Photoactivated iron nanosystems – novel phenomena and their potential for cancer theranostics

• Applicants: Professor Dr. Mika Lindén; Dr. Rainer Wittig
• Subject Area: Hematology, Oncology ; Computer-Aided Design of Materials and Simulation of Materials Behaviour from Atomic to Microscopic Scale ; Nuclear Medicine, Radiotherapy, Radiobiology ; Reproductive Medicine, Urology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449772310

Sensitive and specific tumor diagnosis and effective therapeutic modalities are urgently needed for the management of tumors of high incidence and low survival rate, such as castration-resistant prostate cancer (CRPC) with a 5-year survival rate below 5%. Recently, immune-sensitizing antitumor-effects of iron oxide nanoparticles (IONP, Ferumoxytol), as well as new photophysical phenomena with photosensitizer (PS)-coated IONP have been observed. Our preliminary work indicates an unusually strong photodynamic "sparking" phenomenon of IONP coated with zinc-phthalocyanine (ZnPc) when irradiated with red laser light which led to immediate necrosis and thus could strongly enhance a therapeutic effect in vivo. Next to direct tumor cell killing, the sparking effect may re-establish tumor immunosurveillance, thereby supporting immune checkpoint inhibition strategies for antimetastatic therapy.In the proposed project we want to exploit these new phenomena for precision medicine in CRPC. The German research team, consisting of the biology group at the ILM and the institute for Inorganic Chemistry II at Ulm University, will develop and evaluate silica-coated, PS-functionalized IONP (Fe3O4/Fe2O3 complexes featuring different size, shape and composition) which further feature surface-bound targeting ligands for the prostate specific membrane antigen (PSMA), as well as mannose for M2 macrophage targeting. In iterative work, IONP will be optimized for passive and active tumor targeting and photodynamic efficiency using an in vitro test model providing inducible expression of PSMA, as well as in vitro polarized macrophages. At this step we expect particles providing distinct features for optimum manipulation of PSMA-positive cancer cells and macrophages, respectively. Following the in vitro tests, the cell model will be xenografted to the chorioallantoic membrane (CAM) animal trial replacement model for short-term pilot studies in vivo using single IONP species and / or optimized blends. In parallel, the Russian research focuses on photophysical investigations of the "sparking phenomena", as well as on theoretical modelling aiming at improved fluorescence diagnostics of CRPC. Finally, an immune-competent animal model of PSMA-positive prostate cancer will be established by the Russian research team, which will be subsequently utilized for the evaluation of the optimized PS-coated IONP. Next to cell killing in the primary tumor, (photodynamic) effects on tumor immunosurveillance and synergies with immune checkpoint inhibition enabling improved antimetastatic therapy will be investigated.

• DFG Programme: Research Grants
• International Connection: Russia
• Partner Organisation: Russian Foundation for Basic Research, until 3/2022
• Cooperation Partner: Anastasia Ryabova, Ph.D., until 3/2022