Univ.-Prof. Mag. Dr. Andreas Bernkop-Schnürch
Drug Delivery
The work of our research group focuses on novel, innovative drug delivery systems that transport active pharmaceutical ingredients to the target site and thus enable sustained drug release and improved absorption. These versatile systems include oligomers, polymers, micelles, or lipid nanoparticles.
Many drugs inconveniently have to be administered parenterally due to insufficient residence time at the site of application, resulting in inadequate drug absorption for local or systemic effect. Our systems with cationic or thiol functionalities adhere to the mucosal layers of the respiratory tract, gastrointestinal tract or reproductive tract and provide prolonged residence time for the drug near the site of action. At the cellular level, our systems show improved cellular uptake and reduced efflux of the active ingredients from the cells. Using a slightly more complex method, in which cationic functionalities are masked with anionic charges, we can prevent our systems from adhering too early to the adhesion membranes and thus achieve stronger interactions and a higher drug concentration at the target site.
The drug delivery systems used could open up new ways of non-parenteral drug delivery, for example in ocular, oral, buccal and nasal application with reduced application quantity and frequency.
The non-parenteral administration of drugs offers several advantages over parenteral administration, such as simple and convenient application for patients and a strong local effect. Particularly advantageous are mucoadhesive application systems, which establish close contact with the mucous membrane and prolong the residence time of the therapeutics. Ionic forces, hydrogen bridges and the formation of disulfide bridges between thiolated carriers and cysteine-rich sub-domains of mucus glycoproteins can promote mucoadhesion and thus increase the efficacy of these systems. In this project we focus on the synthesis and application of cationic and thiolated nanoparticles, as well as oligo- and polymers as mucoadhesive delivery systems. Our results to date show excellent application potential for these systems in the non-parenteral administration of drugs, with prolonged residence time in the mucosa and sustained drug release.
An important factor for successful drug delivery is the internalisation of the carrier systems into the target cells. Due to the anionic nature of the cell membrane and membrane proteins with multiple thiol functionalities on the extracellular site, the introduction of cationic or thiolated moieties on drug carriers leads to stronger cell membrane association and consequently to improved cellular uptake. We have already synthesized several oligo- and polymeric systems, as well as nanoparticles, with numerous cationic and/or thiol units and tested them on different cell lines. Our experiments show that these modified carrier systems can be internalized by the cells to a greater extent than the unmodified analogues. Furthermore, the efflux activity of cell membrane glycoproteins counteracts the increased accumulation of drugs in the cells, decreases their concentration at the target site and leads to reduced therapeutic outcomes and potential drug resistance. Thiolated oligomers showed a high potential to inhibit such efflux and could thus improve the bioavailability of various therapeutics.
The polycationic surface of nanoparticles (NPs) shows strong interactions with negatively charged mucosa and cell membranes. Consequently, these nanocarriers cannot diffuse through the mucus layer to reach the absorption membrane and interact non-selectively with all cells. In contrast, negatively charged nanoparticles can penetrate into a deep mucus layer close to the absorption membrane, but cannot trigger cellular uptake due to the lack of interaction due to their anionic nature. Charge-reversible NPs have attracted considerable interest due to their dynamic surface charge. Cationic NPs covered with anionic oligo- and polyphosphates penetrate into the deep mucus layer where enzymatic degradation of the phosphate coating leads to cationic NPs that trigger mucosal adhesion close to the absorption membrane. With such adaptive multilayer NPs, which have a stealth effect, lower immunogenicity and longer circulation times, selective and improved cellular uptake can also be achieved.