Shardool Jain, a doctoral candidate in the Department of Pharmaceutical Sciences, wins the prestigious 2013 Graduate Student Award (BIOTEC Section) sponsored by Eli Lilly at the American Association of Pharmaceutical Scientists sponsored National Biotechnology Conference in San Diego, CA.
Working in the laboratory of Distinguished Professor and Chair Mansoor Amiji, Shardool’s thesis research focuses on “Macrophage-Targeted Based Alginate Nanoparticle as Non-Viral Vector for Anti-Inflammatory Gene Therapy in Treatment of Experimental Arthritis”. Rheumatoid arthritis (RA) is as an autoimmune systemic disease associated with stiffness, pain, and swelling of several joints. The severity of RA has been directly linked to the number of macrophages present in the arthritic synovium. Additionally, macrophages in the synovial lining are characterized by strong HLA-DR expression and found in an activated state. There is strong evidence indicating that synovial macrophages are capable of secreting pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), growth factors (GM-CSF), chemokines and chemo-attractants (IL-8, macrophage inflammatory protein (MIP)-1, and monocyte chemo-attractant protein (MCP)-1 that contribute towards inflammation and joint destruction. Thus, targeting macrophages from a therapeutic perspective is a rational approach given their presence in abundance and central role in cytokine mediated inflammation associated with RA.
The therapeutic goal of this project is to develop a safe and effective non-viral gene delivery system for IL-10-expressing plasmid DNA and transfection for anti-inflammatory therapy for the treatment of experimental arthritis in male Lewis rats. The system utilized to make nanoparticles is based on a non-condensing approach that focuses on physical encapsulation of the plasmid DNA rather than electrostatic complexation with the delivery system. Furthermore, the surface of the nanoparticles is modified with tuftsin peptide to target macrophages. The in-vitro studies conducted in J774A.1 macrophage cell line demonstrated that tuftsin-modified alginate nanoparticles are superior in their ability to target macrophages and thus, can afford higher transgene expression as compared to commercially available transfection reagents. The therapeutic efficacy study conducted in adjuvant-induced arthritis rats provides evidence on the ability of tuftsin-modified alginate nanoparticles as an effective non-condensing DNA delivery system targeted to activated macrophages for the treatment of systemic inflammation. Treatment with peptide-modified nanoparticles resulted in amelioration of inflammation. Both qualitative and quantitative measures of efficacy at the physical and molecular levels indicated that not only tuftsin-modified particles resulted in alleviation of pro-inflammatory markers but also these animals were able to retain their mobility whereas animals in the control group suffered from uncontrolled inflammation and consequently, reduced mobility. In addition, these studies will be further bolstered by experiments to highlight the switch in the synovial macrophage phenotype from pro-inflammatory (M1-classically activated state) to anti-inflammatory (M2-alternate activated state) upon IL-10 transgene expression using tuftsin-modified alginate nanoparticle treatment.