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Tacrolimus-Eluting Disk within the Allograft Enables Vascularized Composite Allograft Survival with Site-Specific Immunosuppression without Systemic Toxicity

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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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Author notes

  1. Alexander Spiess and Raman Venkataramanan contributed equally to this work and are the co-corresponding authors.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 7220 Salk Hall, 3501 Terrace Street, Pittsburgh, PA, 15261, USA

    Firuz G. Feturi & Raman Venkataramanan

  2. Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Scaife Hall, Suite 6B, 3550 Terrace Street, Scaife Hall, Suite 6B, Pittsburgh, PA, 15261, USA

    Jignesh V. Unadkat, Wensheng Zhang, Yong Wang, Chiaki Komatsu, Damian Grybowski, Zhaoxiang Zhang, Sean Mcclaine, Kia M. Washington, Mario G. Solari & Alexander M. Spiess

  3. Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Mohamed El Hag & Raman Venkataramanan

  4. Department of Plastic, Reconstructive and Aesthetic Surgery, Medical Park Gaziantep Hospital, Gaziantep, Turkey

    Vasil Erbas

  5. Private Cagsu Hospital, Duzce, Turkey

    Huseyin Sahin

  6. Department of Plastic, Reconstructive and Aesthetic Surgery, School of Medicine, Gulhane Military Medical Academy, Ankara, Turkey

    Sinan Oksuz

  7. Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland

    Jan Plock

  8. Departments of Surgery, Ophthalmology and Bioengineering, Wake Forest School of Medicine, Wake Forest Institute of Regenerative Medicine, Winston Salem, NC, USA

    Vijay S. Gorantla

  9. Division of Plastic and Reconstructive Surgery, University of Colorado Hospital, Aurora, CO, 80045, USA

    Kia M. Washington

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  1. Firuz G. Feturi
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Contributions

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.

Corresponding authors

Correspondence to Raman Venkataramanan or Alexander M. Spiess.

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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

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