*Purpose: In this study we seek to improve targeted nanoparticle (NP) delivery during ex-vivo normothermic machine perfusion through fibrinolysis for more homogenous treatment of human kidneys.

*Methods: To improve targeting efficacy, endothelial targeted NPs with a series of targeting antibodies, loaded with fluorescent dyes, were injected into discarded pairs of human kidneys during normothermic machine perfusion in the absence or presence of fibrinolytic treatment to resolve microvascular obstructions. Relative amounts of nanoparticle accumulation were analyzed via fluorescent microscopy and quantified in MATLab.

*Results: We have previously shown that nanoparticles can be targeted to vascular endothelium during normothermic machine perfusion. However, at sites of microvascular obstruction, nanoparticles would accumulate non-specifically and have no targeting benefit. We have recently demonstrated that tPA treatment in the presence of exogenous plasminogen is able to clear these microvascular obstructions, enabling more effective targeting of our NPs. Endothelial targeted NPs, with optimal targeting ligands, were shown to have significantly higher specific accumulation in both interstitial microvessels and glomeruli when delivered after fibrinolytic treatment during normothermic machine perfusion (Figure 1).

*Conclusions: This is the first study done in whole human kidneys to analyze patterns of drug delivery following fibrinolytic treatment. These results demonstrate the importance of clearing microvascular obstructions and picking an optimal antibody to facilitate strong targeted NP accumulation, ultimately leading to more efficient drug delivery.

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