In an effort to enhance efficacy and reduce side effects, paradigms in the realm of drug delivery have shifted toward combining toxic drugs with molecular vehicles with subsequent in-depth investigation of the altered pharmacokinetic and pharmaco-dynamic properties. Such carrier systems are usually of sufficient size to permit passive accumulation within regions of enhanced permeability, specifically tumor and inflamed tissue. The specificity and therapeutic efficacy of such materials can be further improved through the addition of an active targeting moiety or ligand that is specific for receptors found only within the diseased region. Thus, targeted drug delivery makes real the possibility of designing drug loaded carrier systems to treat specific diseases. The principle investigator's long term objective is to tailor delivery systems for the selective treatment of rheumatoid arthritis. Polysaccharides are natural, biodegrable, non-immunogenic polymers of increasing interest in the field of drug delivery. Poly(sialic acid) in particular has garnered attention because the body lacks all known receptors; therefore, carrier systems based upon poly(sialic acid) are anticipated to increase circulatory stability and reduce uptake by the reticuloendothelial system beyond other more commonly used materials. The intellectual merit of this proposal lies in the use of poly(sialic acid)-based nanoparticle carrier systems for the treatment of rheumatoid arthritis. Additionally, another polysaccharide, hyaluronic acid, will be used facilitate active targeting of the CD44 hyaluronic acid receptor that is over-expressed by synovial cells found within inflamed joint tissue. We hypothesize that polysaccharide-based nanoparticle carriers will (1) facilitate site specific delivery and (2) increase the efficacy and reduce the non-specific toxicity of existing therapeutics. The first objective will be the design, synthesis, and characterization of polysaccharide-based nanoparticles in the form of gels and micelles for the encapsulation of methotrexate and cyclosporine A respectively. As a second objective, the drug loaded polysaccharide-based nanoparticles will be tested in vitro with rheumatoid arthritis synovial fibroblasts by monitoring uptake with confocal microscopy and assessing changes in the cytokine profile by multiplex immunoassay. The third objective will be administration of the polysaccharide-based nanoparticles to a murine model of rheumatoid arthritis to examine biodistribution and efficacy. Thus, the principle investigator will successfully develop an improved system for the treatment of rheumatoid arthritis. A key aspect of this project is the broader participation plan which aims to increase the number of students with disabilities in engineering at Syracuse University. With 60% of diagnosed people unable to work or attend school for extended periods of time over the course of the disease, rheumatoid arthritis is closely associated with physical disability. The proposed research topic therefore uniquely integrates with the broader participation plan. The principle investigator will be working closely with the Burton Blatt Institute (BBI) located at Syracuse University. Worldwide, the BBI is the premiere organization for advancing the civic, economic, and social participation of persons with disabilities. Locally, the BBI is committed to integrating disability related content into existing curricula, increasing the number of enrolled students with disabilities, and creating a more disability friendly campus. Through the BBI, the PI will become increasingly involved in the discussion and research of issues that affect people with disabilities. The PI will be a speaker in an ongoing seminar series held by the BBI at Syracuse University and will be an active participant in meetings, workshops, and other public engagements organized by the BBI. In addition to these activities intended to increase awareness of members of both the University and the local community to disabilities, particularly those related to rheumatoid arthritis, the PI intends to recruit two students with disability to her laboratory (one undergraduate, one graduate) with the assistance of the BBI and the support of the Dean of the College of Engineering and Computer Science. These initial recruitment efforts will matriculate in an increase in the number of students with disabilities in the engineering program at Syracuse University.

Project Report

Historically, rheumatoid arthritis (RA), a chronic inflammatory disease, has been treated with broad range immunosuppressants, such as cyclosporine and dexamethasone, or with cytotoxic cancer therapeutics that have immunosuppressive side effects, particularly methotrexate. These so called disease-modifying anti-rheumatic drugs (DMARDs) have severe, potentially life threatening, consequences due to non-specific targeting, i.e. delivery to non-diseased tissue, in combination with impaired immune function. In recent years, toxic drugs have been combined with molecular vehicles to promote delivery exclusively to the diseased region, thereby increasing drug effectiveness and reducing side effects. To further enhance this specificity, the carrier systems are often combined with functional groups, or ligands, such as antibodies, oligosaccharides, and small peptides that target receptors found on the diseased tissue. The goal of this research was to generate non-immunogenic, biodegradable drug delivery systems that tarted inflamed tissue for the treatment of RA from natural polymers, specifically polysaccharides. Nano-sized carriers for entrappment of DMARDs (cyclosporine, dexamethasone, and methotrexate) were prepared with the appropriate sizes for escape from the "leaky" blood vessels that characterize the disease. These carrier systems can be further modified with oligosaccharide ligands that will bind specifically to receptors found on RA synovial fibroblasts, the so-called conductors of joint destructions. Methotrexate and dexamethasone were able to retain bioactivity upon entrapment in the nanocarriers. This research program was used to encourange/facilitate the participation of women and students with disabilities in STEM. Recruitment efforts attracted two students with physical disabilites and two students with learning disabilites to the lab. All of these students made key contributions and have continued on towards careers in engineering. In addition, a collaboration was established with Girls Incorporated of the YWCA of Syracuse and Onondaga County to provide support and positive encouragement for young girls to participate in science and engineering.

Project Start
Project End
Budget Start
2010-09-01
Budget End
2013-08-31
Support Year
Fiscal Year
2010
Total Cost
$174,990
Indirect Cost
Name
Syracuse University
Department
Type
DUNS #
City
Syracuse
State
NY
Country
United States
Zip Code
13244