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Asialoglycoprotein receptor

Nkosiyethu K Mkhwanazi, Charles B de Koning, Willem A L van Otterlo, Mario Ariatti, Moganavelli Singh
Hepatocellular carcinoma is a burgeoning health issue in sub-Saharan Africa and East Asia where it is most prevalent. The search for gene medicine treatment modalities for this condition represents a novel departure from current treatment options and is gaining momentum. Here we report on nonPEGylated and on sterically stabilized PEGylated cationic liposomes decorated with D-galacto moieties linked to 24.1 Å spacers for asialoglycoprotein receptor (ASGP-R)-targeted vehiculation of pCMV-luc plasmid DNA. Cargo DNA is fully liposome associated at N/P ratio=3:1 and is partially protected from the effects of serum nucleases...
January 7, 2017: Zeitschrift Für Naturforschung. C, A Journal of Biosciences
Liping Huang, Yutong Wang, Xiang Ling, Birendra Chaurasiya, Chen Yang, Yunai Du, Jiasheng Tu, Yerong Xiong, Chunmeng Sun
Core-crosslinked pullulan nanoparticles (Pull-LA-CLNPs) were synthesized by the reduction-sensitive strategy for paclitaxel (PTX) delivery. Pull-LA-CLNPs showed high stability against extensive dilution, high salt concentration and organic solvent. In vitro drug release study showed that PTX release from Pull-LA-NPs at pH 7.4 and 5.4 was significantly influenced by addition of DTT. In cytotoxicity assay, PTX loaded Pull-LA-CLNPs showed a low IC50 at 0.51μg/mL. Asialoglycoprotein receptor (ASGPR) competitive inhibition and intracellular distribution studies performed by flow cytometer, fluorescence microscope and confocal laser scanning microscopy (CLSM) showed that Pull-LA-NPs could be efficiently taken up by the cells via ASGPR-mediated endocytosis and mainly distributed in cytoplasm...
March 1, 2017: Carbohydrate Polymers
Cheng Chen, Kesang Li, Hua Jiang, Fei Song, Huiping Gao, Xiaorong Pan, Bizhi Shi, Yanyu Bi, Huamao Wang, Hongyang Wang, Zonghai Li
Adoptive immunotherapy leveraging chimeric antigen receptor-modified T (CAR-T) cells holds great promise for the treatment of cancer. However, tumor-associated antigens often have low expression levels in normal tissues, which can cause on-target, off-tumor toxicity. Recently, we reported that GPC3-targeted CAR-T cells could eradicate hepatocellular carcinoma (HCC) xenografts in mice. However, it remains unknown whether on-target, off-tumor toxicity can occur. Therefore, we proposed that dual-targeted CAR-T cells co-expressing glypican-3 (GPC3) and asialoglycoprotein receptor 1 (ASGR1) (a liver tissue-specific protein)-targeted CARs featuring CD3ζ and 28BB (containing both CD28 and 4-1BB signaling domains), respectively, may have reduced on-target, off-tumor toxicity...
December 29, 2016: Cancer Immunology, Immunotherapy: CII
J Stefan, K Kus, A Wisniewska, K Kaminski, K Szczubialka, J Jawien, M Nowakowska, R Korbut
Pullulan is a biocompatible polysaccharide obtained from black, yeast-like fungus Aureobasidium pullulans. This polymer is used to deliver various substances to the liver because of its specificity for this organ. Pullulan is internalized into hepatocytes in the process of asialoglycoprotein receptor mediated endocytosis. Recently, by reaction with glycidyltrimethylammonium chloride (GTMAC) we have successfully synthesized a cationically-modified pullulan (Pull-GTMAC). Pull-GTMAC exhibits some unique beneficial effects not found for its native counterpart...
October 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Saeedeh Askarian, Khalil Abnous, Sara Ayatollahi, Sara Amel Farzad, Reza Kazemi Oskuee, Mohammad Ramezani
Targeted nano-carriers are highly needed to promote nucleic acid delivery into the specific cell for therapeutic approaches. Pullulan as a linear carbohydrate has an intrinsic liver targeting property interacting with asialoglycoprotein receptor (ASGPR) found on liver cells. In the present study, we developed polyamidoamine (PAMAM)-pullulan conjugates and investigated their targeting activity in delivering gene into liver cells. The particle size, zeta potential, buffering capacity and ethidium bromide exclusion assays of the conjugates were evaluated...
