Selbstorganisierende Polymer-Cyclopeptid-Konjugate als multifunktionelle Wirkstoffträgersysteme
Pharmazie
Präparative und Physikalische Chemie von Polymeren
Zusammenfassung der Projektergebnisse
Cyclic peptides consisting of alternating L and D amino acids provide a unique scaffold for anisotropic structures due to their ability to form large tubular structures guided by strong hydrogen bonds. These strong interactions even tolerate the attachment of polymer arms to the peptide to create rigid, supramolecular (non-covalent) polymer bottlebrushes. Features like anisotropic shape, the modular design and the reversible assembly make these materials promising candidates for drug delivery applications. The aim of this project was to develop facile synthesis methods to create functional drug delivery vectors based on polymer-cyclic peptide conjugates and test their potential in-vitro on various cell lines. The first step comprised the investigation of suitable reactions which can provide a robust and versatile procedure to be able to prepare a large variety of functional polymer-cyclic peptide conjugates with good yields. Employing state-of-the-art coupling chemistry we could develop optimal conditions to synthesise not only symmetrically modified peptides, but also asymmetric structures with various functionalities. Subsequent studies of the self-assembly of these conjugates revealed that only strong repulsive forces such as coulomb repulsion or sterically very demanding polymer arms are able to interfere with the formation of hydrogen bonds between the peptide cores. Based on these results and the optimized synthesis several potentially interesting materials were selected and prepared for further in vitro studies on cells. The low overall toxicity of neutral conjugates built the basis of a future application as drug delivery vectors. However, more interesting features were observed comparing these anisotropic, cylindrical materials to the respective polymers. In one case a neutral and symmetrically substituted peptide conjugate demonstrated a significantly enhanced efficiency of transporting an attached drug to the location of action in a cancer cell and therefore this conjugate was more potent in neutralizing these cells than the pure drug or the drug attached to a similar polymer alone. Most importantly the cylindrical materials showed a higher selectivity for cancer cells in comparison to healthy cells than the other applied materials An unexpected behaviour in these cell studies was observed for asymmetrical modified, amphiphilic polymer-cyclic peptide conjugates. We previously observed that these materials form rigid core-shell cylinders in aqueous solutions with a hydrophobic core and a hydrophilic shell. Although no functional groups were incorporated, which are usually required to fuse with lipid bilayer, these so called tubisomes were able to interact with cell membrane in the endosome and perforate it so that small molecules were able to escape into the cytosol of the cell. This ability was so far only demonstrated by viruses or bacteria, but not by a purely synthetic material. Together with the excellent biocompatibility, the low toxicity and the charge-neutral structure, this ability opens an unprecedented pathway to safely transport desired drugs into cells. The results of this project certainly demonstrate the unique potential of these anisotropic materials for application in pharmacy and medicine, while the synthetic procedures remain scalable and straightforward. However this work represents only the early steps required and further research is required to address issues such as the distribution in-vivo and modification for active targeting.
Projektbezogene Publikationen (Auswahl)
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Cyclic peptide–polymer conjugates: Grafting-to vs grafting-from, J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 1003-1011
Sophie C. Larnaudie, Johannes C. Brendel, Katrina A. Jolliffe and Sébastien Perrier
