusters.

Metal clusters have gained a lot of interest for their remarkable photoluminescence and catalytic properties. However, a major drawback of such materials is their poor stability in air and humidity conditions. Herein we describe a versatile method to synthesize luminescent Cu(I) clusters inside the pores of zeolites, using a sublimation technique with the help of high vacuum and high temperature. The porous materials play an essential role as a protecting media against the undesirable and easy oxidation of Cu(I). The obtained clusters show fascinating luminescence properties, and their reactivity can be triggered by insertion in the pores of organic monodentate ligands such as pyridine or triphenylphosphine. The coordinating ligands can lead to the formation of Cu(I) complexes with completely different emission properties. In the case of pyridine, the final compound was characterized and identified as a cubane-like structure. A thermochromism effect is also observed, featuring, for instance, a hypsochromic effect for a phosphine derivative at 77K. The stability of the encapsulated systems in zeolites is rather enthralling: they are stable and emissive even after several months in the air.

Chiral Fibers Formation Upon Assembly of Tetraphenylalanine Peptide Conjugated to a PNA Dimer.

Self-assembly of biomolecules such as peptides, nucleic acids or their analogues affords supramolecular objects, exhibiting structures and physical properties dependent on the amino-acid or nucleobase composition. Conjugation of the peptide diphenylalanine (FF) to peptide nucleic acids triggers formation of self-assembled structures, mainly stabilized by interactions between FF. In this work we report formation of homogeneous chiral fibers upon self-assembly of the hybrid composed of the tetraphenylalanine peptide (4F) conjugated to the PNA dimer adenine-thymine (at). In this case nucleobases seem to play a key role in determining the morphology and chirality of the fibers. When the PNA "at" is replaced by guanine-cytosine dimer "gc", disordered structures are observed. Spectroscopic characterization of the self-assembled hybrids, along with AFM and SEM studies is reported. Finally, a structural model consistent with the experimental evidence has also been obtained, showing how the building blocks of 4Fat arrange to give helical fibers.

Molecular Probes, Chemosensors, and Nanosensors for Optical Detection of Biorelevant Molecules and Ions in Aqueous Media and Biofluids.

Synthetic molecular probes, chemosensors, and nanosensors used in combination with innovative assay protocols hold great potential for the development of robust, low-cost, and fast-responding sensors that are applicable in biofluids (urine, blood, and saliva). Particularly, the development of sensors for metabolites, neurotransmitters, drugs, and inorganic ions is highly desirable due to a lack of suitable biosensors. In addition, the monitoring and analysis of metabolic and signaling networks in cells and organisms by optical probes and chemosensors is becoming increasingly important in molecular biology and medicine. Thus, new perspectives for personalized diagnostics, theranostics, and biochemical/medical research will be unlocked when standing limitations of artificial binders and receptors are overcome. In this review, we survey synthetic sensing systems that have promising (future) application potential for the detection of small molecules, cations, and anions in aqueous media and biofluids. Special attention was given to sensing systems that provide a readily measurable optical signal through dynamic covalent chemistry, supramolecular host-guest interactions, or nanoparticles featuring plasmonic effects. This review shall also enable the reader to evaluate the current performance of molecular probes, chemosensors, and nanosensors in terms of sensitivity and selectivity with respect to practical requirement, and thereby inspiring new ideas for the development of further advanced systems.

Fluorescent Nanozeolite Receptors for the Highly Selective and Sensitive Detection of Neurotransmitters in Water and Biofluids.

The design and preparation of synthetic binders (SBs) applicable for small biomolecule sensing in aqueous media remains very challenging. SBs designed by the lock-and-key principle can be selective for their target analyte but usually show an insufficient binding strength in water. In contrast, SBs based on symmetric macrocycles with a hydrophobic cavity can display high binding affinities but generally suffer from indiscriminate binding of many analytes. Herein, a completely new and modular receptor design strategy based on microporous hybrid materials is presented yielding zeolite-based artificial receptors (ZARs) which reversibly bind the neurotransmitters serotonin and dopamine with unprecedented affinity and selectivity even in saline biofluids. ZARs are thought to uniquely exploit both the non-classical hydrophobic effect and direct non-covalent recognition motifs, which is supported by in-depth photophysical, and calorimetric experiments combined with full atomistic modeling. ZARs are thermally and chemically robust and can be readily prepared at gram scales. Their applicability for the label-free monitoring of important enzymatic reactions, for (two-photon) fluorescence imaging, and for high-throughput diagnostics in biofluids is demonstrated. This study showcases that artificial receptor based on microporous hybrid materials can overcome standing limitations of synthetic chemosensors, paving the way towards personalized diagnostics and metabolomics.

