EXTH-75. A MACROPHAGE-BASED DRUG DELIVERY PLATFORM FOR GLIOMA TREATMENT

Abstract

Abstract There is an urgent need for more effective treatment strategies against gliomas. Even though various drugs have potent anti-tumor activity in vitro, their application in vivo is limited by ineffective delivery and systemic toxicity. Therefore, novel strategies are needed to deliver these drugs effectively and safely to the tumor site. Here, we developed an adoptive transfer strategy against malignant brain tumors utilizing monocyte-derived macrophages that are loaded with ferritin-protein cages containing drugs or other proteins and transfer these nanocarriers effectively to cancer cells for intracellular release and cancer cell killing. Using flow cytometry and microscopy, we observed a high transfer efficiency of ferritin-cages from loaded macrophages into human and mouse glioma cells in vitro in co-culture assays. We also confirmed the transfer of ferritin-cages from macrophages to glioma cells in vivo upon intravenous or intratumoral treatment of GL-261 or CT-2A glioma-bearing mice using in vivo imaging and ex vivo flow cytometry and microscopy. To study the anti-glioma activity with therapeutically active payloads, we loaded murine/human macrophages with ferritin cages carrying cytotoxic auristatin. Co-culture of these loaded macrophages with murine or human glioma cells in vitro revealed a time- and concentration-dependent cytotoxicity to glioma cells. In vivo, intravenous or intratumoral administration of ferritin-drug protein cages was tolerated without toxicities and conferred a survival benefit in two orthotopic murine glioma models (GL-261 and CT-2A) leading to a large fraction of long-term surviving mice. Interactome studies of ferritin-cage-binding proteins revealed phagocytic and cytoskeleton re-arrangement pathways to be involved in uptake and transfer of ferritin-cages from macrophages to glioma cells. This ‘Trojan Horse’ approach based on macrophages-ferritin-protein cages constitutes a promising platform to deliver cytotoxic drugs effectively and safely to gliomas and provides a rationale for clinical translation.