(732a) Alginate/Chitosan Microparticles for Gastric Passage and Intestinal Release of Therapeutic Protein Nanoparticles

Proteins have significant potential to treat diseases due to their specific mechanisms of action compared to small molecule drugs. Protein nanoparticles offer a means to turn soluble protein, which has very low cellular uptake, into a colloidal protein carrier capable of enhanced uptake and subsequent intracellular activity. Previous work produced a stable therapeutic nanoparticle formulation encapsulating a bacterial effector protein, AvrA, which is capable of modulating inflammatory signals in an in vivo inflammatory bowel disease (IBD) mouse model. A major drawback is that these nanoparticles are instilled transrectally, limiting delivery to lower regions of the colon. To implement our protein nanoparticles as a clinically viable treatment for IBD with access to the entire intestinal tract and improved patient compliance, an oral formulation must be designed.

Localized intestinal delivery of protein therapeutics via the oral route is a highly attractive approach, however, the harsh acidic and enzymatic conditions in the gastrointestinal tract challenge retention of protein function. The approach is to deliver protein nanoparticles within gastro-protective microparticles made from alginate and chitosan that would release the nanoparticles in the intestine. A flow focusing microfluidic device was used to control alginate droplet diameters by tuning the continuous and dispersed phase flow rates. Alginate droplets encapsulating protein nanoparticles were then simultaneously crosslinked with calcium and layered with chitosan to form uniform, coated microparticles with high loading efficiency. Protein nanoparticles encapsulated within crosslinked alginate/chitosan microparticles retained approximately 50% of their activity after 1 hr incubation in simulated gastric fluid (SGF). Subsequent incubation in simulated intestinal fluid (SIF) released all remaining active protein within 3 hrs. Alginate vs. chitosan droplets, chitosan concentration, alginate concentration, number of layers, and crosslinker type were tuned to optimize protein protection in SGF and controlled release in SIF. Altogether, these hydrogel microparticles could serve as a potential oral delivery vehicle for protein therapeutics.