Date: Sunday, April 30, 2017
Session Name: Poster Session B: Allorecognition and T Cell Biology
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
Complications from long-term use of calcineurin inhibitors are a major concern for transplant patients. To develop CNI-free therapies, we investigated an innovative drug delivery method based on solid lipid nanoparticles (SLN) to deliver the immunosuppressant tofacitinib (Tofa) and optimize its use as adjuvant for tolerogenic strategies.
Tofa-containing SLN (Tofa-SLN) and control SLN (c-SLN) were tested for their impact on the maturation of mouse bone marrow-derived dendritic cells (DC) via flow cytometry. Allostimulatory capacity of Tofa-SLN-conditioned DC was then assessed via CFSE-MLR. Finally, the specific in vivo SLN distribution was assessed via whole body live imaging comparing multiple administration routes: subcutaneous (s.c.), intraperitoneal (i.p.), and oral (gavage).
Uptake of SLN by DC was observed after 5 minutes of exposure and continued to increase for the whole observation period plateauing overnight. Tofa-SLN-conditioned DC were profoundly inhibited in their maturative response to LPS. Accordingly, alloreactive CD4 and CD8 T-cell proliferation induced by Tofa-SLN-DC was significantly decreased when compared to c-SLN-DC or untreated DC. In vivo biodistribution analysis revealed that SLN have the unique property of selective accumulation in lymphoid tissues, with a tropism dictated by the administration route. S.c. injection at the base of the tail resulted in SLN accumulation exclusively in the inguinal lymph nodes. Following i.p. injection, SLN accumulated in the mesenteric and pancreatic lymph nodes, and the spleen. Finally, oral gavage indicated a unique accumulation of SLN in the mesenteric lymph node and spleen that cannot be achieved with other polymeric nanoparticles. Flow analysis of these lymphoid tissues showed significant uptake by APCs (macrophages, DC, and B cells), although to different extents.
Our results show that Tofa-SLN are very effective in targeting APCs, regulating their maturation and allostimulatory capacity. Also, the targetable and selective accumulation in lymphoid tissues underscores the potential of this novel delivery system to maximize the spatial and temporal targeting of Tofacitinib to immune cell populations while minimizing its side effects.
CITATION INFORMATION: Raimondi G, Calderon-Colon X, Budihardjo J, Mirdad A, Iglesias-Lozano M, Walch J, Lee W, Brandacher G, Patrone J. Tofacitinib-Loaded Solid Lipid Nanoparticles Inhibits Dendritic Cell Antigen Presenting Functions and Achieve Selective In Vivo Targeting. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Raimondi G, Calderon-Colon X, Budihardjo J, Mirdad A, Iglesias-Lozano M, Walch J, Lee W, Brandacher G, Patrone J. Tofacitinib-Loaded Solid Lipid Nanoparticles Inhibits Dendritic Cell Antigen Presenting Functions and Achieve Selective In Vivo Targeting. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/tofacitinib-loaded-solid-lipid-nanoparticles-inhibits-dendritic-cell-antigen-presenting-functions-and-achieve-selective-in-vivo-targeting/. Accessed February 26, 2020.
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