Functionalization of LbL-Microcarriers as Drug Delivery System for Elastase Inhibitors and HOCl Scavengers for the Termination of Chronic Inflammation

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The treatment of chronic inflammation represents an important medical challenge in the modern world. The application of systemically acting pharmaceuticals is often accompanied by multiple side effects. Therefore, the development of new drug delivery systems has to consider targeted and locally sustained applications of pharmaceuticals with high efficiency and reduced side effects.Layer by Layer (LbL) coated microcarriers represent an excellent choice for the treatment of local inflammations occurring, for instance, in arthritic joints. The modular principle of construction, that is the step-wise adsorption of oppositely charged polyelectrolytes onto a spherical micro-template forming a multilayer for an integration of active agents, offers many advantages: Using biocompatible and biodegradable polymers, time controlled and sustained release of one or more active agents, specific cell targeting and high biocompatibility can be realized. The subject of this proposal is to continue the conceptual development and investigation of those specific carriers regarding the transport of antiinflammatory substances into inflamed tissues. Here, neutrophils are in the focus of the investigations: These immune cells generate continuously considerable amounts of aggressive enzymes which contribute to chronification and massive tissue destruction. A specific enzyme, elastase, plays a major role in these processes. For an effective inhibition, LbL microcarriers will be designed to promote intracellular and extracellular elastase inhibition by a1antitrypsin (AT) by only one approach. Additionally, the modular construction of LbL microcarriers will be used to provide more than one active agent, but with different release kinetics: Neutrophils also release reactive oxygen species (ROS) as well as HOCl leading to the activity loss of AT. Therefore, an HOCl scavenger, cefoperazone, will be integrated into the multilayer to maintain AT activity. In this proposal, the influence of the assembling sequence of both agents within the multilayer or template on their intra and extracellular functionality will be investigated. The direct comparison with another drug delivery system, complexes of Cell Penetrating Peptide (CPP) and AT, should help to establish the advantages of LbL microcarriers. Additionally, the uptake behavior and phagolysosomal processing of the LbL microcarriers with regard to an additional lipid layer surface modification will be studied. This modification is an interesting platform for the specific binding of functional molecules (antibodies, CPP) or active agents although the availability and release profiles of the multilayer-embedded active agents are still unknown. It is expected that the obtained data will support the development of new and highly specific drug delivery systems, particularly by using the multifunctional attributes of Layer by Layer technology.