Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: In solid organ transplantation the host immune system acts to reject the graft. This process is facilitated at the endothelial surface, where inflamed donor endothelial cells (ECs) upregulate adhesion molecules and recruit effector cells of the host immune system. To combat this, we have designed a strategy for sustained delivery of anti-inflammatory agents directly to the endothelium using antibody (Ab)-targeted polymer nanoparticles (NPs) during ex vivo normothermic machine perfusion (EVNMP) of the organ. This strategy relies on the rapid accumulation of NPs on ECs during a 1-2 h EVNMP period. Available platforms to optimize targeted nanomedicines for this purpose pose limitations: results obtained from isolated cells can lack relevance to more complex in vivo environments, whereas the quantitative assays needed to determine the impact of NP design on targeting efficacy are difficult to perform in animal models and may translate poorly to human systems. To address the need for an improved testing platform, we developed an Isolated Vessel Perfusion System (IVPS) to enable dynamic and quantitative study of vascular-targeted nanomedicines in readily obtainable human vessels isolated from umbilical cords or placenta (Fig 1A).
*Methods: Using this platform, the parameters that are critical to targeting efficacy can be evaluated (including flow rate, selection of targeting molecule, and temperature (Fig 1B)), which we demonstrate using easily produced biologic replicates in independent, modular chambers.
*Results: We have discovered that rapid accumulation of NPs relies on both the density and accessibility of the potential ligands, and that these parameters can be measured directly in the relevant vessel setting. Further, human placental artery segments perfused ex vivo in this platform were able to be transplanted as end‐to‐end interposition grafts in descending aortae of C.B-17 SCID/bg mice. NP retention was evaluated by immunofluorescence microscopy after 7 days (Fig 1C), creating a model to evaluate drug duration after perfusion.
*Conclusions: This IVPS can be used as part of a high throughput preclinical strategy to optimize therapy for human organ transplant.
To cite this abstract in AMA style:Bracaglia LG, Lysyy T, Qin L, Albert C, Pober JS, Tellides G, Saltzman WM, Tietjen GT. Ex Vivo Isolated Human Vessel Perfusion System for the Design and Assessment of Nanomedicines Targeted to the Endothelium [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/ex-vivo-isolated-human-vessel-perfusion-system-for-the-design-and-assessment-of-nanomedicines-targeted-to-the-endothelium/. Accessed June 13, 2021.
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