The potential therapeutic application of oligonucleotides (ONs) that selectively suppress target genes through antisense and RNA interference mechanisms has attracted great attention. The clinical applications of ONs have overcome multiple obstacles and become one of the most active areas for the development of novel therapeutics. To achieve efficient and specific cellular internalization, conjugation of a variety of functional groups to ONs has been the subject of intensive investigations over the past decade. Among them, a promising liver-targeted N -acetylgalactosamine (GalNAc) ligand has been evaluated in multiple preclinical and clinical trials for improving the cellular uptake and tissue specific delivery of ONs. GalNAc-based delivery relies on the fact that liver hepatocytes abundantly and specifically express the asialoglycoprotein receptor that binds and uptakes circulating glycoproteins via receptor-mediated endocytosis. In recent years, encouraging progress has been made in the field of GalNAc conjugates. This review aims to provide an overview of GalNAc-mediated liver-targeted delivery of small interfering RNA and antisense oligonucleotides, and the immense effort as well as recent advances in the development of GalNAc-conjugated agents are described.

Heparin, which has been used as an anticoagulant drug for decades, inhibits angiogenesis, whereas thrombin promotes tumor-associated angiogenesis. However, the mechanisms underlying the regulation of angiogenesis by heparin and thrombin are not well understood. Here, we show that microRNA-10b (miR-10b) is down-regulated by heparin and up-regulated by thrombin in human microvascular endothelial cells (HMEC-1). Overexpression of miR-10b induces HMEC-1 cell migration, tube formation, and angiogenesis, and downregulates homeobox D10 (HoxD10) expression via direct binding of miR-10b to the putative 3 UTR of HoxD10. In addition, HMEC-1 cell migration and tube formation are induced by HoxD10 knockdown, whereas angiogenesis is arrested when HoxD10 expression is increased after anti-miR-10b or heparin treatments. Furthermore, expression of miR-10b and its transcription factor Twist are up-regulated by thrombin, whereas HoxD10 expression is impaired by thrombin. Using quartz crystal microbalance analysis, we show that heparin binds to thrombin, thereby inhibiting thrombin-induced expression of Twist and miR-10b. However, the expression of miR-10b is not attenuated by heparin any more after thrombin expression is silenced by its siRNA. Interestingly, we find that heparin attenuates miR10b expression and induces HoxD10 expression in vivo to inhibit angiogenesis and impair the growth of MDA-MB-231 tumor xenografts. These results provide insight into the molecular mechanism by which heparin and thrombin regulate angiogenesis.Thrombosis is considered an early clinical indication and frequent complication of cancer (1, 2). Malignant tumors often exhibit increased expression of tissue factor and cancer procoagulant, which can be followed by activation of cell surface protease receptors and fibrin generation (3). In addition, tumor cells can interact with blood cells, particularly monocytes, macrophages, and platelets, leading to the generation of thrombin and thrombosis through the clotting cascade or platelet activation (4). Moreover, aggressive antitumor therapies such as chemotherapy, radiation, and surgery also increase the risk of thrombosis.Positive feedback signaling loops exist between tumor tissue and the coagulation system (5, 6). For instance, it is widely accepted that elements of the coagulation and fibrinolytic system may aid in cancer cell survival, proliferation, invasion, and metastasis, as well as tumor angiogenesis (7). Therefore, inhibition of the activation of coagulation could be a useful antitumor strategy. A number of studies have shown that anticoagulant drugs can extend survival in patients with certain types of cancer (8), and studies are currently ongoing to confirm the effects of anticoagulant therapy in a range of tumor types. However, the molecular mechanisms involved in the action of anticoagulants in this process are not well understood.Heparins, in particular those of low molecular weight, are effective in the prevention and treatment of thromboembolic events in cancer patients (9, 10). As early...

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