Loco-regional Delivery of Tacrolimus prolongs Vascularized Composite Allograft Survival
Firuz G. Feturi, PhD, Jignesh Unadkat, MD, Damian Grybowsky, MD, Yong Wong, MD, Bing Wang, MD, Vasil Erbas, MD, Lewei Dong, MD, Zhaoxiang Zhang, MD, Huseyin Sahin, MD, Wensheng Zhang, MD, Vijay Gorantla, MD, Kia Washington, MD, Mario G. Solari, MD, Raman Venkataramanan, PhD, Alexander M. Spiess, MD.
University of Pittsburgh, Pittsburgh, PA, USA.
More than 185,000 amputations occur in United States each year. VCA provides another option for hand reconstruction. The skin component of VCA is highly antigenic and mandates high doses of systemic immunosuppressive drugs and thereby systemic side effects. We propose a drug delivery platform that consists of an encapsulated sustained-release version of oral TAC to minimize systemic drug exposure and facilitate VCA survival.
TAC loaded polycaprolactone discs were prepared by solvent casting. Following hind limb allotransplantation, animals (n=6/group) received one disc in transplanted (TX) limb (Group 1), or one disc in un-TX limb (Group 2), or TAC, IP, 1mg/kg/day (Group 3). TAC levels in blood and tissues were measured using LC-MS/MS. Allograft survival and systemic toxicity were evaluated.
A single TAC disc (5mg, 5 % w/w) resulted in blood levels between 5 to 10 ng/ml during the first 20 days, followed by 2 to 5 ng/ml for 100 days. High levels of TAC were achieved locally compared with blood (P<0.05). Group 1 sustained the allograft for >120days with increased generation of T regs. Group 2 had a median survival 71 ± 7 days. No change in creatinine clearance was observed in group 1, 2, as compared with Group 3 (P<0.05).
A single TAC disc implanted into TX limb was effective in promoting allograft survival via loco-regional immunosuppression, without systemic side effects. Our study offers an alternative to the current treatment paradigms which use systemic immunosuppression, to loco regional immunosuppression using a locally implantable drug delivery system.
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