February 10, 2017: Carbohydrate Polymers
Xiangang Huang, Jean-Christophe Leroux, Bastien Castagner
Targeted delivery of therapeutic agents to hepatocytes is a particularly attractive strategy for the treatment of hepatocellular carcinoma and other liver diseases. The asialoglycoprotein receptor (ASGP-R) is abundantly expressed on hepatocytes and minimally found on extra-hepatic cells, making it an ideal entry gateway for hepatocyte-targeted therapy. Numerous multivalent ligands have been developed to target ASGP-R, among which well-defined multivalent ligands display especially high binding affinity to the receptor...
December 27, 2016: Bioconjugate Chemistry
Nidhi Gupta, Catherine H Wu, George Y Wu
BACKGROUND: Mitochondrial defects in hepatocytes can result in liver dysfunction and death. Hepatocytes have cell-surface asialoglycoprotein receptors (AsGRs) which internalize AsGs within endosomes. The aim of this study was to determine whether mitochondria could be targeted to hepatocytes by AsGR-mediated endocytosis. MATERIALS AND METHODS: An AsG, AsOR, was linked to polylysine to create a conjugate, AsOR-PL, and complexed with healthy and functional mitochondria (defined by normal morphology, cytochrome c assays, and oxygen-consumption rates)...
2016: Hepatic Medicine: Evidence and Research
Pu Zhang, Zhide Guo, Deliang Zhang, Chang Liu, Guibing Chen, Rongqiang Zhuang, Manli Song, Hua Wu, Xianzhong Zhang
The aim of this study is to develop a copolymer-based single-photon emission computed tomography/magnetic resonance (SPECT/MR) dual-modality imaging agent that can be labeled with both technetium-99m ((99m)Tc) and gadolinium (Gd) and target asialoglycoprotein receptor (ASGPR) via galactose. Monomers of N-p-vinylbenzyl-6-(2-(4-dimethylamino)benzaldehydehydrazono) nicotinate (VNI) for labeling of (99m)Tc, 5,8-bis(carboxymethyl)-3-oxo-11-(2-oxo-2-((4-vinylbenzyl)amino)ethyl)-1-(4-vinylphenzyl)-2,5,8,11-tetraazatridecan-13-oic acid (V2DTPA) for labeling of Gd, and vinylbenzyl-O-β-d-galactopyranosyl-d-gluconamide (VLA) for targeting ASGPR were synthesized, respectively...
2016: Molecular Imaging
Maja M Janas, Yongfeng Jiang, Mark K Schlegel, Scott Waldron, Satya Kuchimanchi, Scott A Barros
Single-stranded (ss) 2'-fluoro (2'-F)-modified oligonucleotides (ONs) with a full phosphorothioate (PS) backbone have been reported to be cytotoxic and cause DNA double-strand breaks (DSBs) when transfected into HeLa cells. However, the molecular determinants of these effects have not been fully explored. In this study, we investigated the impact of ON structure, chemistry, delivery method, and cell type on in vitro cytotoxicity and DSBs. We found that ss PS-ONs were more cytotoxic than double-stranded (ds) PS-ONs, irrespective of the 2'-ribose chemistry, inclusive of the 2'-F modification...
December 6, 2016: Nucleic Acid Therapeutics
Bijay Singh, Yoonjeong Jang, Sushila Maharjan, Hyeon-Jeong Kim, Ah Young Lee, Sanghwa Kim, Nomundelger Gankhuyag, Myeon-Sik Yang, Yun-Jaie Choi, Myung-Haing Cho, Chong-Su Cho
Despite advances in technology, neither conventional anti-cancer drugs nor current nanoparticle (NP) drugs have gained substantial success in cancer treatment. While conventional chemotherapy drugs have several limitations such as low potency, poor in vivo stability and limited bioavailability, non-specific targeting of NP drugs diminishes their potency at actual target sites. In addition, the development of drug resistance to anti-cancer drugs is another challenging problem. To overcome these limitations, we aimed to develop a polymer-drug conjugate, which functions as an active NP drug and drug carrier both, to deliver a chemotherapeutic drug for combination therapy...
