Research ArticleOrgan Transplantation

Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys

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Science Translational Medicine  29 Nov 2017:
Vol. 9, Issue 418, eaam6764
DOI: 10.1126/scitranslmed.aam6764

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Particle perfusion for organ transplant

Ischemia-reperfusion injury, which occurs when a tissue or organ is temporarily cut off from blood flow, is a major issue limiting organ viability for transplantation. Tietjan et al. devised a way to target the injury-sensitive endothelium of organs during ex vivo perfusion. Using nanoparticles conjugated to an antibody targeting a protein expressed on endothelial cells, the authors demonstrated that they could perfuse human kidneys and that nanoparticles accumulated in kidney endothelial cells. In addition to expanding the pool of viable organs for transplant, this approach could potentially be used to deliver targeted therapies to organs during ex vivo perfusion rather than treating the transplant recipient systemically.

Abstract

Ex vivo normothermic machine perfusion (NMP) is a new clinical strategy to assess and resuscitate organs likely to be declined for transplantation, thereby increasing the number of viable organs available. Short periods of NMP provide a window of opportunity to deliver therapeutics directly to the organ and, in particular, to the vascular endothelial cells (ECs) that constitute the first point of contact with the recipient’s immune system. ECs are the primary targets of both ischemia-reperfusion injury and damage from preformed antidonor antibodies, and reduction of perioperative EC injury could have long-term benefits by reducing the intensity of the host’s alloimmune response. Using NMP to administer therapeutics directly to the graft avoids many of the limitations associated with systemic drug delivery. We have previously shown that polymeric nanoparticles (NPs) can serve as depots for long-term drug release, but ensuring robust NP accumulation within a target cell type (graft ECs in this case) remains a fundamental challenge of nanomedicine. We show that surface conjugation of an anti-CD31 antibody enhances targeting of NPs to graft ECs of human kidneys undergoing NMP. Using a two-color quantitative microscopy approach, we demonstrate that targeting can enhance EC accumulation by about 5- to 10-fold or higher in discrete regions of the renal vasculature. In addition, our studies reveal that NPs can also nonspecifically accumulate within obstructed regions of the vasculature that are poorly perfused. These quantitative preclinical human studies demonstrate the therapeutic potential for targeted nanomedicines delivered during ex vivo NMP.

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