OS10.4.A A macrophage-based drug delivery platform for glioma treatment

Abstract

Abstract Background There is an urgent need for more effective treatment strategies against gliomas. At present, 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 macrophages that are loaded with ferritin-protein cages containing drugs or other proteins and transfer these nanocarriers to cancer cells in vitro and in vivo. Material and Methods Live-time imaging, microscopy and flow cytometry were utilized to investigate the transfer of ferritin cages from loaded macrophages to human or mouse glioma cells. Co-cultures of glioma cells and macrophages loaded with ferritin-drug cages were used to study the anti-glioma activity in vitro and orthotopic immunocompetent mouse glioma models were used to study the anti-glioma activity in vivo. Affinity purification-mass spectrometry (AP-MS) was used to elucidate the mechanisms of transfer by characterizing the interactome of ferritin cages within macrophages and cancer cells. Results We observed a high transfer efficiency of ferritin-cages from loaded macrophages into human and mouse glioma cells in vitro in co-culture assays and confirmed the transfer from macrophages to glioma cells also in vivo upon intravenous or intratumoral treatment of GL-261 or CT-2A glioma-bearing mice. To study the anti-glioma activity with therapeutically active payloads, we loaded murine/human macrophages with ferritin cages carrying cytotoxic payloads. 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). 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. Conclusion This ‘Trojan Horse’ approach constitutes a promising platform to deliver cytotoxic drugs effectively and safely to gliomas and provides a rationale for clinical translation.