Introduction: While short-term lung transplant outcomes have improved over the years, long-term survival rates remain stagnant. Many injuries occur to the donor organ before transplantation, such as, brain-death, cold storage, warm ischemia, and reperfusion injury upon implantation. These initial injuries contribute to early graft failure and bronchiolitis obliterans (BO). Rapamycin, is often used clinically once evidence of BO. While it is an effective immunosuppressant, rapamycin causes many side-effects impeding its use in the perioperative period. In order to deliver the drug locally and obviate these peri-operative complications we have developed a targeted rapamycin micelle (TRaM). As a prove of concept we propose that adding our TRaM to the organ during cold storage in University of Wisconsin (UW) solution will lessen these early injuries, and improve outcomes.

Methods: We have designed and characterized a novel Targeted Rapamycin Micelle (TRaM), which targets to αVβ3 integrins present on respiratory epithelial cells by arginine-glycine-aspartate (RGD) targeting moieties. For in vitro studies, to mimic cold storage, BEAS-2b cells were exposed to cold hyperoxic conditions with UW solution plus TRaM nanoparticles, or free rapamycin at 100, 200, and 400ng/mL, for 18hrs at 4oC, prior to reperfusion with normal media for 24 hrs. Supernatants were analyzed for proinflammatory cytokine secretion using ELISA. For in vivo studies, Balb/c donor mice were utilized in both heterotopic and orthotopic tracheal allotransplant models. Procured donor tracheas were stored in UW solution plus TRaM or rapamycin for 4 hrs at concentrations of 100 and 1000ng/mL. Grafts were harvested at 3, 7, and 28 for analysis.

Results: Supplementation of UW solution with TRaM significantly improved in-vitro cell viability and reduced cytokine release. TRaM therapy of tracheas in UW solution for 4 hrs lead to a significant protection from early graft inflammation (3, 7 days) and OB, as compared to rapamycin or UW alone.

Conclusion: These data demonstrate that TRaM therapy can successfully integrate into epithelial cells in-vitro and in-vivo and have a therapeutic effect in vitro and in vivo when used as an additive to cold storage solution.

CITATION INFORMATION: Bazzle G, Dixit S, Patel K, Broome A.-M, Nadig S, Atkinson C. Rapamycin Encapsulated Nanoparticles as Pre-Treatment in Lung Transplantation. Am J Transplant. 2016;16 (suppl 3).

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