Wolfgang G Kreyling

• Dr. rer. nat. Dipl. Phys.
• Consultant at Helmholtz Zentrum München - National Research Center for Environmental Health

Holistic deciphering of spatially-resolved delivery and biokinetics of nanoparticles (NPs) in the lung, along with the mobility of tissue-resident macrophages (TRMs) and their role in regulating NP cellular fate, remains unclear. Multimodal imaging and deep learning were applied to elucidate the longitudinal inter- and intra-acinar deposition featu...

Pulmonary delivery is not only of increasing importance to exploit local therapy for lung diseases like COVID-19, but also plays an essential role in interpreting health impact of inhaled hazardous (nano-)materials. Deciphering of biodistribution, biokinetics, and cell-mediated immunity of pulmonary delivered nanoparticles (NPs) remains insufficien...

Background Physiologically based pharmacokinetic (PBPK) modeling is an important tool in predicting target organ dosimetry and risk assessment of nanoparticles (NPs). The methodology of building a multi-route PBPK model for NPs has not been established, nor systematically evaluated. In this study, we hypothesized that the traditional route-to-route...

Background: There is a steadily increasing quantity of silver nanoparticles (AgNP) produced for numerous industrial, medicinal and private purposes, leading to an increased risk of inhalation exposure for both professionals and consumers. Particle inhalation can result in inflammatory and allergic responses, and there are concerns about other nega...

In recent animal experiments with suspensions of radiolabeled TiO2 nanoparticles large and highly variable radioactivity fractions were retained in disposable plastic syringes. After unloading between 10% and up to 70% of the loaded dose were still present in the syringes. As a consequence the effectively delivered nanoparticle dose to the animals...

Background: Industrially produced quantities of TiO2 nanoparticles are steadily rising, leading to an increasing risk of inhalation exposure for both professionals and consumers. Particle inhalation can result in inflammatory and allergic responses, and there are concerns about other negative health effects from either acute or chronic low-dose ex...

After the publication of this article [1] it was hihglighted that the number of deaths related to natural disasters was incorrectly reported in the second paragraph of the Hazards from Natural particulates and the evolution of the biosphere section. This correction article shows the correct and incorrect statement. This correction does not change t...

Background Particles and fibres affect human health as a function of their properties such as chemical composition, size and shape but also depending on complex interactions in an organism that occur at various levels between particle uptake and target organ responses. While particulate pollution is one of the leading contributors to the global bur...

The increasing use of gold nanoparticles leads to a possible increase of exposure by inhalation. Therefore, we have studied the deposition patterns of inhaled 20-nm gold nanoparticles (AuNP) in 7 to 90 day old rats and their biokinetics in 60 day old ones. Wistar-Kyoto rats inhaled intratracheally 20-nm 195Au-radiolabeled AuNP by negative pressure...

Nanoparticle in vitro toxicity studies often report contradictory results with one main reason being insufficient material characterization. In particular the characterization of nanoparticles in biological media remains challenging. Our aim was to provide robust protocols for two of the most commonly applied techniques for particle sizing, i.e. dy...

Background We previously showed that cerium oxide (CeO2), barium sulfate (BaSO4) and zinc oxide (ZnO) nanoparticles (NPs) exhibited different lung toxicity and pulmonary clearance in rats. We hypothesize that these NPs acquire coronas with different protein compositions that may influence their clearance from the lungs. Methods CeO2, silica-coated...

BACKGROUND: A rich body of literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), and there is strong support for an important role of ultrafine (nanosized) particles. At present, relatively few human health or epidemiology data exist for engineered nanomaterials (NMs) despite...

Gold nanoparticles (AuNPs) have been extensively explored in biomedical applications, for example as drug carriers, contrast agents, or therapeutics. However, AuNP can exhibit cytotoxic profile, when the size is below 2 nm (ultrasmall AuNP; usAuNP) and when the stabilizing ligands allow for access to the gold surface either for the direct interacti...

To study the influence of colloidal stability on protein corona formation, gold nanoparticles are synthesized with five distinct surface modifications: coating with citric acid, bis(p-sulfonatophenyl)phenylphosphine dihydrate dipotassium salt, thiol-terminated methoxy-polyethylene glycol, dodecylamine-grafted poly(isobutylene-alt-maleic anhydride),...

