Magnetically powered chitosan milliwheels for rapid translation, barrier function rescue, and delivery of therapeutic proteins to the inflamed gut epithelium

Abstract

Inflammatory bowel disease (IBD) is mediated by an overexpression of tumor necrosis factor- (TNF) by mononuclear cells in the intestinal mucosa. Intravenous delivery of neutralizing anti-TNF antibodies can cause systemic immunosuppression and up to one-third of people are non-responsive to treatment. Oral delivery of anti-TNF could reduce adverse effects; however, it is hampered by antibody degradation in the harsh gut environment during transit and poor bioavailability. To overcome these shortcomings, we demonstrate magnetically powered hydrogel particles that roll along mucosal surfaces, provide protection from degradation, and sustain local release of anti-TNF. Iron oxide nanoparticles are embedded into a crosslinked chitosan hydrogel and sieved to produce 100-200 m particles called milliwheels (m-wheels). Once loaded with anti-TNF, these m-wheels release 10% to 80% of their payload over one week at a rate that depends on crosslinking density and pH. A rotating magnetic field induces a torque on the m-wheels that results in rolling velocities greater than 500 m/s on glass and mucus-secreting cells. The permeability of TNF challenged gut epithelial cell monolayers was rescued in the presence of anti-TNF carrying m-wheels which both neutralized the TNF and created an impermeable patch over leaky cell junctions. With the ability to translate over mucosal surfaces at high speed, provide sustained release directly to the inflamed epithelium, and provide barrier rescue, m-wheels demonstrate a potential strategy to deliver therapeutic proteins for the treatment of IBD.