The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics.

a b s t r a c tOver the past decades, road safety in highly-motorised countries has made significant progress. Although we have a fair understanding of the reasons for this progress, we don't have conclusive evidence for this. A new generation of road safety management approaches has entered road safety, starting when countries decided to guide themselves by setting quantitative targets (e.g. 50% less casualties in ten years' time). Setting realistic targets, designing strategies and action plans to achieve these targets and monitoring progress have resulted in more scientific research to support decision-making on these topics. Three subjects are key in this new approach of evidence-based and data-driven road safety management: ex-post and ex-ante evaluation of both individual interventions and intervention packages in road safety strategies, and transferability (external validity) of the research results. In this article, we explore these subjects based on recent experiences in four jurisdictions (Western Australia, the Netherlands, Sweden and Switzerland). All four apply similar approaches and tools; differences are considered marginal. It is concluded that policy-making and political decisions were influenced to a great extent by the results of analysis and research. Nevertheless, to compensate for a relatively weak theoretical basis and to improve the power of this new approach, a number of issues will need further research. This includes ex-post and ex-ante evaluation, a better understanding of extrapolation of historical trends and the transferability of research results. This new approach cannot be realized without high-quality road safety data. Good data and knowledge are indispensable for this new and very promising approach.

SPIONs) which are clinically used as magnetic resonance imaging contrast agents. [4] In addition, application of an (alternating) external magnetic field for therapeutic purposes offers interesting perspectives in oncology, in that such nanoparticles can be used for a hyperthermia therapy or to target drug loaded particles to tumors. The latter is referred to as magnetic drug targeting. [5] In order to study the in vivo biodistribution of such particles, they have to be labeled by conjugation of fluorescent or radioactive agents. However, these chemical modifications can significantly change the interaction patterns with biological matter since they have a direct impact on particle size and polydispersity, electrokinetic potential (ζ-potential), and possibly the protein corona. [6][7][8][9] It is therefore recommended to carry out, whenever possible, physicochemical characterization, formulation development, pharmacokinetic studies, and hazard and safety evaluations with non-tagged nanoparticles. [10] In recent years, magnetic particle imaging (MPI), magnetic resonance imaging (MRI) or computed tomography [11] have been discussed as label-free alternative to trace engineered metal nanoparticles within a biological system. The latter technology takes advantage of their strong X-ray absorption. [12,13] In medical research, laboratory-based micro-computed tomography (μCT) has been used to monitor the biodistribution of metal-based nanoparticles in vitro or in small experimental animals. [13][14][15][16] A challenge Metal-based nanoparticles are clinically used for diagnostic and therapeutic applications. After parenteral administration, they will distribute throughout different organs. Quantification of their distribution within tissues in the 3D space, however, remains a challenge owing to the small particle diameter. In this study, synchrotron radiation-based hard X-ray tomography (SRμCT) in absorption and phase contrast modes is evaluated for the localization of superparamagnetic iron oxide nanoparticles (SPIONs) in soft tissues based on their electron density and X-ray attenuation. Biodistribution of SPIONs is studied using zebrafish embryos as a vertebrate screening model. This label-free approach gives rise to an isotropic, 3D, direct space visualization of the entire 2.5 mm-long animal with a spatial resolution of around 2 μm. High resolution image stacks are available on a dedicated internet page (http://zebrafish.pharma-te.ch). X-ray tomography is combined with physico-chemical characterization and cellular uptake studies to confirm the safety and effectiveness of protective SPION coatings. It is demonstrated that SRμCT provides unprecedented insights into the zebrafish embryo anatomy and tissue distribution of label-free metal oxide nanoparticles.

No abstract

Enzyme immobilization is of high interest for industrial applications. However, immobilization may compromise enzyme activity or stability due to the harsh conditions which have to be applied. The authors therefore present a new and improved crosslinked layer-by-layer (cLbL) approach. Two different model enzymes (acid phosphatase and β-galactosidase) are immobilized under mild conditions on biocompatible, monodisperse, sub-micrometer poly(lactide-co-glycolide) (PLGA) particles. The resulting PLGA enzyme systems are characterized regarding their size, surface charge, enzyme activity, storage stability, reusability, and stability under various conditions such as changing pH and temperature. The developed and characterized cLbL protocol can be easily adapted to different enzymes. Potential future uses of the technology for biomedical applications are discussed. PLGA-enzyme particles are therefore injected into the blood circulation of zebrafish embryos in order to demonstrate the in vivo stability and activity of the designed system.

No abstract

Altering local dielectric properties induced by solvent shielding, enhances polar interactions and leads to enthalpically driven recognition of polar substrates.

No abstract