Despite advancements in the synthesis of protein therapeutics, the standard administration method has remained by injection. This delivery route has frequently resulted in poor patient compliance, especially among children. Considerable effort has thus been placed on developing alternative and non-invasive delivery routes, in particular through oral administration. Though the oral route is regarded as the most convenient and practical administration route, two major obstacles limit its viability: enzymatic degradation in the gastrointestinal tract (GI) and physical transport across the epithelial layer into systemic circulation. These barriers limit the bioavailability of most proteins to well below 1%.

The proposed delivery mechanism involves encapsulating proteins within a biodegradable polymer shell, which protects proteins from enzyme digestion. In addition, the polymer shell releases proteins in a sustained release manner rather than all at once, maintaining blood levels for longer periods. However, these polymer vehicles typically exhibit a burst release where 10-80% of the encapsulated drug is released within the first 24 hours, raising toxicity concerns. The burst is attributed to the absorption of proteins within the polymer shell rather than the core during the encapsulation process, allowing them to readily diffuse out when delivered. To counteract this initial release, the proposed delivery vehicle will contain protein conjugated to the shell to provide an additional diffusion resistance. To do this, a biodegradable polymer based on PLGA will be engineered that contains functional groups along the repeating unit capable of protein conjugating.

To increase physical uptake across the epithelial layer, the polymer vehicle will be conjugated to transferrin (Tf), an active carrier protein involved in iron transport. Transferrin is highly expressed in the GI tract, and thus been investigated as an active carrier for orally delivered drugs. The nanoparticle-Tf conjugate will take advantage of a receptor-mediated transport pathway that actively transports the drug carrier across the cell rather than relying on passive diffusion. These polymer carrier-Tf conjugates have been shown to increase uptake by up to 400% in tumor cells, where Tf-receptors are also high expressed.

The resulting polymer carrier will reduce the burst release typically seen in these delivery systems, thus creating a sustained-release formulation that protects from enzyme degradation, making this a viable delivery method. Utilizing an active transport pathway to increase epithelial uptake will increase the bioavailability of the orally delivered protein, potentially creating a practical alternative to injected protein therapeutics.