A number of methods are known for selectively targeting cells in a patient for delivery of diagnostic or therapeutic agents. Selective targeting has led to the introduction of various entities of interest including diagnostic agents for visualization of tissues, such as contrast agents useful in Magnetic Resonance Imaging (MRI), radio-diagnostic compositions, and the like. Introduction of therapeutic agents, such as compositions for chemotherapy, various proteins, and nucleic acids, liposomes, antibiotics and antiviral agents has been demonstrated. Efforts to improve the selectivity of targeting or 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 tissue and the complex syntheses required for the preparation of these conjugates as well as their stability and solubility under physiologic conditions.
A novel receptor targeted molecular transport system for cellular uptake and non-genetic cell engineering
The current project “P8-Transporter” focus on the generation of novel receptor ligandconjugates suitable for targeted receptor-mediated signal transduction and cellular uptake of entities of desired activity and function. Along this line, we designed and synthesise of a novel class of PAR2 (protease activated receptor 2) agonist ligand denoted P8, which is able to specifically bind and activate cell surface human PAR2, in a manner similar to the native activation process mediated by serine proteases. Activation of the receptor also initiates the β- arrestin-mediated and clathrin- and dynamin-dependent endocytosis of PAR2 itself. This mechanism has been demonstrated to play a crucial role for PAR2-mediated uptake of melanin loaded melanosomes into human skin cell, the natural process to protect the skin against UV-irradiation. In this regard, our synthetic PAR2 agonist P8 can be employed to trigger endocytosis and enables the target-specific uptake of molecules, proteins and other biofunctional material or particles into cells, when directly linked to them. Hence, this novel molecular transport system paves the way for a new generation of pharmacological, therapeutical and biotechnological applications, such as target drug delivery or directed cell engineering.
The project has started in 2016 and involves interdisciplinary cooperation partners from the fields of regenerative medicine (Wound Repair Unit, CBIB, Bremen) biochemistry (CBIB, Bremen), material science (Advanced Ceramics, Uni Bremen) biophysics (nanoBiomaterials, Uni Bremen), microsystems technology (IMSAS, Uni Bremen) and plant biology (CBIB, Uni Bremen).
Dr. Mario Waespy (CBIB)
|Prof. Dr. Sørge Kelm (CBIB)|
E-Mail: skelmprotect me ?!uni-bremenprotect me ?!.de
|Prof. Dr. Dr. Ursula Mirastschijski (CBIB)|
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