Hepsin cleavable nanocapsules for precision medicine in prostate carcinoma (HEPSIN-NANOLYSIS

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The serine protease hepsin is overexpressed in 90% of prostate cancer cases, exhibits pericellular proteolytic activity, and promotes tumor progression and metastasis in mice. Due to these features, hepsin is an attractive target molecule for both diagnosis and therapy of prostate cancer. We intend to use the enzymatic activity of hepsin for the site-specific release of antitumour drugs. A novel, peptide-based nanoscale drug carrier system will be developed and evaluated. The nanocarriers will be designed for selective opening at the surface of prostate cancer cells, thereby enabling specific and efficient therapeutic intervention under considerable reduction of side effects.LY294002, a thoroughly characterized antagonist of PI3-Kinase / AKT-mediated signalling, reveals potent anti-tumor activity in prostate cancer cell lines, either alone or combined with the pro-apoptotic and cancer-specific cytokine TRAIL (tumor necrosis factor related apoptosis-inducing ligand). By encapsulating these drugs in the nanocarrier system to be developed, we aim at a significant improvement of bioavailabilty and efficacy and a minimization of side effects in vivo. The concept will be biologically evaluated using experimental prostate cancer xenografts featuring inducible expression of hepsin in the chicken chorioallantoic membrane (CAM) model.The capsules will be prepared using the inverse miniemulsion method. Co-monomers and synthesis strategies will be optimized. The selection of a hepsin-specific target sequence will be achieved by screening of a bead-based combinatorial peptide library. Aggregation- and adsorption characteristics of peptide-based capsules in biological media will be analysed along with iterative adaptations of surface properties, ultimately leading to nanocarriers which i) are completely biodegradable; ii) efficiently accumulate in tumors, but not in vessels or organs; iii) reveal a surface which is accessible for proteolysis; iv) are specifically degradable by hepsin; and v) rapidly release their cargo upon exposure to enzymatically active hepsin protease. The interdisciplinary project will provide a groundwork for upcoming approaches aiming at the systematic development and evaluation of enzymatically cleavable nanocarriers for cancer therapy. In addition to the establishment of a library-based screening technology and a universal strategy for nanocarrier synthesis and loading, highly standardized in vitro models as well as in vivo analyses in the CAM xenograft model will provide reliable data in preclinical research, which will be achieved under avoidance of animal trials.