Mainz-based scientists decipher stealth effect of nanocarriers evading clearance by the immune system

Stealth effect of nanocarriers for drug delivery vehicles conferred more efficiently

22.02.2016

By using drug delivery vehicles, so-called nanocarriers, pharmaceuticals reach the diseased area in the body. There they accelerate the healing process. But in order to prevent them from getting ingested by phagocytes, the surfaces of the nanocarriers are typically coated with the biocompatible synthetic polymer poly(ethylene glycol) (PEG). This recruits specific proteins from the blood plasma, which build a kind of stealth effect of the nanocarriers. Scientists at the Mainz University Medical Center and the Max Planck Institute for Polymer Research have now identified these specific proteins that need to adhere to the PEG. Based on this discovery, published in the February issue of Nature Nanotechnology, nanocarriers as drug delivery vehicles can be protected from the immune system's macrophages more effectively. The researchers have also been able to apply their findings to other polymers, so-called polyphosphates. Contrary to PEG, these are fully biodegradable and therefore potential candidates for drug carriers in the long-term treatment of chronic diseases.

Polymers recruit specific proteins from the blood for the stealth effect

The ability of PEG to extend the blood circulation periods of nanocarriers and other substances is already known in medicine. However, it has been explained by the fact that PEG causes a reduced protein adsorption on nanocarrier surfaces. The work of Dr. Frederik Wurm and Professor Katharina Landfester from the Max Planck Institute for Polymer Research as well as PD Dr. Volker Mailänder from the University Medical Center of Johannes Gutenberg University Mainz (JGU) brings about a paradigm shift in this kind of surface modification. Together with their colleagues, the scientists have shown that it is not a reduced uptake of proteins, but rather a specific adsorption of certain proteins from the blood plasma which is responsible for the stealth effect. Consequently, it is not PEG, but the adsorption of, first and foremost, apolipoprotein J, also named clusterin, that cloaks the nanocarriers. Through the selective adsorption of clusterin the camouflaging of the nanocarriers is made possible so that they can reach their respective destinations in the body.

The physicians and life science researchers altered different nanocarriers and conducted comparative studies with adhering proteins. "Using high-resolution mass spectrometry, we were able to analyze precisely the complex mixture of the blood plasma, the proteins that adhere to the nanocarriers and their components," explained Mailänder. "Thanks to these findings, we could also establish a new polymer class as an alternative to PEG: polyphosphate is degradable, while the currently used PEG may accumulate in the body and cause intolerances when taken over a period of several years," Wurm pointed out. "This insight also provides the possibility to dispense with artificial materials completely using naturally occurring proteins for the stealth effect." Landfester added: "Mainz provides a unique location for such a research project as it combines polymer synthesis, colloid chemistry and biomedicine providing an ideal starting point." "Nanocarriers play an important role in the therapeutical treatment. The new findings of PD Dr. Volker Mailänder and Dr. Frederik Wurm are milestones in this field," emphasized the Chief Scientific Officer of the Mainz University Medical Center, Professor Ulrich Förstermann.

Agents reach their destination efficiently

These results will significantly affect the development of new drugs and the treatment of diseased tissues, such as tumors. As an example, the total dose of a drug can be reduced while simultaneously prolonging its blood half-life. This is vital for therapies with rich side effects, as in the chemotherapeutic tumor therapy.

The project is funded by the Collaborative Research Center (CRC) 1066 "Nanodimensional polymer therapeutics for tumor therapy" of the German Research Foundation (DFG), by the Research Center for Immunotherapy (FZI) of Johannes Gutenberg University Mainz, and by the JGU "BiomaTiCS – Biomaterials, Tissues and Cells in Science" research unit.