RT Journal Article
SR Electronic
T1 Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.03.281923
DO 10.1101/2020.09.03.281923
A1 Jacqueline A. Burke
A1 Xiaomin Zhang
A1 Sharan Kumar Reddy Bobbala
A1 Molly A. Frey
A1 Carolina Bohorquez Fuentes
A1 Helena Freire Haddad
A1 Sean D. Allen
A1 Reese A.K. Richardson
A1 Luís A. Nues Amaral
A1 Guillermo A. Ameer
A1 Evan A. Scott
YR 2020
UL http://biorxiv.org/content/early/2020/09/04/2020.09.03.281923.abstract
AB Rapamycin is an orally administered immunosuppressant that is plagued by poor bioavailability and a wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, a wide range of side effects and provides inadequate transplantation protection. Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)) (PEG-b-PPS) polymersome (PS) nanocarriers modulates the cellular biodistribution of rapamycin to change its immunosuppressive mechanism of action 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 StatementJ.B., S.D., E.S., and G.A. are coinventors on a patent application related to the work presented in this manuscript.