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Allograft Targeted Delivery of Tacrolimus prolongs Vascularized Composite Allograft Survival with Negligible Blood Levels
Firuz Feturi, PhD, Jignesh Unadkat, MD, Yong Wang, MD, Bing Li, MD, Wensheng Zhang, MD, PhD, Vasil Erbas, MD, Lewei Dong, MD, Zhaoxiang Zhang, MD, Husyein Sahin, MD, Vijay Gorantla, MD, Kia Washington, MD, Mario Solari, MD, Raman Venkatramanan, PhD, Alexander Spiess, MD
University of Pittsburgh
2018-02-15
Presenter: Firuz Feturi
Affidavit:
The work on this project represents the original work of the researcher.
Director Name: Mario Solari
Author Category: Resident Plastic Surgery
Presentation Category: Basic Science Research
Abstract Category: Hand
Purpose
Oral dosing of tacrolimus (TAC) leads to fluctuating blood levels, risking toxicity or lack of efficacy and rejection. We propose a drug delivery platform that consists of an encapsulated sustained-release version of oral TAC that provides sustained drug release into the graft tissues, while minimizing systemic blood levels. This facilitates VCA survival without the need for daily oral dosing of TAC with its complications.
Methods
TAC loaded polycaprolactone discs were prepared by solvent casting. Following orthotopic hind limb allotransplantation, animals (n=6/group) received no treatment (Group 1), TAC 1mg/kg/day intraperitoneally (Group 2), one disc in un-transplanted limb (Group 3), or in transplanted limb (Group 4). TAC levels were measured using LC-MS/MS. Allograft survival and systemic toxicity were evaluated.
Results
A single TAC disc resulted in blood levels between 2 to 5 ng/ml for nearly 50 days. High levels of TAC were achieved locally in the transplanted limb, when compared to levels in the contralateral limb (**P<0.01). These levels could inhibit immune activation and sustained the allografts for >150 day (Group 4), while animals in group 3 had median survival 71 ± 7 days (* p=0.02). No significant change in BW, glucose levels, and CrCL was observed in group 4, as compared to Group 2 (*P<0.05).
Conclusion
A single TAC disc implanted into the transplanted limb was effective in sustaining allograft survival via loco-regional immunosuppression (IS), without systemic side effects. Our study offers an alternative to the current treatment paradigms which use systemic IS, to loco-regional IS using locally implantable biomaterials.
