Developing future nanomedicines.

Quantitative analysis of biodistribution and clearance may improve nanoparticle development.

The use of a complex tetra-culture alveolar model to study the biological effects induced by gold nanoparticles with different physicochemical properties.

A substantial increase in engineered nanoparticles in consumer products has been observed, heightening human and environmental exposure. Inhalation represents the primary route of human exposure, necessitating a focus on lung toxicity studies. However, to avoid ethical concerns the use of in vitro models is an efficient alternative to in vivo models. This study utilized an in vitro human alveolar barrier model at air-liquid-interface with four cell lines, for evaluating the biological effects of different gold nanoparticles. Exposure to PEGylated gold nanospheres, nanorods, and nanostars did not significantly impact viability after 24 h, yet all AuNPs induced cytotoxicity in the form of membrane integrity impairment. Gold quantification revealed cellular uptake and transport. Transcriptomic analysis identified gene expression changes, particularly related to the enhancement of immune cells. Despite limited impact, distinct effects were observed, emphasizing the influence of nanoparticles physicochemical parameters while demonstrating the model's efficacy in investigating particle biological effects.

Uptake and Intracellular Fate of Fluorophore Labeled Metal-Organic-Framework (MOF) Nanoparticles.

The uptake and the fate of Zr-based metal-organic-framework nanoparticles labeled with organic fluorophores in HeLa cells has been monitored with fluorescence detection and elemental analysis. The nanoparticles have been selected as a model system of carrier nanoparticles (here Zr-based metal-organic-framework nanoparticles) with integrated cargo molecules (here organic fluorophores), with aze that does not allow for efficient exocytosis, a material which only partly degrades under acidic conditions as present in endosomes/lysosomes, and with limited colloidal stability. Data show that, for Zr-based metal-organic-framework nanoparticles of 40 nm size as investigated here, the number of nanoparticles per cells decreases faster due to particle redistribution upon proliferation than due to nanoparticle exocytosis and that, thus, also for this system, exocytosis is not an efficient pathway for clearance of the nanoparticles from the cells.

Photodegradation of CuBi2 O4 Films Evidenced by Fast Formation of Metallic Bi using Operando Surface-sensitive X-ray Scattering.

CuBi2 O4 has recently emerged as a promising photocathode for photo-electrochemical (PEC) water splitting. However, its fast degradation under operation currently poses a limit to its application. Here, we report a novel method to study operando the semiconductor-electrolyte interface during PEC operation by surface-sensitive high-energy X-ray scattering. We find that a fast decrease in the generated photocurrents correlates directly with the formation of a metallic Bi phase. We further show that the slower formation of metallic Cu, as well as the dissolution of the electrode in contact with the electrolyte, further affect the CuBi2 O4 activity and morphology. Our study provides a comprehensive picture of the degradation mechanisms affecting CuBi2 O4 electrodes under operation and poses the methodological basis to investigate the photocorrosion processes affecting a wide range of PEC materials.

Local Environments Created by the Ligand Coating of Nanoparticles and Their Implications for Sensing and Surface Reactions.

ConspectusThe ligand shells of colloidal nanoparticles (NPs) can serve different purposes. In general, they provide colloidal stability by introducing steric repulsion between NPs. In the context of biological applications, the ligand shell plays a critical role in targeting, enabling NPs to achieve specific biodistributions. However, there is also another important feature of the ligand shell of NPs, namely, the creation of a local environment differing from the bulk of the solvent in which the NPs are dispersed. It is known that charged ligand shells can attract or repel ions and change the effective charge of a NP through Debye-Hückel screening. Positively charged ions, such as H+ (or H3O+) are attracted to negatively charged surfaces, whereas negatively charged ions, such as Cl- are repelled. The distribution of the ions around charged NP surfaces is a radial function of distance from the center of the NP, which is governed by a balance of electrostatic forces and entropy of ions and ligands. As a result, the ion concentration at the NP surface is different from its bulk equilibrium concentration, i.e., the charged ligand shell around the NPs has formed a distinct local environment. This not only applies to charged ligand shells but also follows a more general principle of induced condensation and depletion. Polar/apolar ligand shells, for example, result in a locally increased concentration of polar/apolar molecules. Similar effects can be seen for biocatalysts like enzymes immobilized in nanoporous host structures, which provide a special environment due to their surface chemistry and geometrical nanoconfinement. The formation of a local environment close to the ligand shell of NPs has profound implications for NP sensing applications. As a result, analyte concentrations close to the ligand shell, which are the ones that are measured, may be very different from the analyte concentrations in bulk. Based on previous work describing this effect, it will be discussed herein how such local environments, created by the choice of used ligands, may allow for tailoring the NPs' sensing properties. In general, the ligand shell around NPs can be attractive/repulsive for molecules with distinct properties and thus forms an environment that can modulate the specific response. Such local environments can also be optimized to modulate chemical reactions close to the NP surface (for example, by size filtering within pores) or to attract specific low abundance proteins. The importance hereby is that this is based on interaction with low selectivity between the ligands and the target molecules.

