Engineering Nanoshapes to Optimize Tumor Associated Macrophage Re-Education Jessica A. Widman and Laura J. Suggs Department of Biomedical Engineering, The University of Texas at Austin Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is unresponsive to most targeted treatment options, including current immunotherapies. Additionally, TNBC survival rates are inversely correlated with the immunosuppressive tumor associated macrophage (TAM) population. Thus, an emerging immunotherapeutic strategy is re-educating the TAM population towards an inflammatory, anti-tumor phenotype. Due to the phagocytic nature of TAMs, and the enhanced permeability and retention effect, nanocarriers have been used to deliver TAM-re-educating therapeutics. However, the efficacy of these nanocarriers are limited by their tumor accumulation, tumor penetration, and TAM uptake rate. We are engineering three distinctly shaped nanoparticles to investigate how nanoparticle shape influences tumor accumulation, tumor penetration, and TAM uptake rate to optimally deliver TAM-targeted therapeutics in a TNBC model. We hypothesize that the short dimensions of nanorods and nanotriangles will promote tumor penetration while the long dimensions will improve circulation time and tumor accumulation. We have synthesized nano-rods, -triangles, and -shells, which have one, two and three long dimensions, respectively. They have equivalent long dimension lengths of approximately 75 nm. We have shown that our nanoshapes are cytocompatible and can be imaged in cells without the addition of an exogenous fluorescent molecule. To our knowledge, these nanoshapes are the first otherwise physicochemically equivalent nanoparticles synthesized to study the fundamental impact of shape on TAM nanoparticle uptake and distribution. These nanoshapes are size tunable; inherently excited by 2-photon imaging; cytocompatible; and capable of carrying a drug molecule or targeting ligand, such as CpG. Future studies include investigating the impact of nanoparticle shape on macrophage uptake rate in vitro and investigating spatial and cellular distribution in a TNBC model in vivo. Additionally, we will explore the use of laser irradiation and CpG conjugation with these nanoshapes to induce an effective immune response in a TNBC model.
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