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

• Published in: bioRxiv
• Main Authors: Burke, Jacqueline A, Zhang, Xiaomin, Sharan Kumar Reddy Bobbala, Frey, Molly A, Carolina Bohorquez Fuentes, Helena Freire Haddad, Allen, Sean D, Reese Ak Richardson, Ameer, Guillermo A, Scott, Evan A
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 06.10.2020
• Subjects: Bioavailability; Biodistribution; CD4 antigen; CD8 antigen; Cell proliferation; Dendritic cells; Hydrophobicity; Immunomodulation; Immunostimulation; Immunosuppression; Immunosuppressive agents; Inflammation; Islet cells; Ly-6 antigen; Lymphocytes T; Major histocompatibility complex; Monocytes; Pancreatic islet transplantation; Patent applications; Polyethylene glycol; Rapamycin; Side effects
• DOI: 10.1101/2020.09.03.281923

Abstract Oral rapamycin administration rapamycin is plagued by poor bioavailability and wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, numerous side effects and provides inadequate transplantation protection. Parental formulation was not possible due to rapamycin’s hydrophobicity (log P 4.3). Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)(PEG-b-PPS) polymersome (PS) nanocarriers modulates cellular biodistribution of rapamycin to change its immunosuppressive mechanism for enhanced efficacy while minimizing side effects. While oral rapamycin inhibits naïve T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) instead modulated Ly-6Clow monocytes and tolerogenic semi-mature dendritic cells, with immunosuppression mediated by CD8+ Tregs and rare CD4+ CD8+ double-positive T cells. As PEG-b-PPS PS are uniquely non-inflammatory, background immunostimulation from the vehicle was avoided, allowing immunomodulation to be primarily attributed to rapamycin’s cellular biodistribution. Repurposing mTOR inhibition significantly improved maintenance of normoglycemia in a clinically relevant, MHC-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of engineered nanocarriers to repurpose drugs for alternate routes of administration by rationally controlling cellular biodistribution. Competing Interest Statement J.B., S.D., E.S., and G.A. are coinventors on a patent application related to the work presented in this manuscript. Footnotes * The author list, figures and results were updated.