Abstract
Aim
Widespread clinical application of vascularized composite allotransplantation (VCA) has been limited by the need for lifelong systemic immunosuppression to prevent rejection. Our goal was to develop a site-specific immunosuppressive strategy that promotes VCA allograft survival and minimizes the risk of systemic side effects.
Methods
Tacrolimus loaded polycaprolactone (TAC-PCL) disks were prepared and tested for their efficacy in sustaining VCA allograft survival via site-specific immunosuppression. Brown Norway-to-Lewis rat hind limb transplantations were performed; animals received one TAC disk either in the transplanted (DTx) or in the contralateral non-transplanted (DnonTx) limbs. In another group, animals received DTx and lymphadenectomy on Tx side. Blood and allograft levels of TAC were measured using LC–MS/MS. Systemic toxicity was evaluated.
Results
Animals that received DTx achieved long-term allograft survival (> 200 days) without signs of metabolic and infectious complications. In these animals, TAC blood levels were low but stable between 2 to 5 ng/mL for nearly 100 days. High concentrations of TAC were achieved in the allografts and the draining lymph nodes (DLN). Animals that underwent lymphadenectomy rejected their allograft by 175 days. Animals that received DnonTx rejected their allografts by day 70.
Conclusion
Controlled delivery of TAC directly within the allograft (with a single TAC disk) effectively inhibits rejection and prolongs VCA allograft survival, while mitigating the complications of systemic immunosuppression. There was a survival benefit of delivering TAC within the allograft as compared to a remote site. We believe this approach of local drug delivery has significant implications for drug administration in transplantation.
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Acknowledgements
We thank Drs. Ernest Manders (University of Pittsburgh School of Medicine), Fadi Lakkis (Thomas Starzle Institute), and Taylor Skelly (University of Pittsburgh School of Pharmacy) for providing input and advice to our work; Spiros Giannoutsos, Shirley Tylor, and Joshua Sailor at the Clinical Laboratory Building, Special Chemistry Laboratory for aiding in samples analysis, and Sean Mcclaine for providing technical assistance with the figures. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding
This study was supported by intramural support from the Department of Plastic and Reconstructive Surgery and Department of Pharmaceutical Sciences, University of Pittsburgh. None of the authors have any conflicts of interest that may affect the content of the study.
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F.G.F., J.V.U., W.Z., J.A.P., V.S.G., K.M.W., M.G.S., R.V., and A.M.S. designed research; F.G.F., J.V.U., W.Z., Y.W., C.K., D.G., Z.Z., V.E.E., H.S., S.M and S.O. performed research; F.G.F.,R.V contributed new reagents/analytic tools; F.G.F., J.V.U., W.Z., M. E., J.A.P., V.S.G., K.M.W., M.G.S., R.V.R., and A.M.S. analyzed data; and F.G.F wrote the first draft and F.G.F. M.G.S., R.V.R., and A.M.S. provided feedback and revised the manuscript.
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Feturi, F.G., Unadkat, J.V., Zhang, W. et al. Tacrolimus-Eluting Disk within the Allograft Enables Vascularized Composite Allograft Survival with Site-Specific Immunosuppression without Systemic Toxicity. Pharm Res 39, 2179–2190 (2022). https://doi.org/10.1007/s11095-022-03345-4
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DOI: https://doi.org/10.1007/s11095-022-03345-4