Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Complications from long-term use of calcineurin inhibitors remain a major issue for transplant patients and alternative therapies are highly needed. We investigated two innovative drug delivery methods based on a peptide-based hydrogel and solid lipid nanoparticles (SLN) to optimize the delivery of the immunosuppressant tofacitinib (Tofa) as part of a novel tolerogenic strategy.
Methods. The ability of locally-administered Tofa-Hydro to synergize with systemic CTLA4-Ig was tested in a mouse BALB/c to C57BL/6 heterotopic heart transplant model. In parallel, Tofa-containing SLN (Tofa-SLN) were tested for their impact on the maturation of bone marrow-derived dendritic cells (DC) by flow cytometry. Allostimulatory capacity of Tofa-SLN-conditioned DC was assessed via CFSE-MLR. Finally, in vivo SLN distribution was assessed by live whole animal imaging.
Results. Tofa-Hydro releases Tofa in a continuous fashion over a period of 7-10 days. A one-time application of Tofa-Hydro in the area surrounding the transplanted heart (combined with systemic CTLA4-Ig) renders long-term graft survival (MST=127d Vs CTLA4-Ig MST=36, P<0.05). Importantly, application of Tofa-Hydro to a distal site ablates this synergistic improvement of survival, demonstrating the importance of the site of delivery. Tofa-SLN-conditioned DC are profoundly inhibited in their maturative response to LPS. These DC are less stimulatory for both CD4 and CD8 alloreactive T-cell and can work in concert with CTLA4-Ig to minimize T cell activation. Moreover, in vivo imaging studies confirm the unique property of SLN to accumulate in the lymphatics, reach draining lymphoid tissues, and be taken up by immune cells.
Conclusion. Our results highlight two promising strategies for the controlled and localized delivery of Tofa. Peptide hydrogels allow a sustained localized delivery that effectively synergizes with CTLA4-Ig, requiring only one application and a fraction of the dose of Tofa dose required when delivered systemic. Tofa-SLN can be passively directed to lymphoid tissues and effectively target and modulate antigen presenting cells. Overall, these strategies can maximize the immunomodulatory impact of Tofa while minimizing its toxic side-effects.
CITATION INFORMATION: Raimondi G., Majumder P., Ivanova V., Calderon-Colon X., Mirdad A., Iglesias Lozano M., Lee W., Brandacher G., Schneider J., Patrone J. Biomaterial-Based Localized and Controlled Delivery of Tofacitinib to Actuate Enhanced Costimulation Blockade and Promote Long-Term Transplant Survival Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Raimondi G, Majumder P, Ivanova V, Calderon-Colon X, Mirdad A, Lozano MIglesias, Lee W, Brandacher G, Schneider J, Patrone J. Biomaterial-Based Localized and Controlled Delivery of Tofacitinib to Actuate Enhanced Costimulation Blockade and Promote Long-Term Transplant Survival [abstract]. https://atcmeetingabstracts.com/abstract/biomaterial-based-localized-and-controlled-delivery-of-tofacitinib-to-actuate-enhanced-costimulation-blockade-and-promote-long-term-transplant-survival/. Accessed November 17, 2019.
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