Abstract 577: NF-kB Inhibition via Celastrol-Loaded Nanocarriers Induces Distinct Changes in Atheroma-Resident Immune Cell Composition in Male vs. Female ldlr -/- Mice

Abstract

The immune component of atherosclerosis is strongly influenced by inflammatory signaling. Although NF-kB signaling is a key regulator of cytokine expression and activation of atheroma-resident macrophages and dendritic cells, previous attempts at its therapeutic inhibition have generated inconsistent results. These difficulties may arise from nonspecific systemic administration of inhibitors that have pleiotropic effects in both immune and non-immune cells in multiple organs. To address these concerns, we have developed a nanocarrier delivery system (NCs) capable of transporting both hydrophobic and hydrophilic therapeutics to the cytosol of specific immune cell subsets. Following I.V. administration, our NCs are readily endocytosed by macrophages and dendritic cells within atheromas for modulation of signaling pathways. We hypothesized that delivery of the NF-kB pathway inhibitor celastrol to these cells via celastrol-loaded NCs (Cel-NCs) may alleviate atherosclerotic inflammation while minimizing off-target effects. Celastrol has potent anti-inflammatory effects, but also modulates unrelated signaling pathways in a range of cells and is cytotoxic near its effective inhibitory concentration (EIC). The low water solubility of celastrol is not amenable to I.V. injection, and oral administration achieves poor bioavailability and specificity for atheroma-resident cells. We have found that loading celastrol into Cel-NCs expands its EIC, reduces cytotoxicity, and allows it to be administered via I.V. injection for improved targeting of atheroma. When injected into ldlr -/- mice, Cel-NCs modulated the immune composition within the aorta and spleen. Notably, these changes differed between male and female mice, possibly due to immuno-endocrine related mechanisms. Our work introduces a nanotherapeutic to reduce atherosclerotic inflammation and highlights the need to identify the effects of anti-inflammatory strategies in both sexes.