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Locally Implantable Biodegradable Polymeric Tacrolimus Disc Prolongs Survival of Vascularized Composite Allografts without Morbid Adverse Effects
Firuz G. Feturi, B. Pharm., PhD, Jignesh V. Unadkat, MD, Vasil E. Erbas, MD, Liwei Dong, MD, Vijay S. Gorantla, MD., PhD, Mario G. Solari, MD, Raman Venkataramanan, PhD, Alexander M. Spiess, MD.
University of Pittsburgh, Pittsburgh, PA, USA.
Purpose
Widespread application of Vascularized Composite Allografts (VCA) has been limited due to systemic side effects associated with chronic use of oral immunosuppressive drugs (hyperglycemia and nephrotoxicity). Biodegradable polymeric materials are potential drug delivery systems due to their ability to effectively deliver the drug to the target sites. Feasibility and efficacy of use of these materials have not been explored in VCA. We developed a locally implantable drug delivery system that provides controlled and sustained release of tacrolimus (TAC) directly to the allograft over a prolonged time period. We studied its in-vitro/in-vivo characteristics, and we evaluated its safety and efficacy in sustaining the allograft survival without systemic complications.
Methods
TAC loaded polycaprolactone discs were prepared by solvent casting. Drug release kinetics was evaluated in-vitro in PBS and in-vivo by subcutaneous implantation of the disc in hind limb of rats. Following orthotopic hind limb allotransplantation, animals (n=4/group) received either one disc in transplanted limb (Group 1) or in the contralateral un-transplanted limb (Group 2), or TAC 1mg/kg/day intraperitoneally (Group 3). TAC levels in blood and tissues were measured using LC-MS/MS. In addition to allograft survival, systemic toxicity was evaluated using percent change in body weight (BW), glycaemia, and creatinine clearance (CrCl).
Results
In vitro, TAC was released in a sustained manner with a total dose released of 36.5 % in one month. In vivo, single TAC disc (5mg, 5 % w/w) provided sustained release for 20 days achieving therapeutic blood levels (5-10ng/ml), followed by sub therapeutic blood levels. High levels of TAC were achieved locally in the disc implanted limb compared to TAC levels in whole blood and/or contralateral limb (P<0.05). Draining lymph nodes and sciatic nerves had the highest levels compared to other tissues (20 times). When blood levels fall < 5ng/ml (on day 21), 3 out of 4 animals received TAC disc at TX limb didn’t show signs of allograft rejection while 3 out of 4 animals received TAC disc in contralateral un transplanted limb had grade I rejection. Glucose intolerance and decreased CrCl was not observed in TX animals received TAC disc compared to animals received standard systemic therapy.
Conclusion
In vitro/in vivo studies demonstrated the ability of the disc to provide loco-regional drug delivery to the allograft and thereby for potential applications in VCA. TAC disc implanted in TX limb was effective in sustaining allograft survival via loco-regional immunosuppression, and without systemic complications compared to the standard systemic therapy. Out study participates not only to shift the current research paradigms of the use of systemic immunosuppression to local immunosuppression using locally implantable polymer based drug delivery systems, but also to establish the basis to develop more advanced technologies to targeted immunosuppressive drug delivery.
| Groups | # of animals with Grade I rejection on day 20 | Average blood levels on day 20 (ng/ml) | | 1 | 3 out of 4 | 3.8 ± 1 | | 2 | 1 out of 4 | 4.2 ± 1 | | 3 | 0 | 8 ± 2 |
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