Large-Scale Synthesis of Hybrid Conductive Polymer-Gold Nanoparticles Using "Sacrificial" Weakly Binding Ligands for Printing Electronics.

We describe the gram-scale synthesis of hybrid gold nanoparticles with a shell of conductive polymers. A large-scale synthesis of hexadecyltrimethylammonium bromide (CTAB)-capped gold nanoparticles (AuNP@CTAB) was followed by ligand exchange with conductive polymers based on thiophene in a 10 L reactor equipped with a jacket to ensure a constant temperature of 40 °C and a mechanical stirrer. Slow and controlled reduction of the gold precursors and the presence of small amounts of silver nitrate are revealed to be the critical synthesis variables to obtain particles with a sufficiently narrow size distribution. Batches of approximately 10 g of faceted AuNP@CTAB with tunable average particle sizes from 54 to 85 nm were obtained per batch. Ligand exchange with poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) in the same reactor then yielded hybrid Au@PEDOT:PSS nanoparticles. They were used to formulate sinter-free inks for the inkjet printing of conductive structures without the need for a sintering step.

Reversible Conductive Inkjet Printing of Healable and Recyclable Electrodes on Cardboard and Paper.

Conductive inkjet printing with metal nanoparticles is irreversible because the particles are sintered into a continuous metal film. The resulting structures are difficult to remove or repair and prone to cracking. Here, a hybrid ink is used to obviate the sintering step and print interconnected particle networks that become highly conductive immediately after drying. It is shown that reversible conductive printing is possible on low-cost cardboard samples after applying standard paper industry coats that are adapted in terms of surface energy and porosity. The conductivity of the printed films approaches that of sintered standard inks on the same substrate, but the mobility of the hybrid particle film makes them less sensitive to cracks during bending and folding of the substrate. Damages that occur can be partially repaired by wetting the film such that particle mobility is increased and particles move to bridge insulating gaps in the film. It is demonstrated that the conductive material can be recovered from the cardboard at the end of its life time and be redispersed to recycle the particles and reuse them in conductive inks.

Development of Silica-Based Biodegradable Submicrometric Carriers and Investigating Their Characteristics as in Vitro Delivery Vehicles.

Nanostructured silica (SiO2)-based materials are attractive carriers for the delivery of bioactive compounds into cells. In this study, we developed hollow submicrometric particles composed of SiO2 capsules that were separately loaded with various bioactive molecules such as dextran, proteins, and nucleic acids. The structural characterization of the reported carriers was conducted using transmission and scanning electron microscopies (TEM/SEM), confocal laser scanning microscopy (CLSM), and dynamic light scattering (DLS). Moreover, the interaction of the developed carriers with cell lines was studied using standard viability, proliferation, and uptake assays. The submicrometric SiO2-based capsules loaded with DNA plasmid encoding green fluorescence proteins (GFP) were used to transfect cell lines. The obtained results were compared with studies made with similar capsules composed of polymers and show that SiO2-based capsules provide better transfection rates on the costs of higher toxicity.

Laterally and Temporally Controlled Intracellular Staining by Light-Triggered Release of Encapsulated Fluorescent Markers.

Fluorescent molecular markers were encapsulated. The capsules were additionally modified with plasmonic nanoparticles. The encapsulated markers were endocytosed by cells. Upon light stimulation the plasmonic nanoparticles generated heat, which opened the encapsulation and transiently perforated the endosomal/lysosomal membrane surrounding the capsule, thus allowing for release of the marker into the cytosol. Fluorescence labeling of different intracellular compartments was demonstrated in this way. Most important, the cells do not need to be fixed and perforated, as the molecular markers are introduced into cells by endocytosis and subsequent light-induced release. Thus this technique allows for intracellular fluorescence labeling of living cells.

Comprehensive and Systematic Analysis of the Immunocompatibility of Polyelectrolyte Capsules.

