The gastrointestinal tract is the site of most drug delivery and therapeutic interventions for the management and treatment of numerous diseases. However, selective access to its mucosa, especially in the small bowel, is challenging. Here we develop an orally administered gut-coating formulation that provides a transient coating of the bowel. Through a materials screening campaign, we identified a sucrose octasulfate aluminium complex and further engineered the pH-dependent material into a complex coacervate formulation linked via pH-independent electrostatic interaction, which allowed an effective transient physical coating on the gastrointestinal mucosa, independent of gastric acid exposure. We tested the therapeutic values of this technology in two settings. Oral administration of this gut-coating formulation modulated the nutrient contact with bowel mucosa, which lowered the glucose responses in rodent models indicating a potential therapeutic utility in diabetes. Furthermore, the formulation protected biological agents from gastric acid exposure and degradation, which enabled oral delivery to the small bowel mucosa.
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This work was supported by NIH grant GM086433 to J.M.K., NIH grant DK084064 to A.T., Partners Innovation Development Grants Program and BRI Translational Technologies and Care Innovation Grant from Brigham Research Institute (BRI) to J.M.K. and A.T., Diabetes Action Research and Education Foundation Grant to J.M.K., Accelerator Award from CIMIT to J.M.K. and A.T., the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education of Korea (2012R1A6A3A03041166) and the Korea Institute for Advancement of Technology (N0002123) to Y.L. This work was supported in part by the Netherland–America Foundation (NAF) Fulbright Fellowship, the Ivy Circle Award and the Prince Bernard Culture Foundation Award to T.E.D. We thank J.N.M. IJzermans at Erasmus University Medical Center, Rotterdam, for his role as educational supervisor to T.E.D. The authors thank J. Tolkoff and F. Schoen for critical feedback. We thank S. Wang for the CT imaging and W. Li for the IVIS imaging.
Supplementary Methods, Supplementary Figures 1–10, Supplementary Table 1, Supplementary Movie Captions 1–7, Supplementary References 1–6
Representative 3D projection CT image of SD rats gavaged with 450 mg kg–1 rat sucralfate (dosage calculated based on the rat weight) 1 hr before the CT imaging
Representative 3D projection CT image of SD rats gavaged with 450 mg kg–1 rat sucralfate (dosage calculated based on the rat weight) 2.5 hr before the CT imaging
Video clip showing LuCI paste hydrated in SIF (pH 6.5) manually spread onto a freshly harvested rat intestine mucosa
Video clip showing LuCI paste hydrated in SIF (pH 6.5) manually spread onto a freshly harvested rat intestine mucosa (the same sample from Movie S3) and shaken in normal saline
Representative 3D projection CT image of SD rats gavaged with 450 mg kg–1 rat LuCI (dosage calculated based on the rat weight) 1 hr before the CT imaging
Representative 3D projection CT image of SD rats gavaged with 450 mg kg–1 rat LuCI (dosage calculated based on the rat weight) 5 hr before the CT imaging
Representative 3D projection CT image of SD rats gavaged with 450 mg kg–1 rat LuCI (dosage calculated based on the rat weight) 24 hr before the CT imaging