Localized heat application as a strategy for enhanced oral peptide absorption - A proof-of-concept study

The oral delivery of peptides remains a major challenge, particularly due to poor permeability across the gastrointestinal mucosa. While chemical permeation enhancers (PEs) are commonly used to improve absorption, recent efforts have explored physical strategies, including mechanical disruption of the gut lining. In this study, we investigated the potential of localized mild heat (≤ 42 °C) as a permeation-enhancing approach, alone and in combination with the chemical PE sodium caprate (C10). Applied to colorectal adenocarcinoma cell monolayers, heat treatment of 2 h moderately increased permeability and reduced transepithelial electrical resistance without inducing significant cytotoxicity. Heat exposure led to reorganization of tight junction (TJ) proteins without altering their expression. Phosphorylation-dependent modulation of TJ complexes was considered as a possible mechanism. In subsequent in vitro and ex vivo experiments, the combination of heat and C10 led to an additive increase in permeability. These findings support the concept of mild heat as a potential complementary physical enhancer in combination with chemical PEs to improve the bioavailability of orally administered macromolecules.