Vascularized composite allotransplantation (VCA) have highly immunogenic skin component mandates high doses of systemic immunosuppressive drugs. Oral dosing leads to fluctuating, unpredictable blood levels that can hardly fall into the narrow therapeutic range. We propose a system that can provide an optimal, sustained or on-cue drug release in transplanted organ facilitating graft survival without systemic complications. We characterized in vitro release kinetics of drugs from gels in absence and presence of ultrasound (US), and evaluated the efficacy of the system in vivo in absence of US. Orthotopic hind limb transplanted rats (4/group) received gel loaded with either TAC 10mg, Rapa 10mg, or TAC and Rapa 10 mg each, injected into the allograft. Drug levels were analyzed by LC–MS/MS. In addition to allograft survival, systemic toxicity was evaluated using percent change in body weight (BW) and creatinine clearance (CrCL). In vitro, TAC and Rapa exhibited a low baseline level of release in absence of US while pulsatile US application triggered drug release, leading to increased levels after each pulse. In vivo, low baseline level of release in the absence of US (5-10ng/ml). Level in allograft was higher than in blood (P<0.05). Decrease in BW was observed in the first 2 weeks post gel injection. BW gradually increase over time. No significant change in CrCL post gel injection over time (>0.05). Rats received Rapa developed grade 3 rejection on day 21, while rats received TAC and/or TAC and Rapa sustained the allograft survival (>100 days). TREAT system provides an optimal, sustained drug release in graft tissues facilitating graft survival with no systemic adverse effects. Further efforts are being made to use US to control the release of drugs. We developed dibenzocyclooctyne (DBCO)-immunosuppressant prodrugs that can be reloaded into the azido-modified alginate gels via Click chemistry, with the goal of refilling the alginate scaffolds with immunosuppressive drugs once the encapsulated drugs are running out and thus maintaining the immunosuppressive effect for a long term without replacing the gel scaffolds via surgery method.

CITATION INFORMATION: Feturi F, Wang H, Brudno Y, Erbas V, Zhang Z, Sahin H, Mooney D, Gorantla V, Venkataramanan R. New Approach for Targeted Immunotherapy in Vascularized Composite Allotransplantation. Am J Transplant. 2017;17 (suppl 3).

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