(641a) Invited Talk: Particle Shape Modulates Macrophage Phenotypes: Insights for Cell-Mediated Drug Delivery to Solid Tumors

Adoptive cell transfers have emerged as a promising approach for delivering bioactive drugs packaged in micro/nanoparticles to inflamed tissues. Immune cells like macrophages have the capacity to enhance particle delivery in vivo through chemotaxis, and once delivered, the cells can participate in the intended therapeutic effect as well. However, surface-bound or internalized particles are known to exert stresses on macrophages, causing the cell to polarize toward proinflammatory or anti-inflammatory phenotypes. Despite this understanding, little is known about how the transcriptional and translational state changes as a function of particle shape and how these changes might be leveraged to improve the performance of adoptive cell transfers. It has been demonstrated that spherical particles are rapidly phagocytosed in the phagosome within minutes to hours; however, certain non-spherical particle geometries such as discoidal backpacks are capable of resisting phagocytosis by macrophages for days. Herein, we study the interaction of poly(D,L lactic-co-glycolic acid) discoidal (major axis 7.7 ± 0.5 µm, thickness 276.4 ± 31.8 nm) and spherical (diameter 2.3 ± 0.3 µm) particles on C57BL/6-derived primary macrophages to respectively suppress or promote phagocytosis. Discoidal and spherical particles of a fixed volume were fabricated using microcontact printing and homogenization, respectively. Macrophage-disc (Mφ-D) and macrophage-sphere (Mφ-S) complexes were manufactured by associating particles in vitro and resulting gene expression (RNA-Seq), chromatin accessibility (ATAC-Seq), protein expression (flow cytometry), and cytokine secretion (ELISA) were evaluated. Notably, Mφ-D showed significant epigenetic activation [Irf1 (7.9-fold), Stat1 (1.9-fold), Icam1 (4.0-fold)], biomarker expression [Arg1 (31.42-fold), iNOS (3.25-fold), CD206 (1.36-fold), and cytokine secretion [IL-6 (12.54-fold), TNFα (14.22-fold), CCL3 (4.68-fold)] compared to unstimulated controls. Mφ-S, on the other hand, displayed significant changes in gene and protein expression, but far fewer than Mφ-D. Tumor infiltration potential of our adoptive macrophages was quantified by administering cell-particle complexes i.v. in a B16-F10 melanoma model and major organs were processed via homogenization. The accumulation of Mφ, Mφ-D, and Mφ-S in the B16-F10 tumor was 9.95%, 7.62%, and 6.31% per gram of tissue, respectively. Tumor infiltration of macrophages laden with particles was not significantly altered, supporting that particle association does not inhibit macrophage trafficking to inflamed tissue, as desired. If time permits, I will present our recent work on how magnetic discoidal particles and acoustically responsive spherical particles delivered by macrophages can be stimulated to warm immunological cold tumors.