Cell Models & Toxicology

The working group Cell Models & Toxicology deals with the preclinical testing of nanoparticular formulations for medical application and the toxic risk analysis of synthetic nanomaterials.

The synthesis and preclinical testing of nanoparticular formulations for specific “Drug Targeting” is a focus of the group´s work. “Drug-loaded” nanoparticles are able to transport the agent (e. g. cytostatics) directly to the target cell without causing heavy, undesired side effects in the surrounding tissue. It is possible to examine the specific accumulation of the nanoparticles and of the incorporating agent (e. g. tumours) as well as the nanoparticular-mediated surmounting of biological barriers (e. g., blood-brain-barrier, gastro-intestinal-barrier) in different cell culture models. Different nanoparticular formulations are currently being tested in the course of several projects. Corresponding cell culture systems like the cultivation of primary brain capillary endothelial cells in the Transwell® system and co-cultures are established within the working group. The aim is to find new nanoparticular formulations which mediate a target-oriented therapy by selective cellular enrichment of the pharmaceutical substances bound to particle systems and which allow a transport of pharmaceutical substances via e. g. the blood-brain-barrier.

In addition to this, the surmounting of the intestinal barrier is of major importance for the application of oral pharmaceutical substance systems. Corresponding cell culture models, e. g. the Ussing chamber are available for transport studies of newly developed pharmaceutical substance formulations. The working group´s studies could show that such a targeting using functionalized nanoparticular formulations is possible. A range of other cell culture systems for the simulation of further biological barriers, e. g. the skin-lung-barrier, are on hand for testing of similar formulations for other projects or can be established if necessary.

The investigation of nanotoxicological effects and the risk analysis of nanomaterials is a second field of attention for the working group. The focus of the examined nanomaterials is set on synthetic nanomaterials which are commercially interesting. Due to the increasing use of nanotechnology-based consumer products, an increased input of nanomaterials into the environment can be assumed. Alongside the question of ecological and human-toxicological impacts of synthetic nanomaterials, there is increasing focus on the question of improved alternative testing methods for risk analysis, also within REACH. Research is aimed at the development of new cell culture model systems which can be adapted and extended according to the interrogation. E. g. Transwell® system-based methods are available to examine the effect of a unique or chronic exposure to aerosols-containing nanomaterials at the air-liquid interface. Useful analysis methods for toxicological risk analysis are also being established and optimized within the working group.

Furthermore, the working group studies the human and ecotoxicological risk potential of nanomaterials and develops 3R alternatives to animal experiments, also within the framework of the EU chemicals regulation REACH.

It focuses on the following research areas:

• REACH - Toxicological risk assessment according to international standards
  
• Pathways of entry of nanoparticles into the organism
• Behaviour of nanomaterials in the environment
    

REACH – Toxicological risk assessment according to international standards
The working group performs standard toxicological tests according to REACH test procedures (EC 440/2008) to assess the toxic potential of nanomaterials, chemicals, new materials and medical devices. It supports the development of new materials or products as well as the approval of chemicals and nanomaterials through acute & subchronic toxicity studies according to international standards (ISO, OECD). We offer genotoxicity, carcinogenicity, mutagenicity and cytotoxicity studies (according to ISO 10993-5), vascularization tests (HET-CAM assay) and immunotoxicological tests. The biological evaluation of (nano)materials is complemented by their physicochemical characterization and analysis of degradation products. From feasibility studies, via toxicological screenings, concept development for preclinical studies to the development and standardization of 3R ("replace", "reduce" and "refine") alternatives to animal experiments, the working group offers all stages of research and development.

Routes of entry into the organism
The working group investigates the interactions of nanomaterials with biological interfaces as well as with organs and barriers in the body. In vitro and ex vivo models for the investigation of the interaction of nanomaterials with air-liquid interfaces (e. g,. lung barrier, skin barrier) and liquid-liquid interfaces (e. g., intestinal barrier, blood-brain barrier) are available and will be adapted to the specific questions. Kinetics studies of cellular uptake and accumulation as well as subcellular distribution of nanomaterials are also performed. In addition to the development of new in vitro and ex vivo test systems, we deal with the development and evaluation of miniaturized cultivation units and non-invasive analysis methods for the investigation of nanoparticle-cell interactions down to the single cell level.

Behaviour of nanomateris in the environment
The working group develops analytical methods for the sensitive determination of the fate and characteristics of nanomaterials in humans and the environment in the low-dose range. The ecotoxicological research focuses on changes in the properties of nanomaterials after their release into the environment and their effect on their biological functionality.