February 2017: Biomaterials
Wen Jing, Jiang Li, Li Qin Tao, Jia Zhe, Li Bao Liang, Zhang Ke
Flow cytometric analysis of asialoglycoprotein receptor (ASGPR) levels on the surface of hepatocytes, which were obtained from the liver specimens of patients that received hepatectomy, were used as predictors of liver dysfunction after major hepatectomy for primary hepatocellular carcinoma (HCC) in Chinese patients, based on our previous study which confirmed the value of ASGPR levels on the surface of hepatocytes in evaluating the liver reserve function. The current study was planned to establish a conversion formula for the value of ASGPR with correlated liver function parameters...
October 2016: JPMA. the Journal of the Pakistan Medical Association
Carol A Casey, Ganapati Bhat, Melissa S Holzapfel, Armen Petrosyan
BACKGROUND: It is known that ethanol (EtOH) and its metabolites have a negative effect on protein glycosylation. The fragmentation of the Golgi apparatus induced by alteration of the structure of largest Golgi matrix protein, giantin, is the major consequence of damaging effects of EtOH-metabolism on the Golgi; however, the link between this and abnormal glycosylation remains unknown. Because previously we have shown that Golgi morphology dictates glycosylation, we examined the effect EtOH administration has on function of Golgi residential enzymes involved in N-glycosylation...
December 2016: Alcoholism, Clinical and Experimental Research
J M O'Sullivan, S Aguila, E McRae, S E Ward, O Rawley, P G Fallon, T M Brophy, R J S Preston, L Brady, O Sheils, A Chion, J S O'Donnell
Essentials von Willebrands factor (VWF) glycosylation plays a key role in modulating in vivo clearance. VWF glycoforms were used to examine the role of specific glycan moieties in regulating clearance. Reduction in sialylation resulted in enhanced VWF clearance through asialoglycoprotein receptor. Progressive VWF N-linked glycan trimming resulted in increased macrophage-mediated clearance. Click to hear Dr Denis discuss clearance of von Willebrand factor in a free presentation from the ISTH Academy SUMMARY: Background Enhanced von Willebrand factor (VWF) clearance is important in the etiology of both type 1 and type 2 von Willebrand disease (VWD)...
December 2016: Journal of Thrombosis and Haemostasis: JTH
Ruyun Lou, Weiting Yu, Yizhe Song, Ying Ren, Huizhen Zheng, Xin Guo, Yunfei Lin, Guoyu Pan, Xiuli Wang, Xiaojun Ma
Galactose moieties are covalently coupled with sodium alginate to enhance liver-specific functions in microcapsules owing to the specific interaction between the galactose moieties and the asialoglycoprotein receptors (ASGPRs) of hepatocytes. In this study, galactosylated alginate (L-NH2-OH-alginate) based microcapsules with desirable stability and a suitable 3D microenvironment are designed and fabricated for primary hepatocyte applications. The designed L-NH2-OH-alginate is fabricated via the application of ethylenediamine grafted lactobionic acid (L-NH2) onto the hydroxyl groups of sodium alginate so that the negatively charged carboxyl groups intact in L-NH2-OH-alginate can effectively bond with Ca(2+) to form a stable three-dimensional gel network; a subsequent reaction with polycations forms a stable membrane of microcapsules...
January 2, 2017: Carbohydrate Polymers
Ruyun Lou, Hongguo Xie, Huizhen Zheng, Ying Ren, Meng Gao, Xin Guo, Yizhe Song, Weiting Yu, Xiudong Liu, Xiaojun Ma
Alginate-galactosylated chitosan/polylysine (AGCP) microcapsules with excellent stability and high permeability were developed and employed in primary hepatocyte applications. The galactosylated chitosan (GC), synthesized via the covalent coupling of lactobionic acid (LA) with low molecular weight and water-soluble chitosan (CS), was ingeniously introduced into the core of alginate microcapsules by regulating the pH of gelling bath. The internal GC of the microcapsules simultaneously provided a large number of binding sites for the hepatocytes and further promoted the hepatocyte-matrix interactions via the recognition of asialoglycoprotein receptors (ASGPRs) on the hepatocyte surface, and afforded the AGCP microcapsules an excellent stability via the electrostatic interactions with alginate...
