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Abstract Number: 2362

Enhanced Efficacy of Dexamethose with Synovial Fibroblast Targeted Micelles in a Collagen-Induced Arthritis Mouse Model

Rebecca A. Bader, David R. Wilson, Arundhati Ramani and Patricia R. Wardwell, Biomedical & Chemical Engineering, Syracuse University, Syracuse, NY

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: dexamethasone, drug therapy, nanomedicine and rheumatoid arthritis (RA)

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Session Information

Session Title: Rheumatoid Arthritis - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose:  A number of conventional, disease modifying anti-rheumatic drugs (DMARDs) are associated with severe side effects due to non-specific targeting and impaired immune function. To improve therapeutic efficacy and reduce negative consequences, our research group has developed a platform for site-specific delivery to the synovial tissue based upon the self-assembly of polycaprolactone modified polysialic acid (PSA-PCL) into micelles. Hydrophobic DMARDs, such as dexamethasone (DM), can be entrapped within the micelles at a loading capacity of 0.1 mg DMARD/mg of PSA-PCL. To further enhance specificity, targeting of the overexpressed CD44 receptor on RA synovial fibroblasts was achieved by modifying the PSA-PCL with hyaluronic acid (HA) oligomers to yield PSA-PCL-HA micelles. The goal of this study was to establish the in vivo therapeutic efficacy of DM-loaded, PSA-PCL-HA micelles using a collagen-induced arthritis (CIA) mouse model.

Methods: 24 male, DBA/1J mice were divided into four treatment groups: non-diseased, diseased (with no drug therapy), free DM (3.0 mg DM/kg), and DM-loaded micelle (3.0 mg PSA-PCL-HA/kg ~ 0.3 mg DM/kg). At day 28 following induction of collagen-induced arthritis (CIA) in 18 of the 24 mice, each mouse was scored for arthritis index (AI). Treatments were administered via tail-vein injection starting on day 32. Subsequently, the mice received IV doses every 3 days until completion of the study on day 44. Treatment groups designated as diseased and non-diseased received tail vein injections of PBS alone (10 mL/kg).

Results: Based upon the average AI, DM, alone and when entrapped within the PSA-PCL-HA micelles, reduced the symptoms of RA. Mice that were administered treatments of DM-loaded micelles were provided with 1/10th the DM dose received by mice within the free DM treatment group. Despite the significantly reduced dose, the DM-loaded micelles yielded a decrease in average AI that was comparable to that obtained with free DM.

Conclusion: This study demonstrated that our targeted, drug delivery platform can be used to enhance the therapeutic efficacy of hydrophobic DMARDS. DM loaded into the PSA-PCL-HA micelles was as effective as free DM when administered at 1/10th the dose to mice with CIA.  


Disclosure:

R. A. Bader,
None;

D. R. Wilson,
None;

A. Ramani,
None;

P. R. Wardwell,
None.

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