Immunological investigations of oligoethylene glycols functionalized with desaminotyrosine and desaminotyrosyltyrosine
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Immunological investigations of oligoethylene glycols functionalized with desaminotyrosine and desaminotyrosyltyrosine Konstanze K. Julich-Gruner1,#, Toralf Roch1,#, Nan Ma1, Axel T. Neffe1, Andreas Lendlein1 1
Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Kantstrasse 55, 14513 Teltow, Germany # Equally contributing authors ABSTRACT Biomaterials require thorough in vitro testing before being applied in vivo. Unwanted contaminations of biomaterials but also their intrinsic properties can cause uncontrolled immune response leading to severe consequences for the patient. Therefore, immunological evaluation of materials for biomedical applications is mandatory before entering clinical application. In order to introduce physical netpoints, the aromatic compounds desaminotyrosine (DAT) and desaminotyrosyl-tyrosine (DATT) were successfully used to functionalize linear and star-shaped oligoethylene glycol (lOEG and sOEG) as previously described. The materials showed properties of surfactants and have potential to be used for solubilization of lipophilic drugs in water. Furthermore, the materials are susceptible for H2O2 degradation as determined by MALDI-ToF MS analyses. This is important for potential in vivo applications, as macrophages can release reactive oxygen species (ROS) under inflammatory conditions. As it is known that surfactant solutions of high concentration can lead to cell lysis, the effects of OEG-DAT(T) solutions on murine RAW macrophages were investigated. Even at highest OEG-DAT(T) concentration of 1000 μg·mL-1 the viability of the RAW cells was not significantly impaired. Additionally, the polymers were incubated with whole human blood and the production of inflammatory cytokines such as the tumor necrosis factor (TNF)- and interleukin (IL)-6 was determined. Only at high concentrations, the OEG-DAT(T) solution induced low levels of TNF- and IL-6, indicating that a mild inflammatory reaction could be expected when such high OEG-DAT(T) concentrations are applied in vivo. Similarly, the OEG-DAT(T) solution did not induce ROS in monocytes and neutrophils after incubation with whole human blood. Conclusively, the data presented here demonstrate that OEG-DAT(T) do not lead to a substantial activation of the innate immune mechanisms and could therefore be investigated for solubilizing pharmaceutical agents. INTRODUCTION When designing a material for biomedical application such as drug delivery, the functionality of the biomaterial needs to be established and fully characterized. Moreover, the possible biological effects induced by the materials need to be studied carefully before application in vivo. Inappropriate materials preparation could result in microbial contaminations such as endotoxins (lipopolysaccharides (LPS)), which are components of the cell wall of gramnegative bacteria and can lead to the unspecific immune activation inducing fever or in the worst case multi organ failure [1]. Furthermore, other microbial products from
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