Background The death toll associated with inhaled ambient particulate matter (PM) is attributed mainly to cardio-vascular rather than pulmonary effects. However, it is unclear whether the key event for cardiovascular impairment is particle translocation from lung to circulation (direct effect) or indirect effects due to pulmonary particle-cell inte...

Recently, interest for the potential impact of consumer-relevant engineered nanoparticles on pregnancy has dramatically increased. This study investigates whether inhaled silver nanoparticles (AgNPs) reach and cross mouse placental barrier and induce adverse effects. Apart from their relevance for the growing use in consumer products and biomedical...

Submicrometer TiO2 particles, including nanoparticulate fractions, are used in an increasing variety of consumer products, as food additives and drug delivery applications are envisaged. Beyond exposure of occupational groups this entails an exposure risk to the public. However, nanoparticle translocation from the organ of intake and potential accu...

The biokinetics of a size-selected fraction (70nm median size) of commercially available and (48)V-radiolabeled [(48)V]TiO2 nanoparticles has been investigated in healthy adult female Wistar-Kyoto rats at retention time-points of 1h, 4h, 24h, 7d and 28d after intratracheal instillation of a single dose of an aqueous [(48)V]TiO2-nanoparticle suspens...

The biokinetics of a size-selected fraction (70nm median size) of commercially available and ⁴⁸V-radiolabeled [⁴⁸V]TiO2 nanoparticles has been investigated in female Wistar-Kyoto rats at retention timepoints 1h, 4h, 24h and 7days after oral application of a single dose of an aqueous [⁴⁸V]TiO2-nanoparticle suspension by intra-esophageal instillation...

Background: A rich literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), with strong support for an important role for ultrafine (nano-sized) particles. At present, relatively little human health or epidemiology data exists for engineered nanomaterials (NM) despite clear par...

Biokinetics data of lung-administered PEI F25-LMW/siRNA polyplexes within different lung compartments are presented. Thereby, at three different timepoints (1h, 3h, 8h), the data was determined by calculations to the 32P-radioactivity in the whole mouse body. Additionally, data was optimized to the available PEI F25-LMW/siRNA polyplexes in the targ...

The biokinetics of inhaled nanoparticles (NP) is more complex than that of larger particles since NP may NP deposited on the nasal mucosa of the upper respiratory tract (URT) may translocate to the olfactory bulb of the brain and also via the trigeminus (URT neuronal route); and (b) NP deposited in the lower respiratory tract (LRT) may cross the AB...

Succesful gene therapy requires stability and sufficient bioavailability of the applied drug at the site of action. In the case of RNA interference (RNAi), non-viral vectors play a promising role for delivering intact siRNA molecules. We selected a low molecular weight polyethyleneimine (PEI F25-LMW) and investigated the biokinetics of PEI F25-LMW/...

ENPRA was one of the earlier multidisciplinary European Commission FP7-funded projects aiming to evaluate the risks associated with nanomaterial (NM) exposure on human health across pulmonary, cardiovascular, hepatic, renal, and developmental systems. The outputs from this project have formed the basis of this review. A retrospective interpretation...

Once inhaled, nanomaterials (particles and fibres) have a high probability of deposition in the lungs mainly by diffusion and to be transported throughout the body. The chemical composition and surface reactivity and dissolution rates are the driving forces for toxicity often starting with oxidative stress which can lead to inflammation, systemic e...

Inorganic nanoparticles are frequently engineered with an organic surface coating to improve their physicochemical properties, and it is well known that their colloidal properties may change upon internalization by cells. While the stability of such nanoparticles is typically assayed in simple in vitro tests, their stability in a mammalian organism...

The National Council on Radiation Protection and Measurements (NCRP) established NCRP Scientific Committee 2-6 to develop a report on the current state of knowledge and guidance for radiation safety programs involved with nanotechnology. Nanotechnology is the understanding and control of matter at the nanoscale, at dimensions between ∼1 and 100 nm,...