The immunocompability of polyelectrolyte capsules synthesized by layer-by-layer deposition has been investigated. Capsules of different architecture and composed of either non-degradable or biodegradable polymers, with either positively or negatively charged outer surface, and with micrometer size, have been used, and the capsule uptake by different cell lines has been studied and quantified. Immunocompatibility studies were performed with peripheral blood mononuclear cells (PBMCs). Data demonstrate that incubation with capsules, at concentrations relevant for practical applications, did not result in a reduced viability of cells, as it did not show an increased apoptosis. Presence of capsules also did not result in an increased expression of TNF-α, as detected with antibody staining, as well as at mRNA level. It also did not result in increased expression of IL-6, as detected at mRNA level. These results indicate that the polyelectrolyte capsules used in this study are immunocompatible.

Gold-Based Nanomaterials for Applications in Nanomedicine.

In this review, an overview of the current state-of-the-art of gold-based nanomaterials (Au NPs) in medical applications is given. The unique properties of Au NPs, such as their tunable size, shape, and surface characteristics, optical properties, biocompatibility, low cytotoxicity, high stability, and multifunctionality potential, among others, make them highly attractive in many aspects of medicine. First, the preparation methods for various Au NPs including functionalization strategies for selective targeting are summarized. Second, recent progresses on their applications, ranging from the diagnostics to therapeutics are highlighted. Finally, the rapidly growing and promising field of gold-based theranostic nano-platforms is discussed. Considering the great body of existing information and the high speed of its renewal, we chose in this review to generalize the data that have been accumulated during the past few years for the most promising directions in the use of Au NPs in current medical research.

Microwave-assisted synthesis of biocompatible europium-doped calcium hydroxyapatite and fluoroapatite luminescent nanospindles functionalized with poly(acrylic acid).

Europium-doped calcium hydroxyapatite and fluoroapatite nanophosphors functionalized with poly(acrylic acid) (PAA) have been synthesized through a one-pot microwave-assisted hydrothermal method from aqueous basic solutions containing calcium nitrate, sodium phosphate monobasic, and PAA, as well as sodium fluoride in the case of the fluoroapatite particles. In both cases a spindlelike morphology was obtained, resulting from an aggregation process of smaller subunits which also gave rise to high specific surface area. The size of the nanospindles was 191 (32) × 40 (5) nm for calcium hydroxyapatite and 152 (24) × 38 (6) nm for calcium fluoroapatite. The luminescent nanoparticles showed the typical red luminescence of Eu(3+), which was more efficient for the fluoroapatite particles than for the hydroxyapatite. This is attributed to the presence of OH(-) quenchers in the latter. The nanophosphors showed negligible toxicity for Vero cells. Both PAA-functionalized nanophosphors showed a very high (up to at least 1 week) colloidal stability in 2-(N-morpholino)ethanesulfonic acid (MES) at pH 6.5, which is a commonly used buffer for physiological pH. All these features make both kinds of apatite-based nanoparticles promising tools for biomedical applications, such as luminescent biolabels and tracking devices in drug delivery systems.

Biodegradable particles for protein delivery: Estimation of the release kinetics inside cells.

A methodology to quantify the efficiency of the protein loading and in-vitro delivery for biodegradable capsules with different architectures based on polyelectrolytes (dextran sulfate, poly-L-arginine and polyethylenimine) and SiO2 was developed. The capsules were loaded with model proteins such as ovalbumin and green fluorescent protein (GFP), and the protein release profile inside cells (either macrophages or HeLa cells) after endocytosis was analysed. Both, protein loading and release kinetics were evaluated by analysing confocal laser scanning microscopy images using MatLab and CellProfiler software. Our results indicate that silica capsules showed the most efficient release of proteins as cargo molecules within 48 h, as compared to their polymeric counterparts. This developed method for the analysis of the intracellular cargo release kinetics from carrier structures could be used in the future for a better control of drug release profiles.

Confining Iron Oxide Nanocubes inside Submicrometric Cavities as a Key Strategy To Preserve Magnetic Heat Losses in an Intracellular Environment.

