PD Dr. Annette Kraegeloh

We report a straightforward methodology to access structurally well-defined hybrid assemblies of plasmonic and excitonic nanoparticles (NPs). The developed strategy is based on the incorporation of quantum dots (QDs) coated with zinc-sulfide shells into poly(ethylene glycol) (PEG) brushes at gold NP surfaces, without the necessity of incorporating specialized functional groups to drive the supracolloidal assembly. Based on control experiments involving PEGs with distinct polymeric architecture and Fourier-transform infrared spectroscopy analysis, we attribute the structure formation to attractive interactions between the QD surface and the monomeric repeat unit of the PEG brushes. This combination leads to short interparticle spacings and plasmon/exciton interactions, resulting in photoluminescence (PL) quenching upon assembly. However, using block-copolymers comprising a NP-adjacent spacer block in addition to a NP-remote PEG block, the distance between gold NPs and QDs can be controlled, which in turn affects the PL properties. The versatility of the structure-formation approach is demonstrated by the possibility of applying it to two distinct core/shell QDs (InP/ZnSe/ZnS and CdSe/CdS/ZnS). This offers new perspectives in the quest for efficient nanomaterial fabrication procedures.

Antibiotic resistance in chronic lung infections caused by Pseudomonas aeruginosa requires alternative approaches to improve antibiotic efficacy. One promising approach is the use of adjuvant compounds that complement antibiotic therapy. This study explores the potential of menadione as an adjuvant to azithromycin against planktonic cells and biofilms of P. aeruginosa, focusing on its mechanisms of action and cytotoxicity in pulmonary cell models. Methods: The effect of menadione in improving the antibacterial and antibiofilm potency of azithromycin was tested against P. aeruginosa. Mechanistic studies in P. aeruginosa and AZMr-E. coli DH5α were performed to probe reactive oxygen species (ROS) production and bacterial membrane disruption. Cytotoxicity of antibacterial concentrations of menadione was assessed by measuring ROS levels and membrane integrity in Calu-3 and A549 lung epithelial cells. Results: Adding 0.5 µg/mL menadione to azithromycin reduced the minimum inhibitory concentration (MIC) by four-fold and the minimum biofilm eradication concentration (MBEC) by two-fold against P. aeruginosa. Adjuvant mechanisms of menadione involved ROS production and disruption of bacterial membranes. Cytotoxicity tests revealed that antibacterial concentrations of menadione (≤64 µg/mL) did not affect ROS levels or membrane integrity in lung cell lines. Conclusions: Menadione enhanced the efficacy of azithromycin against P. aeruginosa while exhibiting a favorable safety profile in lung epithelial cells at antibacterial concentrations. These findings suggest that menadione is a promising antibiotic adjuvant. However, as relevant data on the toxicity of menadione is sparse, further toxicity studies are required to ensure its safe use in complementing antibiotic therapy.

Materials that can be switched between a polycationic/antimicrobial and a polyzwitterionic/protein-repellent state have important applications, e.g., as biofilm-reducing coatings in medical devices. However, the lack of stability under storage and application conditions so far restricts the lifetime and efficiency of such materials. In this work, a polynorbornene-based polycarboxybetaine with an optimized molecular structure for improved hydrolytic stability is presented. The polymer is fully characterized on the molecular level. Surface-attached polymer networks are obtained by spin-coating and UV cross-linking. These coatings are highly uniform and demonstrate charge-switching in zeta-potential studies. Storage stability in the dry state, as well as in aqueous systems at pH 4.5 and 7.4 for 28 days, is demonstrated. At pH 8, hydrolytic degradation is observed. Overall, the materials are substantially more stable than the corresponding ester-based systems.

Formaldehyde is the smallest existing aldehyde, a highly reactive color less gas at room temperature and ubiquitously present in our atmosphere. Because of its reactivity leading to the crosslinking of macromolecules like proteins, it is widely used in industrial applications, but also in cell biology in order to preserve cells and tissues for further analysis. In this work, we show that formaldehyde releasing solutions commonly used for fixation of cells, can diffuse via the gas phase to the neighboring well and influence signaling processes in the therein cultured cells. To analyze this effect, we utilized a stable reporter cell line for YAP signaling or a gene expression-based reporter for activation of the NF-κB pathway. We could show that next to formaldehyde, also glutaraldehyde and acetaldehyde were able to activate those signaling pathways. Additionally, especially the stable reporter cell line based on YAP signaling can also be used as sensor for bioavailable formaldehyde, being highly sensitive, easy to use, and reversible. The observed impact of formaldehyde on cellular signaling underscores the need for careful planning of experimental protocols and emphasizes the importance of implementing proper controls when utilizing this reagent in cellular signaling analyses.

Multifunctional wound dressings, enriched with biologically active agents for preventing or treating infections and promoting wound healing, along with cell delivery capability, are highly needed. To address this issue, composite scaffolds with potential in wound dressing applications were fabricated in this study. The poly-lactic acid/nanodiamonds (PLA/ND) scaffolds were first printed using melt electrowriting (MEW) and then coated with quaternized β-chitin (QβC). The NDs were well-dispersed in the printed filaments and worked as fillers and bioactive additions to PLA material. Additionally, they improved coating effectiveness due to the interaction between their negative charges (from NDs) and positive charges (from QβC). NDs not only increased the thermal stability of PLA but also benefitted cellular behavior and inhibited the growth of bacteria. Scaffolds coated with QβC increased the effect of bacteria growth inhibition and facilitated the proliferation of human dermal fibroblasts. Additionally, we have observed rapid extracellular matrix (ECM) remodeling on QβC-coated PLA/NDs scaffolds. The scaffolds provided support for cell adhesion and could serve as a valuable tool for delivering cells to chronic wound sites. The proposed PLA/ND scaffold coated with QβC holds great potential for achieving fast healing in various types of wounds.

