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Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Nature Nanotechnology volume 17, pages 319–330 (2022)Cite this article

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Abstract

Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin’s cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution.

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Fig. 1: SC rapamycin delivery via rPS tolerizes intraportal islet grafts via direct modulation of APCs instead of T cells.
Fig. 2: SC delivery via PS alters rapamycin’s biodistribution and immunomodulation.
Fig. 3: rPSs modulate APCs to induce T cell costimulation blockade.
Fig. 4: rPS treatment upregulates M/Ms and induces a predominant suppressive phenotype.
Fig. 5: rPS treatment induces upregulation of DP CD4bright CD8dim T cells with suppressor functions.
Fig. 6: rPSs reduce the effective drug dosage to achieve normoglycemia and mitigate side effects in vivo via antigen-specific tolerance.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Raw RNA-seq reads and data are accessible through GEO Series accession number GSE182776. Other raw and analysed datasets generated during the study are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

A.D. Jerez designed and created the illustration in Fig. 1. Modifications were made by J.A.B. This research is based on work supported by the National Science Foundation Graduate Research Fellowship under grant no. DGE-1842165. This work was funded in part by the National Institutes of Health (NIH grant no. 1DP2HL132390-01); the National Science Foundation (NSF grant no. DGE-1842165); the Center for Advanced Regenerative Engineering (CARE) at Northwestern University; services and equipment were used at the Flow Cytometry Facility at the University of Chicago; the Integrated Molecular Structure Education and Research Center (IMSERC) at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF grant no. ECCS-1542205), the State of Illinois and the International Institute for Nanotechnology (IIN); the Northwestern University Center for Advanced Molecular Imaging (CAMI), which is supported by NCI grant no. CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center; the BioCryo facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource (NSF grant no. ECCS-1542205); the MRSEC program (NSF grant no. DMR-1720139) at the Materials Research Center; the IIN; and the State of Illinois, through the IIN; and Northwestern University NUSeq Core Facility (NSF grant no. DMR-1229693). SAXS experiments were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by Northwestern University, The Dow Chemical Company, and DuPont de Nemours, Inc. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Data was collected using an instrument funded by the National Science Foundation under Award No. 0960140.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA

    Jacqueline A. Burke, Carolina Bohorquez Fuentes, Helena Freire Haddad, Guillermo A. Ameer & Evan A. Scott

  2. Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA

    Jacqueline A. Burke, Carolina Bohorquez Fuentes, Helena Freire Haddad, Guillermo A. Ameer & Evan A. Scott

  3. Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Xiaomin Zhang & Evan A. Scott

  4. Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA

    Sharan Bobbala

  5. Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA

    Molly A. Frey, Sean D. Allen, Reese A. K. Richardson, Guillermo A. Ameer & Evan A. Scott

  6. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA

    Guillermo A. Ameer & Evan A. Scott

  7. Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Guillermo A. Ameer

  8. Simpson Querrey Institute, Northwestern University, Chicago, IL, USA

    Guillermo A. Ameer & Evan A. Scott

  9. International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA

    Guillermo A. Ameer & Evan A. Scott

  10. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA

    Evan A. Scott

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  1. Jacqueline A. Burke
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Contributions

J.A.B. designed the experiments with the assistance of S.D.A. J.A.B., X.Z., S.B., M.A.F., C.B.F. and H.F.H. performed the experiments. R.A.K.R. performed computational analysis on the RNA-sequencing data. J.A.B. analysed the data and composed the manuscript. E.A.S. and G.A.A. supervised the study.

Corresponding authors

Correspondence to Guillermo A. Ameer or Evan A. Scott.

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J.A.B., S.D.A., E.A.S. and G.A.A. are coinventors on a patient application related to the work presented in this manuscript. The other authors declare no competing interests.

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Burke, J.A., Zhang, X., Bobbala, S. et al. Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability. Nat. Nanotechnol. 17, 319–330 (2022). https://doi.org/10.1038/s41565-021-01048-2

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