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Abstract

Tumor-Associated Macrophages (TAMs) play an important role in shaping the tumor microenvironment (TME) and in promoting tumor metastasis. When applied to the TME, Superparamagnetic Iron Oxide Nanoparticles (SPIONs) specifically activate TAMs and induce an anti-tumor (pro-inflammatory) phenotype, indicating a potential window for therapeutic development. We have developed and tested a novel type of nanoparticle with or without an iron core. These nanoparticles are taken up specifically by murine bone marrow-derived macrophages (BMDMs) and human macrophages. Importantly, our nanoparticles containing an iron core induce TAM polarization to an anti-tumor phenotype significantly more than nanoparticles lacking the iron core. In both human and mouse systems, the nanoparticle- induced phenotype is characterized by increased mRNA expression of cytokines and chemokines such as TNF, IL1β, IL6 and iNOS, as well as cell surface proteins such as CD80, CD86 and MHC II, suggesting that SPIONs may be a tool for clinical application. This SPION induced phenotype was mediated by a combination of iron stimulation and TLR4 signaling pathways. In co-cultures of macrophages and Lewis lung carcinoma (LLC) cells, SPIONs reduce tumor cell division and trigger an increase in tumor cell death compared to control nanoparticles. The increased cancer cell death was mediated by the secretion of toxic molecules from SPION activated macrophages that induced oxidative stress in LLC cells, suggesting a mechanism of cytotoxic action. Preliminary data indicate that SPIONs, when administered in mice instilled with LLC cells are primarily taken up by macrophages and lead to the recruitment of more myeloid cells to the lungs compared to the control nanoparticles. Based on these data, targeting TAMs in the TME with SPIONs may render lung tumors susceptible to treatment, laying the foundation for a novel avenue of adjuvant drug development.