Zeta potential changing nanocarrier systems

The application of nanotechnology in drug delivery is envisioned to have a great impact on public health. The ability of nanocarriers including particulate systems, micelles, self-nanoemulsifying drug delivery systems (SNEDDS) and liposomes to improve bioavailability, provide targeted drug delivery, or extend drug half-life has resulted in the potential to revolutionize the treatment of many diseases. Because of various barriers that have to be overcome by nanocarriers in order to reach their target and to release their payload there, however, these systems have by far not reached their full potential. One reason for this situation is the positive zeta potential of many nanocarriers being on the one hand necessary to provide adhesion on various membranes, to promote drug absorption or to induce cell uptake. Positively charged nanocarriers being administered to mucosal membranes such as the gastrointestinal, nasal, vaginal or ocular mucosa, on the other hand, however, stick already on the surface of the negatively charged mucus gel layer without reaching the underlying absorption membrane or they reach the membrane having already lost their positive zeta potential by an anionic coating of mucus. The design of nanocarriers exhibiting a neutral or negative charge on the way to their target in the body followed by a change to a positive charge at the target site might therefore be the key to much more efficient nanocarriers for drug delivery. Within this project nanocarriers capable of changing their zeta potential at the mucosal target site from negative to positive are therefore generated. The results of this project should open the door to a new generation of nanocarrier systems for a comparatively much more efficient mucosal drug delivery.

Nanocarriers that can change their surface charge (= zeta potential) have shown great potential for drug delivery and diagnosis. By specific stimuli like shift in pH or redox potential, certain enzymes or exogenous stimuli such as heat or light, they can reverse their surface charge from anionic to cationic. Since almost all surfaces in the human body exhibit an anionic charge binding cationic compounds and particles via ionic interactions, only non-ionic or anionic nanocarriers can freely diffuse, distribute and consequently reach their target. Having reached the target, however, a cationic surface charge is advantageous triggering cellular uptake. This so-called polycation dilemma can be addressed by nanocarriers changing their zeta potential from non-ionic or anionic to cationic directly at the target cell. Within this project nanocarriers exhibiting phosphate substructures on their surface were developed. These phosphate substructures are cleaved off by phosphatases that are found on the cellular surface of target cells. Due to the cleavage of phosphates from the surface of nanocarriers, they lose their anionic charges causing a conversion to positive charge. Within this project in particular polyphosphates and phosphorylated surfactants turned out to be most suitable for the design of such nanocarriers. Results of this project contribute to the design of more efficient drug delivery systems and diagnostics.