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Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

Nature Biomedical Engineering volume 5, pages 983–997 (2021)Cite this article

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Abstract

Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.

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Fig. 1: Bile-acid polymers formulated into drug-loaded biodegradable nanoparticles.
Fig. 2: Composition and dose-dependent pancreatic accumulation of pBA nanoparticles.
Fig. 3: Prevention of T1D.
Fig. 4: Short-term treatment and long-term regression of T1D after pUDCAIns nanoparticle oral ingestion, activation of TGR5-induced endogenous GLP-1 and insulin secretion, and anti-inflammatory effect of pUDCA.
Fig. 5: Increased stability in the stomach milieu, permeation through intestinal cells and pUDCA nanoparticle binding to TGR5 with high avidity.
Fig. 6: Mechanisms of pUDCA biodistribution, pancreatic accumulation and immune modulation after oral ingestion.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data for the figures are provided with this paper. The raw and analysed datasets generated during the study are too large to be publicly shared, but are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

We thank K. Herold and R. Flavell for helpful discussions and input regarding the diabetic animal models and future applications of the technology; Pfizer Autoimmune Inc. (Cambridge, MA) for partial funding of this work; the JDRF for an early pilot grant that motivated the work; the Yale Autoimmune Center of Excellence pilot grant to T.M.F. (director K. Herold). This work was partially supported by NIH grants 1R01CA199004 and 1R01CA026412 to T.M.F and Toralgen Inc., by Novartis Institutes for BioMedical Research and by the Yale Institute for Nanoscience and Quantum Engineering to T.M.F.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    Jung Seok Lee, Shihan Khan, Sean Bickerton, Michael D. McHugh, Alyssa L. Siefert, Jason Criscione, Karlo Perica, Robert Samstein, Ragy Ragheb, Dongin Kim & Tarek M. Fahmy

  2. Chemical and Environmental Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA

    Patrick Han, Rabib Chaudhury & Tarek M. Fahmy

  3. Department of Chemistry, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA

    Hyun Bong Park

  4. Toralgen Inc., Indianapolis, IN, USA

    Gerald Rea

  5. Novartis Institutes for BioMedical Research, Basel, Switzerland

    José M. Carballido

  6. Medicine and Molecular Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    David A. Horwitz

  7. Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Dongin Kim

  8. Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA

    Tarek M. Fahmy

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Contributions

J.S.L. performed most experiments, wrote the methods and edited the manuscript. D.K. helped with the in vivo experiments. P.H. and R.C. assisted with animal experiments. P.H., R.C., S.K., S.B. and M.D.M. helped with flow cytometry, ELISA and data analysis. H.B.P. performed NMR and analysed spectra. G.R. contributed to the pig experiments. J.M.C. and A.L.S. were involved in the experimental design and provided intellectual feedback. D.A.H. provided gifts that partially supported this work and intellectual feedback. K.P., R.S., J.C. and R.R. were involved in the initial design and in vitro testing of the polymer. T.M.F. supervised the project, conceptualized and designed all experiments and prepared the manuscript.

Corresponding author

Correspondence to Tarek M. Fahmy.

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Competing interests

T.M.F is a founder and major shareholder of Toralgen Inc., which focuses on the use of the system described in this work for different disease states, including autoimmunity and specifically type 1 and type 2 diabetes.

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Peer review information Nature Biomedical Engineering thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

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Lee, J.S., Han, P., Chaudhury, R. et al. Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin. Nat Biomed Eng 5, 983–997 (2021). https://doi.org/10.1038/s41551-021-00791-0

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