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

Jacqueline A Burke,Evan A Scott,Sean D Allen,Reese A K Richardson,Xiaomin Zhang,Molly A Frey,Helena Freire Haddad,Guillermo A Ameer,Sharan Bobbala,Carolina Bohorquez Fuentes

doi:10.1038/s41565-021-01048-2

Jacqueline A Burke, Evan A Scott + Show 8 more

Open Access

https://doi.org/10.1038/s41565-021-01048-2

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Abstract

Standard oral rapamycin (i.e. Rapamune®) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, 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)(PEG-b-PPS) polymersome (PS) nanocarriers significantly alters rapamycin’s cellular biodistribution to repurpose its mechanism of action for tolerance instead of immunosuppression while minimizing side effects. While oral rapamycin inhibits naïve T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) modulate antigen presenting cells in lieu of T cells significantly improving maintenance of normoglycemia in a clinically relevant, MHC-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.

Highlights

Type 1 diabetes (T1D) is an endocrine disorder that leads to pancreatic β cell destruction and requires management with lifelong exogenous insulin therapy[1]
Neither the PS vesicular nanostructure nor the polydispersity were significantly modulated by rapamycin loading as assessed by dynamic light scattering (DLS), cryogenic transmission electron micrograph and small angle x-ray scattering (SAXS) (Fig. 2a-c)
The stability of rapamycin loading was assessed in 1X phosphate buffered saline (PBS) at 4 °C, finding approximately 94% of the drug was retained over the course of 1 month (Fig. S1)

Summary

Introduction

Type 1 diabetes (T1D) is an endocrine disorder that leads to pancreatic β cell destruction and requires management with lifelong exogenous insulin therapy[1]. With the advent of the Edmonton protocol, islet transplantation has emerged as a promising treatment for T1D by eliminating the need for exogenous insulin[1]. This protocol involves three key components: acquisition of viable insulin-producing cells, surgical transplantation of these cells into a suitable physiological location to maintain glucose sensitivity and responsiveness, and an immunosuppressive regimen to maintain islet viability and protection from the host immune system[1]. While all three components remain active areas of research, the need for immunosuppression remains the key limitation preventing islet transplantation from becoming the clinical standard of care for all T1D patients[1,2]. More effective than prior immunosuppressive protocols involving intravenous steroid administration, patients undergoing transplantation procedures are still plagued by frequent graft rejection and an unpleasant array of side effects[3,4]

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