December 2016: International Journal of Biological Macromolecules
Yu Zhang, Xiaofeng Zhang, Jinling Zhang, Bin Sun, Lulu Zheng, Jun Li, Sixiu Liu, Guodong Sui, Zhengfeng Yin
Circulating tumor cells (CTCs) have been proposed to be an active source of metastasis or recurrence of hepatocellular carcinoma (HCC). The enumeration and characterization of CTCs has important clinical significance in recurrence prediction and treatment monitoring in HCC patients. We previously developed a unique method to separate HCC CTCs based on the interaction of the asialoglycoprotein receptor (ASGPR) expressed on their membranes with its ligand. The current study applied the ligand-receptor binding assay to a CTC-chip in a microfluidic device...
November 2016: Cancer Biology & Therapy
Kenichi Arai, Toshiko Yoshida, Motonori Okabe, Mitsuaki Goto, Tanveer Ahmad Mir, Chika Soko, Yoshinari Tsukamoto, Toshihiro Akaike, Toshio Nikaido, Kaixuan Zhou, Makoto Nakamura
The development of new three-dimensional (3D) cell culture system that maintains the physiologically relevant signals of hepatocytes is essential in drug discovery and tissue engineering research. Conventional two-dimensional (2D) culture yields cell growth, proliferation and differentiation. However, gene expression and signaling profiles can be different from in vivo environment. Here, we report the fabrication of a 3D culture system using an artificial scaffold and our custom-made inkjet 3D-bioprinter as a new strategy for studying liver-specific functions of hepatocytes...
September 19, 2016: Journal of Biomedical Materials Research. Part A
Dong Yang, Xinchuan Zheng, Ning Wang, Shijun Fan, Yongjun Yang, Yongling Lu, Qian Chen, Xin Liu, Jiang Zheng
Free bacterial lipopolysaccharide (LPS) is generally removed from the bloodstream through hepatic uptake via TLR4, the LPS pattern recognition receptor, but mechanisms for internalization and clearance of conjugated LPS are less clear. Kukoamine B (KB) is a novel cationic alkaloid that interferes with LPS binding to TLR4. In this study, KB accelerated blood clearance of LPS. KB also enhanced LPS distribution in the hepatic tissues of C57 BL/6 mice, along with LPS uptake in primary hepatocytes and HepG2 cells...
September 6, 2016: Oncotarget
Alexander G Majouga, Yan A Ivanenkov, Mark S Veselov, Anton V Lopuhov, Svetlana V Maklakova, Elena K Beloglazkina, Petr V Binevski, Natalya L Klyachko, Yuri B Sandulenko, Natalia Y Galkina, Victor E Koteliansky
During the past decade asialoglycoprotein receptor (ASGP-R) expressed predominantly by hepatocytes has attracted a considerable attention as a convenient biomolecular trap for targeted drug delivery. Currently, several selective galactose-containing ligands equipped by drug molecules, e.g. known anticancer therapeutics, as well as diagnostic tools are under active preclinical development. In this paper, we have carried out a rational in silico screening among the molecules available in ChemDiv collection and compounds provided by our colleagues to reveal potential ASGP-R binders...
2016: Current Drug Delivery
Yiling Mi, Marcy Coonce, Dorothy Fiete, Lindsay Steirer, Gabriela Dveksler, R Reid Townsend, Jacques U Baenziger
The mannose receptor (ManR, Mrc1) and asialoglycoprotein receptor (ASGR, Asgr1 and Asgr2) are highly abundant endocytic receptors expressed by sinusoidal endothelial cells and parenchymal cells in the liver, respectively. We genetically manipulated either receptor individually or in combination, revealing phenotypic changes in female and male mice associated with changes in circulating levels of many glycoproteins. Both receptors rise and fall in response to progesterone during pregnancy. Thirty percent of Asgr2(-/-) and 65% of Mrc1(-/-)Asgr2(-/-) mice are unable to initiate parturition at the end of pregnancy, whereas Mrc1(-/-) mice initiate normally...
September 2, 2016: Journal of Biological Chemistry
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