Precision-cut lung slices (PCLS) are an established ex vivo alternative to in vivo experiments in pharmacotoxicology. The aim of this study was to evaluate the potential of PCLS as a tool in nanotoxicology studies. Silver (Ag-NPs) and zinc oxide (ZnO-NPs) nanoparticles as well as quartz particles were used because these materials have been previous...

PVP-capped silver nanoparticles with a diameter of the metallic core of 70 nm, a hydrodynamic diameter of 120 nm and a zeta potential of -20 mV were prepared and investigated with regard to their biological activity. This review summarizes the physicochemical properties (dissolution, protein adsorption, dispersability) of these nanoparticles and th...

Background There is evidence that nanoparticles (NP) cross epithelial and endothelial body barriers. We hypothesized that gold (Au) NP, once in the blood circulation of pregnant rats, will cross the placental barrier during pregnancy size-dependently and accumulate in the fetal organism by 1. transcellular transport across the hemochorial placenta,...

When particles incorporated within a mammalian organism come into contact with body fluids they will bind to soluble proteins or those within cellular membranes forming what is called a protein corona. This binding process is very complex and highly dynamic due to the plethora of proteins with different affinities and fractions in different body fl...

Persons with cystic fibrosis (CF) are at-risk for health effects from ambient air pollution but little is known about the interaction of nanoparticles (NP) with CF lungs. Here we study the distribution of inhaled NP in a murine CF model and aim to reveal mechanisms contributing to adverse effects of inhaled particles in susceptible populations. Chl...

In order to calculate the dose for nanoparticles (NP), (i) relevant information about the dose metrics and (ii) a proper dose concept are crucial. Since the appropriate metrics for NP toxicity are yet to be elaborated, a general dose calculation model for nanomaterials is not available. Here we propose how to develop a dose assessment model for NP...

Gold nanoparticles (AuNP) provide many opportunities in imaging, diagnostics, and therapy in nanomedicine. For the assessment of AuNP biokinetics, we intratracheally instilled into rats a suite of 198Au-radio-labelled monodisperse, well-characterized, negatively-charged AuNP of five different sizes (1.4, 2.8, 5, 18, 80, 200 nm) and 2.8 nm AuNP with...

Silver nanoparticles (AgNP) are among the most promising nanomaterials, and their usage in medical applications and consumer products is growing rapidly. To evaluate possible adverse health effects, especially to the lungs, the current study focused on the cytotoxic and proinflammatory effects of AgNP after the intratracheal instillation in rats. M...

Abstract Determination of the respiratory tract deposition of airborne particles is critical for risk assessment of air pollution, inhaled drug delivery, and understanding of respiratory disease. With the advent of nanotechnology, there has been an increasing interest in the measurement of pulmonary deposition of nanoparticles because of their uniq...

Chronic rhinosinusitis (CRS) is a common chronic disease of the upper airways and has considerable impact on quality of life. Topical delivery of drugs to the paranasal sinuses is challenging, therefore the rate of surgery is high. This study investigates the delivery efficiency of a pulsating aerosol in comparison to a nasal pump spray to the sinu...

When nanoparticles (NP) enter the body they come into contact with body fluids containing proteins which can adsorb to their surface. These proteins may influence the NP interactions with the biological vicinity, eventually determining their biological fate inside the body. Adsorption of the most abundantly binding proteins was studied after an in...

Inhalative nanocarriers for local or systemic therapy are promising. Gold nanoparticles (AuNP) have been widely considered as candidate material. Knowledge about their interaction with the lungs is required, foremost their uptake by surface macrophages and epithelial cells. Diseased lungs are of specific interest, since these are the main recipient...

Airborne engineered nanoparticles undergo agglomeration, and careful distinction must be made between primary and agglomerate size of particles, when assessing their health effects. This study compares the effects on rats undergoing 15-day inhalation exposure to airborne agglomerates of gold nanoparticles (AuNPs) of similar size distribution and nu...

The intensive use of nano-sized particles in many different applications necessitates studies on their risk assessment as there are still open questions on their safe handling and utilization. For reliable risk assessment, the interaction of nanoparticles (NP) with biological systems after various routes of exposure needs to be investigated using w...

