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Regulation of vascular endothelial signaling with therapeutic nanoparticles that target the NF‐κB pathway
Author(s) -
Pan Hua,
Lanza Gregory M,
Wickline Samuel A
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.956.3
Subject(s) - downregulation and upregulation , vcam 1 , nf κb , microbiology and biotechnology , chemistry , inflammation , endothelial stem cell , signal transduction , cancer research , tumor necrosis factor alpha , cell adhesion molecule , icam 1 , immunology , biology , biochemistry , in vitro , gene
NF‐κB is a pivotal mediator of chronic inflammatory processes in atherosclerosis functioning in part by upregulating endothelial adhesion molecules (VCAM‐1) and by activating cellular components (macrophages). We have developed a VCAM‐targeted nanoparticle‐based therapeutic approach that inhibits pathological upregulation of endothelial NF‐κB yet simultaneously maintains physiological levels of the critical signaling elements that participate in normal cellular immune responsiveness. Multiplexed cargos (targeting and therapeutic) were loaded onto perfluorocarbon nanoparticles (200 nm) with the use of novel amphipathic fusion peptide linkers. VCAM‐1 targeting employed a specific peptide ligand against VCAM‐1; NF‐κB inhibition utilized an IKK‐γNEMO Binding Domain (NBD) inhibitory peptide to prevent IκB depletion. Mouse endothelial cells (2F2B) subjected to TNF‐α stimulation to upregulate NF‐κB expression exhibited significant (p = 0.04687) and normalization ( figure) of total level of phosphorylated p65 at Ser‐468 by Fast Activated Cell‐based ELISA when pretreated with NBD nanoparticles for 1 hour. ELISA revealed that both IL6 and GM‐CSF expression were significantly downregulated (17.53%, p=0.029 and 16.66%, p=0.020, respectively) in treated TNF‐α stimulated endothelial cells. Immunohistochemistry also confirmed concomitant downregulation of endothelial VCAM‐1 expression. We conclude that rationally designed multiplexed anti‐inflammatory targeted nanoparticles enable selective delivery of the endothelial targeted NF‐κB inhibitors and may offer a novel therapeutic strategy for regulating vascular inflammation in atherosclerosis.