Image-Guided Surgical Simulation in Minimally Invasive Liver Procedures: Development of a Liver Tumor Porcine Model Using a Multimodality Imaging Assessment.

Background: Image-guided liver surgery and interventions are growing as part of the current trend to translate liver procedures into minimally invasive approaches. Hands-on surgical training in such techniques is required. Consequently, a meaningful and realistic liver tumor model using multi-imaging modalities, such as ultrasound (US), computed tomography (CT), magnetic resonance (MR), cone beam-CT (CBCT), is mandatory. The first aim of this study is to develop a novel tumor-mimic model and assess it with multi-imaging modalities. The second aim is to evaluate the usefulness of the model during image-guided liver procedures. Materials and Methods: The tumor-mimic model is made of a composition of hydrogel, smashed muscle, and gadolinium contrast solution. Five ex vivo livers and three pigs were included in the study. Procedures were performed in an experimental hybrid operating room. Under general anesthesia, US guidance was required to inject the biotumor formula into the pig's liver. US, CT, CBCT, and MR acquisitions were then performed after the initial injection. In vivo models were then used to perform liver procedures, including US-guided biopsy, radiofrequency ablation, and laparoscopic resection. Results: The formula developed is easily injected generating a tissue-like material. Visualization using multi-imaging modalities was appropriate, thereby allowing to perform image-guided techniques. Conclusion: A novel design of an in vivo and ex vivo tissue-like tumor liver model is presented. Due to the multimodality imaging appraisal, it may provide a realistic and meaningful model allowing to perform image-guided liver procedures.

Aggregation-Induced Emission in Electrochemiluminescence: Advances and Perspectives.

The discovery of aggregation-induced electrochemiluminescence (AIECL) in 2017 opened new research paths in the quest for novel, more efficient emitters and platforms for biological and environmental sensing applications. The great abundance of fluorophores presenting aggregation-induced emission in aqueous media renders AIECL a potentially powerful tool for future diagnostics. In the short time following this discovery, many scientists have found the phenomenon interesting, with research findings contributing to advances in the comprehension of the processes involved and in attempts to design new sensing platforms. Herein, we explore these advances and reflect on the future directions to take for the development of sensing devices based on AIECL.

Organosilica Cages Target Hepatic Sinusoidal Endothelial Cells Avoiding Macrophage Filtering.

Over the last years, advancements in the use of nanoparticles for biomedical applications have clearly showcased their potential for the preparation of improved imaging and drug-delivery systems. However, compared to the vast number of currently studied nanoparticles for such applications, only a few successfully translate into clinical practice. A common "barrier" that prevents nanoparticles from efficiently delivering their payload to the target site after administration is related to liver filtering, mainly due to nanoparticle uptake by macrophages. This work reports the physicochemical and biological investigation of disulfide-bridged organosilica nanoparticles with cage-like morphology, OSCs, assessing in detail their bioaccumulation in vivo. The fate of intravenously injected 20 nm OSCs was investigated in both healthy and tumor-bearing mice. Interestingly, OSCs exclusively colocalize with hepatic sinusoidal endothelial cells (LSECs) while avoiding Kupffer-cell uptake (less than 6%) under both physiological and pathological conditions. Our findings suggest that organosilica nanocages hold the potential to be used as nanotools for LSECs modulation, potentially impacting key biological processes such as tumor cell extravasation and hepatic immunity to invading metastatic cells or a tolerogenic state in intrahepatic immune cells in autoimmune diseases.

Immunologically Inert Nanostructures as Selective Therapeutic Tools in Inflammatory Diseases.

The current therapies based on immunosuppressant or new biologic drugs often show some limitations in term of efficacy and applicability, mainly because of their inadequate targeting and of unwanted adverse reactions they generate. To overcome these inherent problems, in the last decades, innovative nanocarriers have been developed to encapsulate active molecules and offer novel promising strategies to efficiently modulate the immune system. This review provides an overview of how it is possible, exploiting the favorable features of nanocarriers, especially with regard to their immunogenicity, to improve the bioavailability of novel drugs that selectively target immune cells in the context of autoimmune disorders and inflammatory diseases. A focus is made on nanoparticles that selectively target neutrophils in inflammatory pathologies.

Smart Nanocages as a Tool for Controlling Supramolecular Aggregation.

