639. Gene Expression Analysis of LPS Stimulated THP-1 Cells Treated with Antisense IRAK1 Delivered Using a pH-Sensitive, Membrane Disruptive Polymer

Abstract

Goals and Significance: The inflammatory response, which is initiated upon trauma, infection, or in the presence of a foreign body, is necessary for normal wound healing. However, during chronic inflammation, control of this response becomes clinically advantageous. The interleukin-1 (IL-1) pathway to nuclear transcription factor κB (NF-κB) is a major contributor to the inflammatory response. IL-1 Receptor Associated Kinase-1 (IRAK1) is a central kinase in this pathway and is a target molecule for controlling NF-κB activation and the subsequent production of inflammatory mediators. Decreasing the expression of IRAK1 has been accomplished through the use of an antisense oligonucleotide. By delivering an 18-mer oligodeoxynucleotide (ODN) complimentary to the mRNA sequence of IRAK1, production of this kinase was inhibited. ODN uptake generally occurs through endocytosis, after which molecules are trafficked to the lysosome and degraded, resulting in loss of the therapeutic ODN. In an effort to improve the delivery of ODNs and other biological molecules, a family of pH-sensitive membrane disruptive polymers has been developed in our lab. These polymers are able to enhance cytoplasmic delivery of therapeutics by releasing them from the endosome. The polymer used in this study consisted of a hydrophobic, membrane disruptive backbone linked via acid degradable acetal bonds to hydrophilic poly(ethylene glycol) (PEG). The PEG groups mask the hydrophobic backbone until the acetal bonds degrade at the low pH of the endosome or lysosome, freeing the hydrophobic backbone to disrupt the endosomal membrane and deliver the therapeutic cargo to the cytoplasm of the cell.