Carbon nanotubes (CNTs) represent promising vectors to facilitate cellular drug delivery and to overcome biological barriers, but some types may also elicit persistent pulmonary inflammation based on their fibre characteristics. Here, we show the pulmonary response to aqueous suspensions of block copolymer dispersed, double-walled carbon nanotubes...

The article of Gasser et al. [Part Fibre Toxicol. 24; 9:17, 2012] describes the interaction of carbon nanotubes with cells within a complex cell culture model. Besides various toxicity parameters, the influence of coating with pulmonary surfactant was investigated. Pulmonary surfactant covers the entire alveolar region with the main function of dec...

PARTICLE_RISK was one of the first multidisciplinary projects funded by the European Commission's Framework Programme that was responsible for evaluating the implications of nanomaterial (NM) exposure on human health. This project was the basis for this review which identifies the challenges that exist within the assessment of NM risk. We have retr...

With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation.Silver (Ag) NPs...

Researchers need to study the biokinetics of inhaled biopersistent nano- and micrometer-sized particles (NPs and μPs) to assess their toxicity and to develop an understanding of their potential risks. When particles are inhaled, they do not necessarily remain at their sites of deposition in the respiratory tract. Instead they can undergo numerous t...

Background: The pulmonary route is very promising for drug delivery by inhalation. In this regard, nanoparticulate drug delivery systems are discussed, and one very promising nano carrier example is gold nanoparticles (Au NP). Directly after their deposition, inhaled Au NP come into contact with pulmonary surfactant protein D (SP-D). SP-D can aggl...

To investigate the relationship of alveolar macrophages and inhaled nanoparticles (NPs) in the lung. Rats were exposed by inhalation to 16-nm gold NPs for 6 h, and ultramicroscopic observation on the frequency and localization of gold NPs within lavaged macrophages was performed for 7 days. The majority of macrophages examined on day 0 (94%) contai...

The lung surface is an ideal pathway to the bloodstream for nanoparticle-based drug delivery. Thus far, research has focused on the lungs of adults, and little is known about nanoparticle behavior in the immature lungs of infants. Here, using nonlinear dynamical systems analysis and in vivo experimentation in developing animals, we show that nanopa...

The introduction of engineered nanostructured materials into a rapidly increasing number of industrial and consumer products will result in enhanced exposure to engineered nanoparticles. Workplace exposure has been identified as the most likely source of uncontrolled inhalation of engineered aerosolized nanoparticles, but release of engineered nano...

To access the risks and chances of deposition of submicron particles in the gas-exchange area of the lung, a precise three-dimensional (3D)-localization of the sites of deposition is essential--especially because local peaks of deposition are expected in the acinar tree and in individual alveoli. In this study we developed the workflow for such an...

The International Alliance for NanoEHS Harmonization (IANH) organises interlaboratory comparisons of methods used to study the potential biological impacts of nanomaterials. The aim of IANH is to identify and reduce or remove sources of variability and irreproducibility in existing protocols. Here, we present results of the first IANH round robin s...

We present in this article an outline of some cyclotron-based irradiation techniques that can be used to directly radiolabel industrially manufactured nanoparticles, as well as two techniques for synthesis of labelled nanoparticles using cyclotron-generated radioactive precursor materials. These radiolabelled nanoparticles are suitable for a range...

Once inhaled, nanoparticles (NP) deposit on the lung surface and have first contact with the epithelial lung lining fluid (ELF) rich in proteins, which may bind to NP. In this study, we investigate the parameters that influence the binding between NP and proteins. We used the proteins albumin, transferrin (TF), and apolipoprotein A-1 (all known as...

IntroductionNP DosimetrySummaryAcknowledgmentsReferences

Inhalation of fine particulate matter (<2.5 μm; fine PM) has been shown to increase the risk for cardiovascular events. In this letter, we reappraise the role of tissue factor (TF) antigen and we also summarize changes in measured coagulation proteins in humans and rodents by other studies with fine PM. By considering all studies including ours, we...

For imaging with different modalities, labels, which provide contrast for all modalities, are required. Colloidal nanoparticles composed out of an inorganic core and a polymer shell offer progress in this direction. Both, the core and the polymer shell, can be synthesized to be fluorescent, magnetic, or radioactive. When different cores are combine...

