Ultrasound Triggered-Release Embedded Anti-Rejection Therapy (TREAT ) for Targeted Immunomodulation in Vascularized Composite Allotransplantation
Firuz Feturi 1, Hua Wang 2, Yevgeny Brudno 2, Vasil Erbas 3, Liwei Dong 3, Zhaoxiang Zhang3, Huseyin Sahin 3, Wensheng Zhang 3, Mubin Ali Aral 3 , Raman Venkatramanan 1, David Mooney 2, Vijay Gorantla 3
1Department of Pharmaceutical Science, University of Pittsburgh School of Pharmacy2Wyss Institute for Biologically Inspired Engineering, Harvard University3 Department of Plastic and Reconstructive Surgery, University of Pittsburgh School of Medicine
More than 30,000 people receive organ transplants every year in the US. Vascularized composite allotransplantation (VCA) is the newest realm of solid organ transplantation. The skin component of VCA is highly antigenic and mandates high doses of systemic immunosuppressive drugs. Oral dosing of immunosuppressive drugs such as tacrolimus (TAC), rapamycin (Rapa), and mycophenolic acid (MPA) leads to fluctuating, erratic, or unpredictable blood levels risking toxicity or lack of efficacy . We propose a drug delivery platform that can not only provide sustained drug release but also on-cue triggered drug release upon ultrasound stimulation (USS) in graft tissues with stable, low blood levels, minimizing overall drug exposure and facilitating long-term VCA survival with no systemic complications.
An injectable, re-loadable, biocompatible drug eluting hydrogel was prepared. We characterized the in vitro release kinetics of the drugs from alginate gels in absence and /or presence of USS. We evaluated feasibility and efficacy of the system in vivo in absence of USS. Brown Norway to Lewis rats received fully mismatched Brown Norway rat hind limb VCA (4/group) and a single dose of gel subcutaneously injected into the allograft. The gel was loaded with either TAC [10mg], Rapa [10mg], or TAC+Rapa [10mg] each in 1 ml. Drug levels in blood and VCA tissues were analyzed by LCMS/MS. Flow cytometry was performed to detect expression of regulatory marker, FOXP3. 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 (without fluctuation) of release from alginate gels in the absence of USS. Pulsatile USS triggered drug release, leading to increased drug levels after each pulse. Sustained drug release occurred from alginate gels in the absence of ultrasound with blood levels within the therapeutic range (5-10ng/ml). Drug concentration in allograft tissues was higher than in blood and contralateral limb (P<0.05). In the first 2 weeks post gel injection, there was a ?15% change in BW which stabilized with time . BW gradually increased over time. No significant change in CrCL occurred post gel injection over time (>0.05). Rats receiving Rapa developed Banff grade 3 rejection on day 21, while rats receiving TAC or TAC+Rapa showed allograft survival (>100 days). Expression of the regulatory marker FOXP3 was observed which which may indicate peripheral immunomodulation.
We successfully developed, for the first time, a smart hydrogel drug delivery system with sustained baseline and on-demand release of drugs upon USS for use in VCA. The TREAT system provides stable, low drug levels in the blood with preferential drug concentration in VCA tissues facilitating long-term VCA survival/outcomes with no systemic adverse effects. Further efforts are being made to use USS to optimize the on-cue drug release.
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