Peptide-Functionalized Gold Nanorods Increase Liver Injury in Hepatitis

Abstract

Targeted nanomedicine holds enormous potential for advanced diagnostics and therapy. Although it is known that nanoparticles accumulate in liver in vivo, the impact of cell-targeting particles on the liver, especially in disease conditions, is largely obscure. We had previously demonstrated that peptide-conjugated nanoparticles differentially impact macrophage activation in vitro. We thus comprehensively studied the distribution of gold nanorods (AuNR) in mice in vivo and assessed their hepatotoxicity and impact on systemic and hepatic immune cells in healthy animals and experimental liver disease models. Gold nanorods were stabilized with either cetyltrimethylammonium bromide or poly(ethylene glycol) and additional bioactive tripeptides RGD or GLF. Gold nanorods mostly accumulated in liver upon systemic injection in mice, as evidenced by inductively coupled plasma mass spectrometry from different organs and by non-invasive microcomputerized tomography whole-body imaging. In liver, AuNR were only found in macrophages by seedless deposition and electron microscopy. In healthy animals, AuNR did not cause significant hepatotoxicity as evidenced by biochemical and histological analyses, even at high AuNR doses. However, flow cytometry and gene expression studies revealed that AuNR polarized hepatic macrophages, even at low doses, dependent on the respective peptide sequence, toward M1 or M2 activation. While peptide-modified AuNR did not influence liver scarring, termed fibrosis, in chronic hepatic injury models, AuNR-induced preactivation of hepatic macrophages significantly exacerbated liver damage and disease activity in experimental immune-mediated hepatitis in mice. Bioactively targeted gold nanoparticles are thus potentially harmful in clinically relevant settings of liver injury, as they can aggravate hepatitis severity.

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

“…In our study, we could clearly demonstrate that also monocyte-derived inflammatory macrophages and resident Kupffer cells (defined as reported in Ref. 33) expressed high levels of CXCL16. We further demonstrated that CXCL16 mRNA expression was enhanced in chronically injured, especially cirrhotic, human livers compared with control tissue, which is consistent with prior studies mainly conducted in hepatitis C-induced cirrhosis (21,34).…”

Fluorescent cell-traceable dexamethasone-loaded liposomes for the treatment of inflammatory liver diseases

“…The accumulation of nanoparticles in the liver can be partially related to their internalization by hepatic macrophages, such as Kupffer cells, which are located at the fenestrated endothelium and which are in direct contact with blood [9]. Subsequent to their internalization by macrophages [10], nanoparticles are known to influence the state of hepatic macrophage polarization [11].…”

“…M1 macrophages in diseased livers mainly originate from monocytes that translocate into the liver upon injury, and they express F4/80, CD11b and the Ly6C antigen on their surface, whereas Kupffer cells are resident liver macrophages, expressing high levels of F4/80 but low levels of Ly6C and CD11b [14]. Alternatively activated M2 macrophages exhibit characteristic surface markers such as the IL4 receptor a (CD124), which inhibits inflammation [15], the mannose receptor (CD206) and the macrophage C-type lectin domain family 10, member A (CLEC10A, CD301), all of which can potentially be regulated by targeted nanotherapeutics [11].…”

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

“…Here, activation of IL-6-dependent pathways in different cell types -especially immune cells and non-parenchymal liver cells -can also contribute to HCC development. 49 The use of STAT3-cell-type-specific knockout mice bears limitations as gp130, the signaling molecule, is still expressed in the targeted cell. It has been shown that the intracellular gp130 docking sites are not STAT3 specific.…”

“…However, the major hurdle here is to overcome the global IL-6 blockade caused by these drugs. To achieve this goal, a possible therapeutic strategy solution has been recently published by Bartneck et al,49 with the use of gold nanorods, which represent a relatively novel class of nanoparticles that hold significant potential for delivering drugs such as gp130-signaling pathway blockers to specific cell types (e.g., hepatocytes).…”