Delivery of Rapamycin Using In Situ Forming Implants Promotes Immunoregulation and Vascularized Composite Allograft Survival

Damian Sutter,Yara Banz,Jean-Christophe Prost,Lisa Rahnfeld,Esther Vögelin,Robert Rieben,Cedric Bovet,Jonas T Schnider,Paola Luciani,Dzhuliya V Dzhonova,Adriano Taddeo,Jan A Plock,Jean-Christophe Leroux

doi:10.1038/s41598-019-45759-y

Abstract

Vascularized composite allotransplantation (VCA), such as hand and face transplantation, is emerging as a potential solution in patients that suffered severe injuries. However, adverse effects of chronic high-dose immunosuppression regimens strongly limit the access to these procedures. In this study, we developed an in situ forming implant (ISFI) loaded with rapamycin to promote VCA acceptance. We hypothesized that the sustained delivery of low-dose rapamycin in proximity to the graft may promote graft survival and induce an immunoregulatory microenvironment, boosting the expansion of T regulatory cells (Treg). In vitro and in vivo analysis of rapamycin-loaded ISFI (Rapa-ISFI) showed sustained drug release with subtherapeutic systemic levels and persistent tissue levels. A single injection of Rapa-ISFI in the groin on the same side as a transplanted limb significantly prolonged VCA survival. Moreover, treatment with Rapa-ISFI increased the levels of multilineage mixed chimerism and the frequency of Treg both in the circulation and VCA-skin. Our study shows that Rapa-ISFI therapy represents a promising approach for minimizing immunosuppression, decreasing toxicity and increasing patient compliance. Importantly, the use of such a delivery system may favor the reprogramming of allogeneic responses towards a regulatory function in VCA and, potentially, in other transplants and inflammatory conditions.

Highlights

We used a biodegradable in situ forming implant (ISFI) loaded with the immunoregulatory drug rapamycin to deliver low-dose immunosuppression and promote acceptance of Vascularized composite allotransplantation (VCA) grafts by immunoregulatory mechanisms
When used in a VCA model, the ipsilateral injection of Rapa-ISFI promoted graft survival for >100 days. This consistent with the results achieved by other drug delivery systems such as FK506-loaded hydrogels[6,7] or biodegradable disks containing FK506-loaded double-walled microspheres[9], confirming that in situ delivery of immunosuppressive drugs is a feasible and promising approach in VCA
We recently reported the formation of a capsule around injected tacrolimus-loaded hydrogel[26] and the same is reported for other ISFI and biomaterials[27]

Summary

Introduction

We developed an innovative drug delivery system that combines the advantage of in situ delivery with the potential to induce local immune-regulation and transplant survival. To this aim, we designed a solvent-induced phase inversion in situ forming implant (ISFI) using the US Food and Drug Administration approved polymer poly(D,L-lactic-co-glycolic acid) (PLGA). We designed a solvent-induced phase inversion in situ forming implant (ISFI) using the US Food and Drug Administration approved polymer poly(D,L-lactic-co-glycolic acid) (PLGA) We loaded this ISFI with the immunoregulatory drug rapamycin and injected it in close proximity to the transplant. We hypothesized that sustained low-dose delivered rapamycin may promote graft survival with minimal immunosuppression through the induction of immunoregulatory mechanisms such as Treg expansion and increased chimerism levels

Methods

Results

Conclusion