Nanocarrier-formulated NF-kB inhibitors for Inflammatory diseases

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R43AI094664-01A1
Agency Tracking Number: R43AI094664
Amount: $599,949.00
Phase: Phase I
Program: SBIR
Awards Year: 2011
Solicitation Year: 2011
Solicitation Topic Code: NIAID
Solicitation Number: PA10-123
Small Business Information
PHARMAIN CORPORATION
720 BROADWAY, STE 511, SEATTLE, WA, -
DUNS: 167580682
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 GERARDO CASTILLO
 (206) 568-1499
 gcastillo@pharmain.com
Business Contact
 CHERRI POE
Phone: (206) 568-1476
Email: cpoe@pharmain.com
Research Institution
 Stub
Abstract
DESCRIPTION (provided by applicant): 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-actingNF-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 protectthese 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 developa product for the treatment for chronic inflammatory diseases that will lead to FDA approved treatment for humans. PUBLIC HEALTH RELEVANCE: 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 inflammatorydiseases.

* information listed above is at the time of submission.

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