An important aspect in the field of supramolecular chemistry is the control of the composition and aggregation state of supramolecular polymers and the possibility of stabilizing out-of-equilibrium states. The ability to freeze metastable systems and release them on demand, under spatiotemporal control, to allow their thermodynamic evolution toward the most stable species is a very attractive concept. Such temporal blockage could be realized using stimuli-responsive "boxes" able to trap and redirect supramolecular polymers. In this work, we report the use of a redox responsive nanocontainer, an organosilica nanocage (OSCs), for controlling the dynamic self-assembly pathway of supramolecular aggregates of a luminescent platinum compound (PtAC). The aggregation of the complexes leads to different photoluminescent properties that allow visualization of the different assemblies and their evolution. We discovered that the nanocontainers can encapsulate kinetically trapped species characterized by an orange emission, preventing their evolution into the thermodynamically stable aggregation state characterized by blue-emitting fibers. Interestingly, the out-of-equilibrium trapped Pt species (PtAC@OSCs) can be released on demand by the redox-triggered degradation of OSCs, re-establishing their self-assembly toward the thermodynamically stable state. To demonstrate that control of the self-assembly pathway occurs also in complex media, we followed the evolution of the supramolecular aggregates inside living cells, where the destruction of the cages allows the intracellular release of PtAC aggregates, followed by the formation of microscopic blue emitting fibers. Our approach highlights the importance of "ondemand" confinement as a tool to temporally stabilize transient species which modulate complex self-assembly pathways in supramolecular polymerization.

Self-Assembly and Aggregation-Induced Emission in Aqueous Media of Responsive Luminescent Copper(I) Coordination Polymer Nanoparticles.

Luminescent copper(I)-based compounds have recently attracted much attention since they can reach very high emission quantum yields. Interestingly, Cu(I) clusters can also be emissive, and the extension from small molecules to larger architecture could represent the first step towards novel materials that could be obtained by programming the units to undergo self-assembly. However, for Cu(I) compounds the formation of supramolecular systems is challenging due to the coordinative diversity of copper centers. This works shows that this diversity can be exploited in the construction of responsive systems. In detail, the changes in the emissive profile of different aggregates formed in water by phosphine-thioether copper(I) derivatives were followed. Our results demonstrate that the self-assembly and disassembly of Cu(I)-based coordination polymeric nanoparticles (CPNs) is sensitive to solvent composition. The solvent-induced changes are related to modifications in the coordination sphere of copper at the molecular level, which alters not only the emission profile but also the morphology of the aggregates. Our findings are expected to inspire the construction of smart supramolecular systems based on dynamic coordinative metal centers.

Surface functionalization of zeolite-based drug delivery systems enhances their antitumoral activity in vivo.

Zeolites have attractive features making them suitable carriers for drug delivery systems (DDS). As such, we loaded the anticancer drug 5-fluorouracil (5-FU), into two different zeolite structures, faujasite (NaY) and Linde Type L (LTL), to obtain different DDS. The prepared DDS were tested in vitro using breast cancer, colorectal carcinoma, and melanoma cell lines and in vivo using the chick embryo chorioallantoic membrane model (CAM). Both assays showed the best results for the Hs578T breast cancer cells, with a higher potentiation for 5-FU encapsulated in the zeolite LTL. To unveil the endocytic mechanisms involved in the internalization of the zeolite nanoparticles, endocytosis was inhibited pharmacologically in breast cancer and epithelial mammary human cells. The results suggest that a caveolin-mediated process was responsible for the internalized zeolite nanoparticles. Aiming to boost the DDS efficacy, the disc-shaped zeolite LTL outer surface was functionalized using amino (NH2) or carboxylic acid (COOH) groups and coated with poly-l-lysine (PLL). Positively functionalized surface LTL nanoparticles revealed to be non-toxic to human cells and, importantly, their internalization was faster and led to a higher tumor reduction in vivo. Overall, our results provide further insights into the mechanisms of interaction between zeolite-based DDS and cancer cells, and pave the way for future studies aiming to improve DDS anticancer activity.

Solvent-Driven Supramolecular Wrapping of Self-Assembled Structures.

Self-assembly relies on the ability of smaller and discrete entities to spontaneously arrange into more organized systems by means of the structure-encoded information. Herein, we show that the design of the media can play a role even more important than the chemical design. The media not only determines the self-assembly pathway at a single-component level, but in a very narrow solvent composition, a supramolecular homo-aggregate can be non-covalently wrapped by a second component that possesses a different crystal lattice. Such a process has been followed in real time by confocal microscopy thanks to the different emission colors of the aggregates formed by two isolated PtII complexes. This coating is reversible and controlled by the media composition. Single-crystal X-ray diffraction and molecular simulations based on coarse-grained (CG) models allowed the understanding of the properties displayed by the different aggregates. Such findings could result in a new method to construct hierarchical supramolecular structures.