A Comparative Study of Ultrasmall Calcium Carbonate Nanoparticles for Targeting and Imaging Atherosclerotic Plaque.

Atherosclerosis is a complex disease that can lead to life-threatening events, such as myocardial infarction and ischemic stroke. Despite the severity of this disease, diagnosing plaque vulnerability remains challenging due to the lack of effective diagnostic tools. Conventional diagnostic protocols lack specificity and fail to predict the type of atherosclerotic lesion and the risk of plaque rupture. To address this issue, technologies are emerging, such as noninvasive medical imaging of atherosclerotic plaque with customized nanotechnological solutions. Modulating the biological interactions and contrast of nanoparticles in various imaging techniques, including magnetic resonance imaging, is possible through the careful design of their physicochemical properties. However, few examples of comparative studies between nanoparticles targeting different hallmarks of atherosclerosis exist to provide information about the plaque development stage. Our work demonstrates that Gd (III)-doped amorphous calcium carbonate nanoparticles are an effective tool for these comparative studies due to their high magnetic resonance contrast and physicochemical properties. In an animal model of atherosclerosis, we compare the imaging performance of three types of nanoparticles: bare amorphous calcium carbonate and those functionalized with the ligands alendronate (for microcalcification targeting) and trimannose (for inflammation targeting). Our study provides useful insights into ligand-mediated targeted imaging of atherosclerosis through a combination of in vivo imaging, ex vivo tissue analysis, and in vitro targeting experiments.

Preparation of Selenium-Based Drug-Modified Polymeric Ligand-Functionalised Fe3O4 Nanoparticles as Multimodal Drug Carrier and Magnetic Hyperthermia Inductor.

In recent years, much effort has been invested into developing multifunctional drug delivery systems to overcome the drawbacks of conventional carriers. Magnetic nanoparticles are not generally used as carriers but can be functionalised with several different biomolecules and their size can be tailored to present a hyperthermia response, allowing for the design of multifunctional systems which can be active in therapies. In this work, we have designed a drug carrier nanosystem based on Fe3O4 nanoparticles with large heating power and 4-amino-2-pentylselenoquinazoline as an attached drug that exhibits oxidative properties and high selectivity against a variety of cancer malignant cells. For this propose, two samples composed of homogeneous Fe3O4 nanoparticles (NPs) with different sizes, shapes, and magnetic properties have been synthesised and characterised. The surface modification of the prepared Fe3O4 nanoparticles has been developed using copolymers composed of poly(ethylene-alt-maleic anhydride), dodecylamine, polyethylene glycol and the drug 4-amino-2-pentylselenoquinazoline. The obtained nanosystems were properly characterised. Their in vitro efficacy in colon cancer cells and as magnetic hyperthermia inductors was analysed, thereby leaving the door open for their potential application as multimodal agents.

Enabling X-ray fluorescence imaging for in vivo immune cell tracking.

The infiltration of immune cells into sites of inflammation is one key feature of immune mediated inflammatory diseases. A detailed assessment of the in vivo dynamics of relevant cell subtypes could booster the understanding of this disease and the development of novel therapies. We show in detail how advanced X-ray fluorescence imaging enables such quantitative in vivo cell tracking, offering solutions that could pave the way beyond what other imaging modalities provide today. The key for this achievement is a detailed study of the spectral background contribution from multiple Compton scattering in a mouse-scaled object when this is scanned with a monochromatic pencil X-ray beam from a synchrotron. Under optimal conditions, the detection sensitivity is sufficient for detecting local accumulations of the labelled immune cells, hence providing experimental demonstration of in vivo immune cell tracking in mice.

Synthesizing Submicron Polyelectrolyte Capsules to Boost Enzyme Immobilization and Enhance Enzyme-Based Immunoassays.

