Therapeutic targeting of liver inflammation and fibrosis by nanomedicine
Nanomedicine constitutes the emerging field of medical applications for nanotechnology such as nanomaterial-based drug delivery systems. This technology may hold exceptional potential for novel therapeutic approaches to liver diseases. The specific and unspecific targeting of macrophages, hepatic stellate cells (HSC), hepatocytes, and liver sinusoidal endothelial cells (LSEC) using nanomedicine has been developed and tested in preclinical settings. These four major cell types in the liver are crucially involved in the complex sequence of events that occurs during the initiation and maintenance of liver inflammation and fibrosis. Targeting different cell types can be based on their capacity to ingest surrounding material, endocytosis, and specificity for a single cell type can be achieved by targeting characteristic structures such as receptors, sugar moieties or peptide sequences. Macrophages and especially the liver-resident Kupffer cells are in the focus of nanomedicine due to their highly efficient and unspecific uptake of most nanomaterials as well as due to their critical pathogenic functions during inflammation and fibrogenesis. The mannose receptor enables targeting macrophages in liver disease, but macrophages can also become activated by certain nanomaterials, such as peptide-modified gold nanorods (AuNRs) that render them proinflammatory. HSC, the main collagen-producing cells during fibrosis, are currently targeted using nanoconstructs that recognize the mannose 6-phosphate and insulin-like growth factor II, peroxisome proliferator activated receptor 1, platelet-derived growth factor (PDGF) receptor β, or integrins. Targeting of the major liver parenchymal cell, the hepatocyte, has only recently been achieved with high specificity by mimicking apolipoproteins, naturally occurring nanoparticles of the body. LSEC were found to be targeted most efficiently using carboxy-modified micelles and their integrin receptors. This review will summarize important functions of these cell types in healthy and diseased livers and discuss current strategies of cellspecific targeting for liver diseases by nanomedicine.