Dr Mario Waespy, University of Bremen; Prof. Sørge Kelm, University of Bremen; Prof. Ursula Mirastschijski, University of Bremen
Several methods are established for selectively targeting cells for systemic delivery of diagnostic or therapeutic agents. Selective targeting has led to the introduction of various substances for diagnostics of tissue imaging, e.g. contrast agents useful in Magnetic Resonance Imaging (MRI), radio-diagnostic compositions. Novel therapeutic agents were introduced such as drugs for radiotherapy or for neutron capture therapy, compositions for chemotherapy, various proteins, nucleic acids, liposomes, antibiotics, antiviral agents and others. For example, folate conjugates are used for the selective targeting of cell populations expressing folate receptors or other folate binding proteins to label or deliver bioactive compounds to these cells. Efforts to improve the cellular uptake and to increase the diversity of the agents delivered to the cell or tissue by receptor ligand-conjugates have been hampered by a number of complications, including suitable alternative receptors on target cells or tissues and the complex syntheses required for the preparation of these conjugates.
In a general aspect, the present invention relates to novel receptor ligand-conjugates suitable for targeted receptor-mediated cellular uptake of entities with desired activity and function. In brief, we synthesised a novel class of protease activated receptor 2 (PAR2) ligands that are able to specifically bind and activate cell surface human PAR2. Activation of the receptor initiates the β-arrestin-mediated and clathrin- and dynamin-dependent endocytosis of PAR2 itself. In this regard, the novel class of PAR ligands such as the synthetic PAR2 agonist P8 can be employed to trigger endocytosis which enables the enhanced and directed uptake of molecules, proteins and other biofunctional material or particles into cells when directly linked to them.
The PAR2 ligand-conjugates of our present invention pave the way for a new generation of pharmacological, therapeutic and biotechnological applications, such as enhanced cellular drug delivery or directed cell engineering.
Potential fields of our molecular transport system comprise clinical diagnostics, infectious diseases, cancer, autoimmune diseases, wound healing, inflammatory airways diseases as well as non-genetic cell engineering.
Hitherto we have evaluated the biofunctionality of our PAR2-agonist P8 in vitro using different cell lines. In addition, we have decorated metal oxide as well as silicon nanoparticles with our PAR2-agonist and demonstrated the enhanced cellular uptake of these model particles (proof of concept). Currently, we are optimising and testing our molecular transport system for two main applications including wound repair and cancer treatment. In addition, we further optimise our PAR2 ligand-conjugates in a way that they will be released from its cargo upon cell entry without leaving any residuals on the latter which could possibly interfere compound functionality.
International Patent Application PCT/EP2018/075955; Priority Date: 25.09.2017
Patent Aplication PCT/EP2018/075955: "Ligand-conjugates and methods for targeted receptor-mediated cellular uptake"