Bartneck Matthias, Warzecha Klaudia Theresa, Tacke Frank
Department of Medicine III, University Hospital Aachen, 52074 Aachen, Germany.
Hepatobiliary Surg Nutr. 2014 Dec;3(6):364-76. doi: 10.3978/j.issn.2304-3881.2014.11.02.
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 cell-specific targeting for liver diseases by nanomedicine.
纳米医学构成了纳米技术在医学应用中的新兴领域，例如基于纳米材料的药物递送系统。这项技术可能为肝脏疾病的新型治疗方法带来巨大潜力。使用纳米医学对巨噬细胞、肝星状细胞（HSC）、肝细胞和肝窦内皮细胞（LSEC）进行特异性和非特异性靶向已在临床前环境中得到开发和测试。肝脏中的这四种主要细胞类型在肝脏炎症和纤维化的起始和维持过程中所发生的复杂事件序列中起着关键作用。针对不同细胞类型的靶向可以基于它们摄取周围物质的能力、内吞作用，并且通过靶向特征结构（如受体、糖基或肽序列）可以实现对单一细胞类型的特异性。巨噬细胞，尤其是肝脏驻留的库普弗细胞，成为纳米医学的焦点，这是由于它们对大多数纳米材料具有高效且非特异性的摄取，以及在炎症和纤维化形成过程中具有关键的致病功能。甘露糖受体可用于在肝脏疾病中靶向巨噬细胞，但巨噬细胞也可被某些纳米材料激活，例如使它们具有促炎作用的肽修饰金纳米棒（AuNRs）。HSC是纤维化过程中主要的胶原产生细胞，目前使用识别甘露糖6 - 磷酸、胰岛素样生长因子II、过氧化物酶体增殖物激活受体1、血小板衍生生长因子（PDGF）受体β或整合素的纳米构建体进行靶向。直到最近，通过模拟载脂蛋白（身体天然存在的纳米颗粒）才实现了对主要肝实质细胞——肝细胞的高特异性靶向。发现使用羧基修饰的胶束及其整合素受体可以最有效地靶向LSEC。本综述将总结这些细胞类型在健康和患病肝脏中的重要功能，并讨论纳米医学针对肝脏疾病进行细胞特异性靶向的当前策略。
