*Purpose: Hepatic ischemia/reperfusion injury (IRI) is a major inflammatory event in liver transplantation that is mediated by oxidative stress. Doxorubicin (DOX) can mitigate oxidative stress by inducing the expression of heme oxygenase-1; however its clinical use in IRI has been hampered by significant systemic toxicity. Nanodiamonds (ND) are carbon nanoparticles with potential to be high-affinity carriers for the selective delivery of anthracyclines, such as DOX, and thus mitigate the negative effects of systemic delivery. Here, we use ND-adsorbed DOX (NDX) and evaluate its efficacy in a mouse model of hepatic IRI.

*Methods: We used a well-established mouse model of partial hepatic IRI. Partial hepatic ischemia was produced in the left and median lobes for 90 minutes followed by 6 hours reperfusion. Male 8-12 week old Balb/c mice were separated into 6 cohorts; High-DOX (1mg/kg), Low-DOX (0.5mg/kg), ND, High-NDX (1mg/kg equivalent of DOX), Low-NDX (0.5mg/kg equivalent of DOX) and phosphate buffered saline (PBS) were intravenously administered 48 hours prior to inducing ischemic injury.

*Results: Plasma levels of aspartate alanine aminotransferase (AST) and alanine aminotransferase (ALT) at 6 hours after reperfusion were significantly lower in High-DOX and Low-NDX treated mice, when compared with those in PBS treated mice (P<0.05 and P<0.05, respectively). AST and ALT levels of the High-DOX and Low-NDX treated mice were comparable. Histological analysis showed significantly less congestion, necrosis, and vacuolization in the High-DOX and Low-NDX group compared with those in PBS groups as assessed by Suzuki score (P<0.05 and P<0.01, respectively). High-DOX and Low-DOX decreased the local infiltration of the inflammatory cells such as T cells, neutrophils, and macrophages, and it reduced the expression of proinflammatory cytokines and chemokines.Furthermore, apoptosis, as measured by the number of TUNEL positive hepatocytes, was also suppressed in PEG-IDO treated mice.

*Conclusions: The results in this study indicate that NDX complexes protects mice from local inflammation and liver damage induced by hepatic IRI with half the DOX dose. These results support the development of a more clinically effective strategy for DOX in liver transplantation.

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