Hepatic Regulation of Fibrinolysis in Normal and Disease States
Pia Glas-Greenwalt in Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
The second major function of the liver with regard to PA/PAI regulation is related to clearance mechanisms for t-PA, UK, and PA-PAI complexes. Cells in the liver express the well-characterized asialoglycoprotein receptor, which mediates removal of glycoproteins with altered carbohydrate moieties from the plasma. In addition, these cells express receptors for α2-macroglobulin-proteinase complexes.11 Based on results indicating that clearance of radiolabeled t-PA, UK, or PA-PAI complexes rapidly end up in the liver (Table 2),12,13 a number of investigators have attempted to identify and characterize receptors for these components in liver, hepatocytes, and hepatoma cells from a variety of species. Some of the evidence for these receptors is summarized in Table 2.
Gene Delivery
Danilo D. Lasic in LIPOSOMES in GENE DELIVERY, 2019
In addition to the possibilities discussed above, some systems were already tested in vivo. Conjugates of cationic polymer and targeting ligand may act as an efficient delivery vehicle for systemic application. Targeting of liver hepatocytes via internalizing an asialoglycoprotein receptor by covalent conjugates of polylysine and targeting molecule (asialorosomucoid) demonstrated therapeutic activity (see Chapter 13). Polylysine conjugated to transferrin was used to target neoplastic cells which exhibit this receptor because rapidly dividing cells require a high level of iron. Similarly, insulin conjugated to positively charged N-acylurea albumin was also used as a receptor-specific carrier to cells expressing insulin receptor. Macrophages can be targeted by macrophage-expressed lectins which bind mannose, glycans, galactose, or fucosyl-glycoconjugates (Monsigny et al., 1994).
Antigenic Mimicry in Neisseria Species
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
Previous evidence has suggested that the tight inter-cellular adhesions between the outer membrane of gonococci displaying the opacity colony phenotype occurred because Opa proteins expressed on one gonococcus adhered to the LOS of the opposing bacterium. Blade and coworkers, employing a noncompetitive inhibition assay previously used to determine the carbo hydrate structures recognized by the major hepatic asialoglycoprotein receptor, demonstrated that gonococcal LOS structures bind Opa proteins (67). The LOS carbohydrate used in these assays were LOS structures purified from pyocin-resistant LOS mutants of N. gonorrhoeae strain 1291 (21). These data suggest that the gonococcal Opa proteins had the highest affinity for the Gal β(1→4)GlcNAc residue present on the gonococcal lactoneoseries LOS. This affinity was comparable to that reported for the binding of the major hepatic asialoglycoprotein receptor to glycoconjugates containing terminal galactose and TV-acetylgalactosamine. After sialylation of the lactoneoseries LOS, presumably on the terminal galactose residue, the interaction with the Opa proteins was ablated.
Current status and future directions of hepatocellular carcinoma-targeted nanoparticles and nanomedicine
Published in Expert Opinion on Drug Delivery, 2021
Vikas Kumar, Mahfoozur Rahman, Prashant Gahtori, Fahad Al-Abbasi, Firoz Anwar, Hyung Sik Kim
The asialoglycoprotein receptor (ASGPR) is a C-type lectin receptor mainly expressed on the hepatocyte’s sinusoidal surface. The ASGPR was discovered by Gilbert Ashwell and Anatol Morell in 1965. This protein was isolated from the liver of rabbits by affinity chromatography employing asialo-orosomucoid sepharose. It is well documented that alteration in the synthesis and binding activity of ASGPR boost liver inflammation. ASGPR is expressed polar on the basolateral and sinusoidal surface of the hepatocyte plasma membrane. During inflammation, the expression of ASGPR shifts toward the canalicular membrane. In case of cirrhosis, which is end-stage liver disease, ASGPR is over-expressed and asialoglycoprotein levels in the serum are enhanced. In immune-mediated liver disease, ASGPR becomes the target of autoimmune responses, both B and T cell levels. Clinical studies suggest that the ASGPR is mostly exposed to hepatocytes and is poorly diffused into the extra-hepatic tissues [35,36]. HCC patients showed increased expression of ASGPR in the early and advanced stages of the disease. Therefore, this receptor is a target of anticancer drug delivery for treating HCC [37,38]. ASGPR binds to galactosamine or binds with high affinity to galactose. Due to the specific role of glucose and its association with ASGPR, lactoferrin, lactose, galactose moieties, galactose-terminating polysaccharides or galactose-terminating glycoprotein concentration determines the efficacy. In drug delivery systems, carbohydrates with repeated glucose or galactose units are screened for selective hepatocyte targets [39,40].
The glyconanoparticle as carrier for drug delivery
Published in Drug Delivery, 2018
Xueqin Zhang, Gangliang Huang, Hualiang Huang
Since glyconanoparticles can constitute a good model for simulations to intervene in carbohydrate-based life processes, they have been tried in biopharmaceuticals. A novel type of quantum dots (QDs) that wrapped carbohydrate molecules was reported, they could specifically bind to cell surface receptors in certain tissues and organs. Certain liver cells had asialoglycoprotein receptor on their surfaces. It could specifically bind to QDs with galactose residues (Yang et al., 2010). Further studies showed that HepG2 cells were preferentially filled with galactose-QDs via receptor-mediated endocytosis. In mouse experiments, QDs of d-mannose and d-galactose were found to selectively accumulate in mouse hepatocytes. The carbohydrate-encapsulated QDs were concentrated in the liver of mice. The degree was three times that of ordinary QDs, namely the former was more selective. The results showed that the carbohydrate-coated QDs had good potential for in vivo targeting.
In vitro and in vivo evaluation of self-assembled chitosan nanoparticles selectively overcoming hepatocellular carcinoma via asialoglycoprotein receptor
Published in Drug Delivery, 2021
Rensong Sun, Linlin Fang, Xia Lv, Jiani Fang, Yuting Wang, Dapeng Chen, Liang Wang, Jun Chen, Yan Qi, Zeyao Tang, Jianbin Zhang, Yan Tian
Apart from passive targeting method, chitosan nanoparticle can also actively target tumor tissue by grafting certain ligands. Folic acid, biotin, galactose, hyaluronic acid, transferrin and RGD peptides are frequently reported targeting ligands, which can specifically recognize the overexpressed receptors on tumor cells. Asialoglycoprotein receptor (ASGPR), a transmembrane protein, is considered as an ideal receptor for liver targeting. ASGPR is called galactose receptor or hepatic lectin, because it is mainly expressed on hepatocytes and minimally on extra-hepatic cells (D’Souza & Devarajan, 2015). It can specifically recognize nanoparticles with galactose or N-acetylgalactosamine residue, and internalized them via clathrin-mediated endocytosis (D'Souza & Devarajan, 2015; Huang et al., 2018). Galactosylated chitosan (Gal-CS) is a chitosan derivative containing galactose residue, which can be obtained by grafting lactobionic acid onto chitosan. Nanoparticles prepared by Gal-CS have shown great potential in active targeting to liver. Anticancer drugs including gemcitabine, triptolide, doxorubicin, 5-fluorouracil, and siRNA have been loaded in galactosylated chitosan nanoparticles for HCC treatment (Wang et al., 2018; Nair et al., 2019; Zhang et al., 2019; Xiang et al., 2020; Zheng et al., 2020). The results demonstrated that the nanoparticles could significantly enhance the cell uptake, cell apoptosis, and anticancer capabilities of drugs via liver-targeting effect.