This paper presents the outcomes from a workshop of the European Network on the Health and Environmental Impact of Nanomaterials (NanoImpactNet). During the workshop, 45 experts in the field of safety assessment of engineered nanomaterials addressed the need to systematically study sets of engineered nanomaterials with specific metrics to generate...

The intensive use of nano-sized titanium dioxide (TiO2) particles in many different applications necessitates studies on their risk assessment as there are still open questions on their safe handling and utilization. For reliable risk assessment, the interaction of TiO2 nanoparticles (NP) with biological systems ideally needs to be investigated usi...

It is of urgent need to identify the exact physico-chemical characteristics which allow maximum uptake and accumulation in secondary target organs of nanoparticulate drug delivery systems after oral ingestion. We administered radiolabelled gold nanoparticles in different sizes (1.4-200 nm) with negative surface charge and 2.8 nm nanoparticles with...

1.1 Epidemiological evidence A growing body of epidemiological studies have shown consistent associations between the exposure to particulate air pollution in urban areas and acute increases

With the expected increase in the applications of nanotechnology, more and more products will be manufactured containing components which will fit the commonly used definition of the nanoscale, as having a size between approximately 1 and 100 nanometre. There is no scientific evidence in favour of a single upper limit. Moreover, there is no scienti...

Gold nanoparticles (GNP) provide many opportunities in imaging, diagnostics, and therapies of nanomedicine. Hence, their biokinetics in the body are prerequisites for specific tailoring of nanomedicinal applications and for a comprehensive risk assessment. We administered (198)Au-radio-labelled monodisperse, negatively charged GNP of five different...

The pulmonary route is very attractive for drug delivery by inhalation. In this regard, nanoparticulate drug delivery systems, designed as multifunctional engineered nanoparticles, are very promising since they combine several opportunities like a rather uniform distribution of drug dose among all ventilated alveoli allowing for uniform cellular dr...

RNA interference (RNAi) is a promising strategy to inhibit the expression of pathologically relevant genes, which show aberrant (over-)expression, e.g. in tumors or other pathologies. The induction of RNAi relies on small interfering RNAs (siRNAs), which trigger the specific mRNA degradation. Their instability and poor delivery into target tissues...

Industrially manufactured titanium dioxide nanoparticles have been successfully radiolabelled with 48V by irradiation with a cyclotron-generated proton beam. Centrifugation tests showed that the 48V radiolabels were stably bound within the nanoparticle structure in an aqueous medium, while X-ray diffraction indicated that no major structural modifi...

Besides toxicity tests, biokinetic studies are a fundamental part of investigations to evaluate a safe and sustainable use of nanoparticles. Today, gold nanoparticles (Au NPs) are known to be a versatile tool in different areas such as science, engineering or medicine. In this study, we investigated the biokinetics after intravenous and intratrache...

Rationale: Several epidemiological studies associated exposure to increased levels of particulate matter in Augsburg, Germany with cardiovascular mortality and morbidity. To elucidate the mechanisms of cardiovascular impairments we investigated the cardiopulmonary responses in spontaneously hypertensive rats (SHR), a model for human cardiovascular...

With the expected increase in the applications of nanotechnology, more and more products will be manufactured containing components which will fit the commonly used definition of the nanoscale, as having a size between approximately 1 and 100 nanometre. There is no scientific evidence in favour of a single upper limit. Moreover, there is no scienti...

Proof is lacking that pollen count is representative for allergen exposure, also because allergens were found in nonpollen-bearing fractions of ambient air. We monitored simultaneously birch pollen and the major birch pollen allergen Bet v 1 in different size fractions of ambient air from 2004 till 2007 in Munich, Germany. Air was sampled with a Ch...

In the wake of rapid developments in nanotechnologies and nanosciences, the need for an internationally agreed definition of a ‘nanomaterial’ has gained more urgency. A number of definitions are currently available. These are, however, mainly based on size parameter(s), and fall short in terms of applicability to particulate materials that only hav...

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this revie...

Particle biokinetics is important in hazard identification and characterization of inhaled particles. Such studies intend to convert external to internal exposure or biologically effective dose, and may help to set limits in that way. Here we focus on the biokinetics of inhaled nanometer sized particles in comparison to micrometer sized ones. The p...