The design of magnetic nanostructures whose magnetic heating efficiency remains unaffected at the tumor site is a fundamental requirement to further advance magnetic hyperthermia in the clinic. This work demonstrates that the confinement of magnetic nanoparticles (NPs) into a sub-micrometer cavity is a key strategy to enable a certain degree of nanoparticle motion and minimize aggregation effects, consequently preserving the magnetic heat loss of iron oxide nanocubes (IONCs) under different conditions, including intracellular environments. We fabricated magnetic layer-by-layer (LbL) self-assembled polyelectrolyte sub-micrometer capsules using three different approaches, and we studied their heating efficiency as obtained in aqueous dispersions and after internalization by tumor cells. First, IONCs were added to the hollow cavities of LbL submicrocapsules, allowing the IONCs to move to a certain extent in the capsule cavities. Second, IONCs were coencapsulated into solid calcium carbonate cores coated with LbL polymer shells. Third, IONCs were incorporated within the polymer layers of the LbL capsule walls. In aqueous solution, higher specific absorption rate (SAR) values were related to those of free IONCs, while lower SAR values were recorded for capsule/core assemblies. However, after uptake by cancer cell lines (SKOV-3 cells), the SAR values of the free IONCs were significantly lower than those observed for capsule/core assemblies, especially after prolonged incubation periods (24 and 48 h). These results show that IONCs packed into submicrocavities preserve the magnetic losses, as the SAR values remained almost invariable. Conversely, free IONCs without the protective capsule shell agglomerated and their magnetic losses were strongly reduced. Indeed, IONC-loaded capsules and free IONCs reside inside endosomal and lysosomal compartments after cellular uptake and show strongly reduced magnetic losses due to the immobilization and aggregation in centrosymmetrical structures in the intracellular vesicles. The confinement of IONCs into sub-micrometer cavities is a key strategy to provide a sustained and predictable heating dose inside biological matrices.

Photoluminescence quenching of dye molecules near a resonant silicon nanoparticle.

Luminescent molecules attached to resonant colloidal particles are an important tool to study light-matter interaction. A traditional approach to enhance the photoluminescence intensity of the luminescent molecules in such conjugates is to incorporate spacer-coated plasmonic nanoantennas, where the spacer prevents intense non-radiative decay of the luminescent molecules. Here, we explore the capabilities of an alternative platform for photoluminescence enhancement, which is based on low-loss Mie-resonant colloidal silicon particles. We demonstrate that resonant silicon particles of spherical shape are more efficient for photoluminescence enhancement than their plasmonic counterparts in spacer-free configuration. Our theoretical calculations show that significant enhancement originates from larger quantum yields supported by silicon particles and their resonant features. Our results prove the potential of high-index dielectric particles for spacer-free enhancement of photoluminescence, which potentially could be a future platform for bioimaging and nanolasers.

Europium-doped NaGd(WO4)2 nanophosphors: synthesis, luminescence and their coating with fluorescein for pH sensing.

Uniform Eu-doped NaGd(WO4)2 nanophosphors with a spherical shape have been synthesized for the first time by using a wet chemistry method based on a homogeneous precipitation process at low temperature (120 °C) in ethylene glycol/water mixtures. The obtained nanoparticles crystallized into the tetragonal structure and presented polycrystalline character. The europium content in such phosphors has been optimized through the analysis of the luminescence dynamics (lifetime measurements). By coating the Eu3+-doped wolframate based nanoparticles with fluorescein through a layer-by-layer (LbL) approach, a wide range (4-10) ratiometric pH-sensitive sensor has been developed, which uses the pH insensitive emission of Eu3+ as a reference.

Positioning metal-organic framework nanoparticles within the context of drug delivery - A comparison with mesoporous silica nanoparticles and dendrimers.

Nanotechnology enables the creation of delivery vehicles able to overcome physiologically imposed barriers, allowing new approaches for reducing the unwanted side effects of systemic delivery of drug, increasing targeting efficiency and so improving therapy efficacy. Owing to the considerable advances in material sciences and pharmaceutics, a broad range of different inorganic or organic drug nanocarriers have been developed. Furthermore, researchers have shown that the combination of inorganic and organic chemistries in one single material, named metal-organic framework (MOF), offers structural designability at the molecular level together with tunable porosity and chemical functionalisability. While the MOF size can be controlled at the nanometer scale, these features are of paramount interest in the development of the next generation of drug delivery systems. After a short state-of-the-art about MOF technology and within the drug delivery context, this paper discusses the benefits of using MOF nanoparticles compared to dendrimers and mesoporous silica nanoparticles in order to understand the challenges that must still be overcome.

Diverse Applications of Nanomedicine.

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

Luminescent Rare-earth-based Nanoparticles: A Summarized Overview of their Synthesis, Functionalization, and Applications.