Polyelectrolyte capsules (PCs) exhibit attractive superiorities in enzyme immobilization, including providing a capacious microenvironment for enzyme conformational freedom, highly effective mass transfer, and protecting enzymes from the external environment. Herein, we provide the first systemic evaluation of submicron PCs (SPCs, 500 nm) for enzyme immobilization. The catalytic kinetics results show that SPC encapsulation affected the affinities of enzymes and substrates but significantly enhanced their catalytic activity. The stability test indicates that SPC-encapsulated horseradish peroxidase (HRP) exhibits ultrahigh resistance to external harsh conditions and has a longer storage life than that of soluble HRP. The proposed encapsulation strategy enables 7.73-, 2.22-, and 11.66-fold relative activities when working at a pH as low as 3, at a NaCl concentration as high as 500 mM, and at a trypsin concentration as high as 10 mg/mL. We find that SPC encapsulation accelerates the cascade reaction efficiency of HRP and glucose oxidase. Owing to SPCs enhancing the catalytic activity of the loaded enzymes, we established an amplified enzyme-linked immunosorbent assay (ELISA) for the detection of Escherichia coli O157:H7 using HRP-loaded SPCs. The detection sensitivity of SPC-improved ELISA was found to be 280 times greater than that of conventional HRP-based ELISA. Altogether, we provide an elaborate evaluation of 500 nm SPCs on enzyme immobilization and its application in the ultrasensitive detection of foodborne pathogens. This evaluation provides evidence to reveal the potential advantage of SPCs on enzyme immobilization for enzyme-based immunoassays. It has excellent biological activity and strong stability and broadens the application prospect in urine, soy sauce, sewage, and other special samples.

Variations in Biodistribution and Acute Response of Differently Shaped Titania Nanoparticles in Healthy Rodents.

Titanium dioxide nanoparticles (TiO2 NPs) are one of the main sources of the nanoparticulate matter exposure to humans. Although several studies have demonstrated their potential toxic effects, the real nature of the correlation between NP properties and their interaction with biological targets is still far from being fully elucidated. Here, engineered TiO2 NPs with various geometries (bipyramids, plates, and rods) have been prepared, characterized and intravenously administered in healthy mice. Parameters such as biodistribution, accumulation, and toxicity have been assessed in the lungs and liver. Our data show that the organ accumulation of TiO2 NPs, measured by ICP-MS, is quite low, and this is only partially and transiently affected by the NP geometries. The long-lasting permanence is exclusively restricted to the lungs. Here, bipyramids and plates show a higher accumulation, and interestingly, rod-shaped NPs are the most toxic, leading to histopathological pulmonary alterations. In addition, they are also able to induce a transient increase in serum markers related to hepatocellular injury. These results indicate that rods, more than bipyramidal and spherical geometries, lead to a stronger and more severe biological effect. Overall, small physico-chemical differences can dramatically modify both accumulation and safety.

Design of disintegrable nanoassemblies to release multiple small-sized nanoparticles.

The therapeutic and diagnostic effects of nanoparticles highly depend on the efficiency of their delivery to targeted tissues, such as tumors. The size of nanoparticles, among other characteristics, plays a crucial role in determining their tissue penetration and retention. Small nanoparticles may penetrate deeper into tumor parenchyma but are poorly retained, whereas large ones are distributed around tumor blood vessels. Thus, compared to smaller individual nanoparticles, assemblies of such nanoparticles due to their larger size are favorable for prolonged blood circulation and enhanced tumor accumulation. Upon reaching the targeted tissues, nanoassemblies may dissociate at the target region and release the smaller nanoparticles, which is beneficial for their distribution at the target site and ultimate clearance. The recent emerging strategy that combines small nanoparticles into larger, biodegradable nanoassemblies has been demonstrated by several groups. This review summarizes a variety of chemical and structural designs for constructing stimuli-responsive disintegrable nanoassemblies as well as their different disassembly routes. These nanoassemblies have been applied as demonstrators in the fields of cancer therapy, antibacterial infection, ischemic stroke recovery, bioimaging, and diagnostics. Finally, we summarize stimuli-responsive mechanisms and their corresponding nanomedicine designing strategies, and discuss potential challenges and barriers towards clinical translation.

Structural Analysis and Intrinsic Enzyme Mimicking Activities of Ligand-Free PtAg Nanoalloys.