The treatment of Parkinson’s disease has been moving into the focus of pharmaceutical development. Yet, the necessity for reliable model systems in the development phase has made research challenging and in vivo models necessary. We have established reliable, reproducible in vitro model systems to evaluate the binding and transport of dopamine-loaded PLGA nanoparticles for the treatment of Parkinson’s disease and put the results in context with comparable in vivo results. The in vitro models have provided similar results concerning the usability of the investigated nanoparticles as the previously used in vivo models and thus provide a good alternative in line with the 3R principles in pharmaceutical research.

A special issue highlighting contributions of women to Chemical Research in Toxicology. The United Nations sustainable development goals aim to improve health and education and promote economic growth while reducing inequality and ending poverty. The field of toxicology is intrinsically dedicated to these goals, addressing the protection of the world population through improving public health and ensuring access to clean water and the sustainable consumption and production of safe food. Specifically, the identification and quantification of hazards and exposures, the chemical and molecular understanding of associated biological outcomes, and tools and models for the prediction of adverse outcomes form a solid basis for hazard reduction, substitution, or safe and sustainable design. In this context, the necessity for the full inclusion of women in all areas of sustainable development has been elevated by the United Nations by making the empowerment of all women and girls one of its sustainable development goals. (1) To fully reach this goal, this empowerment must include the eradication of the gender gap in research and experimental development in science. According to the UNESCO Institute for Statistics (UIS), in 2016, only 29.3% of employees in R&D worldwide were women. A closer look reveals that regional averages for the share of female researchers are heterogeneous, ranging from 48% for Central Asia and 33% for North America and Western Europe to 19% for South and West Asia. (2) Furthermore, the representation of women seems to be inverse to academic rank or leadership position. (3) Although in some regions, e.g., in Europe, the absolute number of women employed as scientists and engineers grew over ten years by almost 50% to 7.3 million in 2022, this growth represented only a 2% increase in the proportion of women compared to men. (4) Shares of female researchers in the field of toxicology are less well accessible, but it can be assumed that overall women are underrepresented in this field, similar to other sectors. Based on the great success of the virtual issue of Chemical Research in Toxicology in Celebration of the International Day of Women and Girls in Science published earlier this year, (5) it is our pleasure to invite you to contribute to the planned special issue of Chemical Research in Toxicology, devoted to the promotion of the visibility of women in this field through the dissemination of their research. The CRT special issue “Women in Chemical Toxicology” is being Guest Edited by Prof. Dean Naisbitt and Prof. Sayuri Miyamoto, and CRT Associate Editor Dr. Annette Kraegeloh. This special issue is aimed at promoting the participation and accomplishments of women in the field of chemical toxicology. Therefore, we specifically call for submissions by first or corresponding authors at any stage in their career who identify as women. We welcome your submissions of research Articles, Rapid Reports, Perspectives, Reviews, or ToxWatch manuscripts related to the entire scope of Chemical Research in Toxicology. Authors are invited to send a presubmission inquiry to the Editors that includes an abstract and cover letter indicating the intended manuscript format by e-mail (eic@crt.acs.org). The deadline for submission is Monday, January 15, 2024. We look forward to your contributions!

The annual International Day of Women and Girls in Science promotes full and equal access to and participation in science. (1) A focal point for 11 February 2023 is the role of Women and Girls in Science as related to the United Nations sustainable development goals in order to strengthen ties between science, policy, and society. These goals and linking strategies are absolutely central to the field of toxicology! Research published in Chemical Research in Toxicology is an enabling basis for improving many areas of a sustainable future including good health, clean water, and responsible consumption and production. The community of Chemical Toxicologists also contributes to advancing goals for quality education, economic growth, global partnerships, and, relevant in particular with the current initiative, gender equality.

Human respiratory mucus is a biological hydrogel that forms a protective barrier for the underlying epithelium. Modulation of the mucus layer has been employed as a strategy to enhance transmucosal drug carrier transport. However, a drawback of this strategy is a potential reduction of the mucus barrier properties, in particular in situations with an increased exposure to particles. In this study, we investigated the impact of mucus modulation on its protective role. In vitro mucus was produced by Calu-3 cells, cultivated at the air-liquid interface for 21 days and used for further testing as formed on top of the cells. Analysis of confocal 3D imaging data revealed that after 21 days Calu-3 cells secrete a mucus layer with a thickness of 24 ± 6 μm. Mucus appeared to restrict penetration of 500 nm carboxyl-modified polystyrene particles to the upper 5–10 μm of the layer. Furthermore, a mucus modulation protocol using aerosolized N-acetylcysteine (NAC) was developed. This treatment enhanced the penetration of particles through the mucus down to deeper layers by means of the mucolytic action of NAC. These findings were supported by cytotoxicity data, indicating that intact mucus protects the underlying epithelium from particle-induced effects on membrane integrity. The impact of NAC treatment on the protective properties of mucus was probed by using 50 and 100 nm amine-modified and 50 nm carboxyl-modified polystyrene nanoparticles, respectively. Cytotoxicity was only induced by the amine-modified particles in combination with NAC treatment, implying a reduced protective function of modulated mucus. Overall, our data emphasize the importance of integrating an assessment of the protective function of mucus into the development of therapy approaches involving mucus modulation.