Rare-earth-based nanoparticles are currently attracting wide research interest in material science, physics, chemistry, medicine, and biology due to their optical properties, their stability, and novel applications. We present in this review a summarized overview of the general and recent developments in their synthesis and functionalization. Their luminescent properties are also discussed, including the latest advances in the enhancement of their emission luminescence. Some of their more relevant and novel biomedical, analytical, and optoelectronic applications are also commented on.

Synthesis and functionalization of monodisperse near-ultraviolet and visible excitable multifunctional Eu(3+), Bi(3+):REVO4 nanophosphors for bioimaging and biosensing applications.

Near-ultraviolet and visible excitable Eu- and Bi-doped NPs based on rare earth vanadates (REVO4, RE = Y, Gd) have been synthesized by a facile route from appropriate RE precursors, europium and bismuth nitrate, and sodium orthovanadate, by homogeneous precipitation in an ethylene glycol/water mixture at 120 °C. The NPs can be functionalized either by a one-pot synthesis with polyacrylic acid (PAA) or by a Layer-by-Layer approach with poly(allylamine hydrochloride) (PAH) and PAA. In the first case, the particle size can also be tuned by adjusting the amount of PAA. The Eu- Bi-doped REVO4 based nanophosphors show the typical red luminescence of Eu(iii), which can be excited through an energy transfer process from the vanadate anions, resulting in a much higher luminescence intensity in comparison to the direct excitation of the europium cations. The incorporation of Bi into the REVO4 structure shifts the original absorption band of the vanadate anions towards longer wavelengths, giving rise to nanophosphors with an excitation maximum at 342 nm, which can also be excited in the visible range. The suitability of such nanophosphors for bioimaging and biosensing applications, as well as their colloidal stability in different buffer media of biological interest, their cytotoxicity, their degradability at low pH, and their uptake by HeLa cells have been evaluated. Their suitability for bioimaging and biosensing applications is also demonstrated.

Quantitative uptake of colloidal particles by cell cultures.

The use of nanotechnologies involving nano- and microparticles has increased tremendously in the recent past. There are various beneficial characteristics that make particles attractive for a wide range of technologies. However, colloidal particles on the other hand can potentially be harmful for humans and environment. Today, complete understanding of the interaction of colloidal particles with biological systems still remains a challenge. Indeed, their uptake, effects, and final cell cycle including their life span fate and degradation in biological systems are not fully understood. This is mainly due to the complexity of multiple parameters which need to be taken in consideration to perform the nanosafety research. Therefore, we will provide an overview of the common denominators and ideas to achieve universal metrics to assess their safety. The review discusses aspects including how biological media could change the physicochemical properties of colloids, how colloids are endocytosed by cells, how to distinguish between internalized versus membrane-attached colloids, possible correlation of cellular uptake of colloids with their physicochemical properties, and how the colloidal stability of colloids may vary upon cell internalization. In conclusion three main statements are given. First, in typically exposure scenarios only part of the colloids associated with cells are internalized while a significant part remain outside cells attached to their membrane. For quantitative uptake studies false positive counts in the form of only adherent but not internalized colloids have to be avoided. pH sensitive fluorophores attached to the colloids, which can discriminate between acidic endosomal/lysosomal and neutral extracellular environment around colloids offer a possible solution. Second, the metrics selected for uptake studies is of utmost importance. Counting the internalized colloids by number or by volume may lead to significantly different results. Third, colloids may change their physicochemical properties along their life cycle, and appropriate characterization is required during the different stages.

Association of human herpesvirus type 6 DNA with human bladder cancer.

We examined the presence of human herpesvirus type 6 (HHV6) DNA in a series of 74 bladder carcinomas from a Mediterranean population to elucidate their possible role as cofactor in the development of bladder cancer with or without associated human papillomavirus (HPV) infection. HHV-6 type B DNA was present in 5 men (6.8%) out of the 74 tumors investigated; two of them had associated HPV-16 DNA in the same specimen. In one case that had associated urothelial carcinoma in situ, both HHV-6B and HPV-16 DNA were present. In conclusion, the low incidence of HHV-6B in bladder cancer and the ubiquitous nature of HHV-6 infection are more consistent with a bystander role rather than cofactor in the oncogenesis of bladder cancer.