Towards targeted delivery of biologics to chronic inflammation sites using innovative nanosystems
Inflammation is a complex process that involves the infiltration of immune cells and pro-inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), to the site of inflammation. Nanomedicines, including monoclonal antibodies and nanoparticles, are widely used in the treatment and diagnosis of chronic inflammatory diseases. However, repetitive use of biologics can render them ineffective or result in serious toxicities that may, in many cases, reduce the patient’s quality of life. In this dissertation, different nanotechnology approaches were utilized to overcome the inefficacy or toxicity of current medications; such approaches include small interfering RNA (siRNA)-based formulations and monoclonal antibody-chemical conjugation.
There has been growing interest in utilizing siRNA specific to pro-inflammatory
cytokines, such as TNF-α, in chronic inflammation therapy. However, delivery systems that can increase the distribution of siRNA in chronic inflammation sites after intravenous administration are needed. Herein we developed two innovative surface-functionalized siRNA-incorporated formulations that significantly increase the delivery of siRNA in chronic inflammation sites in a mouse model. The first formulation is an acid–sensitive sheddable PEGylated poly (lactic-co-glycolic) acid (PLGA) nanoparticle, which showed significantly higher accumulation or distribution of siRNA in chronic inflammation sites. However, the polymeric nanoparticles suffer from low encapsulation efficiency and high burst release of siRNA. Therefore, we designed a solid lipid nanoparticle (AS-TNF-α-siRNA-SLNs) formulation that has high siRNA encapsulation efficiency and minimum burst release of TNF-α siRNA, and can target inflamed tissues after intravenous administration. This novel composition was intended to avoid siRNA-burst release associated with our previous siRNA formulation. The developed AS-TNF-α-siRNA-SLNs resulted in significantly reduced paw thickness, bone loss, and histopathological scores in a mouse model of collagen antibody-induced arthritis that does not respond to methotrexate therapy.
Finally, we investigated the effect of the size of nanoparticles on their specific distribution and retention in chronic inflammation sites. In this dissertation we discovered that larger nanoparticles (100-200 nm) and macromolecules (e.g. IgM) have a higher specificity to chronic inflammation sites than smaller nanoparticles (2-10 nm) and macromolecules (e.g. IgG); surprisingly, however, smaller nanoparticles of 2-10 nm have longer retention within chronic inflammation sites. Based on these findings, proteins were crosslinked to form redox-sensitive nanoparticles of around 100-200 nm, which were found to increase the specificity of the proteins toward chronic inflammation sites as well as their retention in chronic inflammation sites. The redox-sensitive nanoparticle platform technology can be potentially used to increase the specific distribution of monoclonal antibodies in chronic inflammation sites.