Microneedle-mediated transdermal delivery of FK506 for treatment of acute cardiac allograft rejection

Abstract

FK506 has been widely used to prevent acute rejection in heart transplantation (HT). However, its strong hydrophobicity, poor bioavailability, high pharmacokinetic variability, and narrow therapeutic window are obstacles to its application in HT. It has been demonstrated that localized and sustained immunosuppressant delivery may be a suitable route for FK506 administration. Hence, the objective of this study was to evaluate the efficacy of a FK506-loaded microneedle (FK506 MN) in the treatment of acute rejection in HT. The physicochemical properties of FK506 MN were evaluated, and it exhibited constant release over the course of at least 9 days with a 94.6 % cumulative release rate. Also, the FK506 MN treatment could successfully alleviate acute rejection and prolong allograft survival compared with the untreated group (mean survival time, 12.33 versus 7.25 days). Furthermore, T cell and macrophage infiltration as well as secretion of IL-2, IL-6 and IFN-γ were dramatically reduced in the FK506 MN group. As expected, no hepatoxicity and nephrotoxicity were observed after the application of FK506 MN. Taken together, FK506 MN based drug delivery system provides a novelty strategy to deliver FK506 in heart transplantation, which may be also suitable for other organ transplantations in the future.