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The α1-Acid Glycoprotein: Structure and Possible Functions in the Acute Phase Response
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
α1-AGP consits of a single polypeptide chain containing 181 amino acids, of which 21 can be substituted.2 It is synthesized mainly in the liver,6 but leukocytes (lymphocytes, granulocytes, and monocytes) also synthesize a membranal proform with a molecular weight of 52 kDa which, after cleavage at residue 181, yields the 40-kDa circulating form.7,8 It has been suggested that leukocytes may contribute significantly to the synthesis of α1-AGP during the acute phase response.7 Some synthesis of α1-AGP by human-breast epithelial cells has also been shown.9 Degradation of α1-AGP is mediated by the liver. The plasma half-life of native α1-AGP is around 3 d10 compared with the plasma half-life of asialo-α1-AGP (a form without terminal sialic acid on the polysaccharide chains) of only a few minutes.11 This shorter plasma half-life is due to the presence of receptors for asialoglycoproteins on hepatocytes; these receptors bind and internalize glycoproteins from which the terminal sialic acid has been removed (for a review, see Reference 12).
Hepatic Regulation of Fibrinolysis in Normal and Disease States
Published in Pia Glas-Greenwalt, 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
Published in Danilo D. Lasic, 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).
Targeted IgMs agonize ocular targets with extended vitreal exposure
Published in mAbs, 2020
Yvonne Chen, Maciej Paluch, Julie A. Zorn, Sharmila Rajan, Brandon Leonard, Alberto Estevez, John Brady, Henry Chiu, Wilson Phung, Amin Famili, Minhong Yan, Claudio Ciferri, Marissa L. Matsumoto, Greg A. Lazar, Susan Crowell, Phil Hass, Nicholas J. Agard
Systemic exposure of IgMs was also of interest, as rapid systemic clearance helps restrict activity of ocular therapeutics to the eye. Interestingly, while previous investigations of IgMs isolated from serum or ascites fluid have reported half-lives of a few days,40,41 recombinantly produced IgM typically clears with half-lives of hours.18,42,43 To confirm these findings we compared the pharmacokinetics of non-binding recombinant human IgM pentamer and hexamer dosed at 5 mg/kg versus IgM isolated from human serum at both 1 and 5 mg/kg (Figure 4a). Following intravenous injection into SCID mice, recombinant IgM pentamers and hexamers were rapidly cleared (t1/2 of 0.25 and 0.50 days, respectively), while isolated IgM showed prolonged and dose-proportional exposure (t1/2 = 2.1–2.9 d). We hypothesized that rapid clearance may be due to differential glycan occupancy or composition of the IgMs. There are up to 51 N-linked glycans per human pentamer and 60 per human hexamer. In support of this theory, glycan analysis showed 75% of glycans on IgMs purified from human serum contained at least one sialic acid versus 24% and 29% of recombinant hexamers and pentamers, respectively (Figure 4b) consistent with asialoglycoprotein-mediated clearance.
Harmine-loaded galactosylated pluronic F68-gelucire 44/14 mixed micelles for liver targeting
Published in Drug Development and Industrial Pharmacy, 2019
Jeetendra Prasad Kushwaha, Debjani Baidya, Sharvil Patil
Thus, the current work was planned with an objective of preparing galactosylated HM-loaded mixed micelles of PF68 and GL44 (HM-MM) so as to mitigate challenges associated with HM and to explore potential anticancer activity of HM against liver cancer cells. The literature suggests abundant presence of asialoglycoprotein (ASGP) receptors on the surface of hepatocytes which are overexpressed in many hepatic diseases including carcinoma. Galactose has been found to interact with ASGP receptors. Thus in the present work, galactose was used as a ligand in the formulation of mixed micelles so to target the liver cancer cells. 32 factorial design approach was used for the preparation of HM-MM. The prepared micelles were characterized for size, percent drug entrapped (EE), FTIR, TEM, in vitro drug release, and pharmacokinetic study. Biodistribution study was also carried out to investigate targeting efficiency of the prepared micelles.
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.