Manipulating the NF-κB pathway in macrophages using mannosylated, siRNA-delivering nanoparticles can induce immunostimulatory and tumor cytotoxic functions

Abstract

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.

Intranasal Vaccination with Mannosylated Chitosan Formulated DNA Vaccine Enables Robust IgA and Cellular Response Induction in the Lungs of Mice and Improves Protection against Pulmonary Mycobacterial Challenge

“…vaccination (Figure 6 ). In addition to our data, previous study showed that mannosylated polymer nanoparticles specifically and effectively delivered siRNA to tumor associated macrophages (TAMs) (Ortega et al, 2015 ) and made the encapsulated siRNA more capable to manipulate NF-κB signaling in the tumor (Ortega et al, 2016 ); and man-chitosan nanoparticles effectively enhanced the transfection efficiency of DNA and lowered the toxicity of chitosan in peritoneal macrophages (Hashimoto et al, 2006 ). Taken together, we and others demonstrate that mannosylation of drugs, proteins, genes or their delivery vectors significantly enhance their accessibility to and transfection efficiency in the macrophages, therefore may greatly enhance the therapeutic efficiency or vaccine immunogenicity.…”

Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1

“…We and others have shown that metabolic reprogramming and resulting substrate preference in response to activating stimuli play pivotal roles in immune cell biology, acting as a determinant of inflammatory potential in MFs and dictating functionality of NK, T, and B cells (9, 11-13, 19, 54, 66, 68-72). Based on the importance of metabolism in determining immunophenotype and response, nutrient transporters may be excellent targets to regulate MF activation and subtypes, allowing these immune cells to be successfully targeted through approaches such as nanoparticle delivery (73)(74)(75)(76).…”

Tumor-Associated Macrophages as Target for Antitumor Therapy

“…Ortega et al ( 2015 ) reported that mannosylated polymer nanoparticles were able to deliver siRNA to TAMs in vitro and in vivo in the peritoneum of ovarian tumor bearing mice and in TAMs present in lung metastases. In addition, delivery of siRNA targeting the NF-κB pathway into TAMs of tumor bearing mice resulted in induction of a proinflammatory immunogenic phenotype in transfected macrophages and yielded an antitumor phenotype (Ortega et al 2016 ). Moreover, dual targeted immunotherapy via in vivo delivery of biohybrid siRNA-peptide nanoparticles to tumor macrophages substantially reduced the recruitment of TAMs in lung tumor tissue, reduced tumor size, and increased animal survival (Conde et al 2015 ).…”