Despite the success of TNF-inhibitors and other new biological drugs for the treatment of autoimmune and other chronic inflammatory diseases, there are still many patients that respond poorly. Suppressing NF-kB induction as treatment of chronic inflammatory diseases with a primary Th1-type cytokine profile (like e.g. Rheumatoid Arthritis, Multiple sclerosis, Type 1 diabetes and others) is the goal of majority of treatments including TNF-inhibitors. Intracellularly-acting NF-kB activation-inhibitors, such as IkB-kinase inhibitor and NF-kB nuclear translocation inhibitor, are very effective in cultured cells. However, in vivo use of these agents against chronic inflammatory diseases is severely limited by their very short half-life in blood. Formulating these inhibitors into a nanocarrier can protect these inhibitors from enzyme degradation in the blood and rapid excretion by the kidney. In this application these two inhibitors will be formulated into nanocarriers. The nanocarriers are a Protected Graft Copolymer (PGC), in which a polymer backbone is grafted with: 1) polyethylene glycol (PEG) side chains, and 2) reversible binders of the peptide inhibitors. The inhibitors will bind to PGC and the PEG-side chains will protect these inhibitors from enzyme degradation in the blood and rapid excretion by the kidney. Because of size (15-30nm), the complex will accumulate at site of inflammation and will release the inhibitors by an affinity based driven release, which is an equilibrium or dissociation constant (Kd) driven release. Because the inhibitors contain cell penetrating sequences, they will readily enter cells at site of inflammation, inhibit NF-kB activation, and thus suppress inflammatory diseases. Collagen induced arthritis, a mouse model of rheumatoid arthritis, will be treated in this particular application to show proof of concept. The acute and chronic toxicity of the formulations will also be evaluated in this proposed project. Our goal for this project is to develop a product for the treatment for chronic inflammatory diseases that will lead to FDA approved treatment for humans.
Intracellularly-acting NF-kB activation inhibitors, such as IkB-kinase inhibitor and NF-kB nuclear translocation inhibitor, are very effective in cultured cells. However, in vivo use of these agents against chronic inflammatory diseases, although effective, is severely limited by their very short half-life in blood. In this project, these inhibitors will be formulated into nanocarriers that: 1) accumulates at sites of inflammation;2) can protect these inhibitors from enzyme degradation in the blood;and 3) prevent rapid excretion by the kidney. The project will allow use of these agents in many human inflammatory diseases.