Nanozymes are nanomaterials with biocatalytic properties under physiological conditions and are one class of artificial enzymes to overcome the high cost and low stability of natural enzymes. However, surface ligands on nanomaterials will decrease the catalytic activity of the nanozymes by blocking the active sites. To address this limitation, ligand-free PtAg nanoclusters (NCs) are synthesized and applied as nanozymes for various enzyme-mimicking reactions. By taking advantage of the mutual interaction of zeolitic imidazolate frameworks (ZIF-8) and Pt precursors, a good dispersion of PtAg bimetal NCs with a diameter of 1.78 ± 0.1 nm is achieved with ZIF-8 as a template. The incorporation of PtAgNCs in the voids of ZIF-8 is confirmed with structural analysis using the atomic pair-distribution function and powder X-ray diffraction. Importantly, the PtAgNCs present good catalytic activity for various enzyme-mimicking reactions, including peroxidase-/catalase- and oxidase-like reactions. Further, this work compares the catalytic activity between PtAg NCs and PtAg nanoparticles with different compositions and finds that these two nanozymes present a converse dependency of Ag-loading on their activity. This study contributes to the field of nanozymes and presents a potential option to prepare ligand-free bimetal biocatalysts with sizes in the nanocluster regime.

Bioinspired Polyethylene Glycol Coatings for Reduced Nanoparticle-Protein Interactions.

Nanoparticles (NPs) and other engineered nanomaterials have great potential as nanodrugs or nanomedical devices for biomedical applications. However, the adsorption of proteins in blood circulation or similar physiological fluids can significantly alter the surface properties and therapeutic response induced by most nanomaterials. For example, interaction with proteins can change the bloodstream circulation time and availability of therapeutic NPs or hinder the accumulation in their desired target organs. Proteins can also trigger or prevent agglomeration. By combining experimental and computational approaches, we have developed NPs carrying polyethylene glycol (PEG) polymeric coatings that mimic the surface charge distribution of proteins typically found in blood, which are known to show low aggregation under normal blood conditions. Here, we show that NPs with coatings based on apoferritin or human serum albumin display better antifouling properties and weaker protein interaction compared to similar NPs carrying conventional PEG polymeric coatings.

Quantitative Comparison of Gold Nanoparticle Delivery via the Enhanced Permeation and Retention (EPR) Effect and Mesenchymal Stem Cell (MSC)-Based Targeting.

There are still some gaps in existing knowledge in the field of cancer nanotheranostics, e.g., the efficiency of nanoparticle-loaded cells for targeted delivery. In the current study, gold nanoparticles (Au NPs) were delivered to tumors in both subcutaneous tumor and lung metastasis tumor models by intravenous injection of either free Au NPs or of human bone marrow mesenchymal stem cells (MSCs), which were loaded with endocytosed Au NPs. By making injections with the same dose of administrated Au NPs, it was possible to directly compare tumor targeting of both delivery modes. Hereby, the passive targeting of tumor by the plain Au NPs was facilitated by the enhanced permeation and retention (EPR) effect. Au NP retention by tumors, as well as tumor penetration, were found to be improved up to 2.4-to-9.3-fold when comparing the MSC-mediated delivery of Au NPs to the delivery of the plain Au NPs via EPR effect on day 7 post administration. While the absolute retention of Au NPs in the tumor remained low, our data show that, upon injection of the same amount of Au NPs, in fact MSC-mediated delivery is quantitatively higher than EPR-mediated delivery of NPs by half an order of magnitude.

Plasmonic hot carrier injection from single gold nanoparticles into topological insulator Bi2Se3 nanoribbons.

Plasmonic gold nanoparticles injecting hot carriers into the topological insulator (TI) interface of Bi2Se3 nanoribbons are studied by resonant Raman spectroscopy. We resolve the impact of individual gold particles with sizes ranging from 140 nm down to less than 40 nm on the topological surface states of the nanoribbons. In resonance at 1.96 eV (633 nm), we find distinct phonon renormalization in the Eg2- and A1g2-modes that can be associated with plasmonic hot carrier injection. The phonon modes are strongly enhanced by a factor of 350 when tuning the excitation wavelengths into interband transition and in resonance with the surface plasmon of gold nanoparticles. At 633 nm wavelength, a plasmonic enhancement factor of 18 is observed indicating a contribution of hot carriers injected from the gold nanoparticles into the TI interface. Raman studies as a function of gold nanoparticle size reveal the strongest hot carrier injection for particles with size of 108 nm in agreement with the resonance energy of its surface plasmon. Hot carrier injection opens the opportunity to locally control the electronic properties of the TI by metal nanoparticles attached to the surface of nanoribbons.