Manipulating the NF-κB pathway in macrophages using mannosylated, siRNA-delivering nanoparticles can induce immunostimulatory and tumor cytotoxic functions.
Tumor-associated macrophages (TAMs) are critically important in the context of solid tumor progression. Counterintuitively, these host immune cells can often support tumor cells along the path from primary tumor to metastatic colonization and growth. Thus, the ability to transform protumor TAMs into antitumor, immune-reactive macrophages would have significant therapeutic potential. However, in order to achieve these effects, two major hurdles would need to be overcome: development of a methodology to specifically target macrophages and increased knowledge of the optimal targets for cell-signaling modulation. This study addresses both of these obstacles and furthers the development of a therapeutic agent based on this strategy. Using ex vivo macrophages in culture, the efficacy of mannosylated nanoparticles to deliver small interfering RNA specifically to TAMs and modify signaling pathways is characterized. Then, selective small interfering RNA delivery is tested for the ability to inhibit gene targets within the canonical or alternative nuclear factor-kappaB pathways and result in antitumor phenotypes. Results confirm that the mannosylated nanoparticle approach can be used to modulate signaling within macrophages. We also identify appropriate gene targets in critical regulatory pathways. These findings represent an important advance toward the development of a novel cancer therapy that would minimize side effects because of the targeted nature of the intervention and that has rapid translational potential.
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA; Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University, Nashville, TN, USA; Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
Ryan A
RA
Ortega
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
Whitney
W
Barham
Department of Neuroscience, Vanderbilt University, Nashville, TN, USA.
Kavya
K
Sharman
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
Oleg
O
Tikhomirov
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA; Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University, Nashville, TN, USA; Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
Todd D
TD
Giorgio
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
Fiona E
FE
Yull
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D045744:Cell Line, Tumor; D054370:Chemokine CXCL9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D008055:Lipids; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; D008055:Lipids; C086724:Lipofectamine; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha
RNAi; cancer immunology; nanotechnology; targeted nanoparticles