(282g) Invited: A Strawberry-Derived Solution to Oral Protein Delivery Conference: AIChE Annual MeetingYear: 2019Proceeding: 2019 AIChE Annual MeetingGroup: Food, Pharmaceutical & Bioengineering DivisionSession: Micro- and Nano-Scale Technologies in Life Sciences I Time: Tuesday, November 12, 2019 - 9:48am-10:28am Authors: Whitehead, K., Carnegie Mellon University Oral delivery is one of the most desired, patient-friendly modes of drug administration. Unfortunately, it is not possible for most biologic drugs, especially therapeutic proteins and nucleic acids, because of the low permeability of macromolecules from the intestines to the bloodstream. Although many chemical permeation enhancers have been identified that improve the intestinal absorption of biologics, they often cause cytotoxicity or damage the intestinal mucosa. To address this issue, we sought to identify a permeation enhancer derived from fruits and vegetables, hypothesizing that the compounds found in natural foods would be well-tolerated by the GI tract. To this end, we screened over 100 fruits, vegetables, herbs, and fungi for their effect on the permeability of the intestinal epithelial in vitro (Caco-2 monolayers). Of these, we identified strawberry as a potent enhancer of macromolecular permeability both in vitro and in vivo. In mice, it boosted the absorption of both 4 kDa and 40 kDa dextran by over 100%, demonstrating its versatility in improving the delivery of macromolecules of varied size. Natural product chemistry techniques were used to isolate pelargonidin, an anthocyanidin, as the active compound within the strawberry. In mice, pelargonidin- enabled 100% relative bioactivity of intestinally-instilled insulin, and intestinal permeability returned to baseline levels within four hours of treatment. Further, in vitro mechanistic studies revealed that the strawberry treatment temporarily rearranges the cytoskeletal protein actin and the tight junction protein ZO-1. These results underscore the potential of naturally-derived compounds in biomedical applications and demonstrate pelargonidin as a promising new enhancer for the oral delivery of biologics.