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Asialoglycoprotein receptor

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https://www.readbyqxmd.com/read/28230359/efficient-liver-targeting-by-polyvalent-display-of-a-compact-ligand-for-the-asialoglycoprotein-receptor
#1
Carlos A Sanhueza, Michael M Baksh, Benjamin Thuma, Marc D Roy, Sanjay Dutta, Cathy Préville, Boris A Chrunyk, Kevin Beaumont, Robert Dullea, Mark Ammirati, Shenping Liu, David Gebhard, James E Finley, Christopher T Salatto, Amanda King-Ahmad, Ingrid Stock, Karen Atkinson, Benjamin Reidich, Wen Lin, Rajesh Kumar, Meihua Tu, Elnaz Menhaji-Klotz, David A Price, Spiros Liras, M G Finn, Vincent Mascitti
A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo...
February 23, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28219253/in-vitro-and-in-vivo-evaluation-of-macromolecular-prodrug-gc-fua-based-nanoparticle-for-hepatocellular-carcinoma-chemotherapy
#2
Can Huang, Na-Mei Li, Pei Gao, Sa Yang, Qian Ning, Wen Huang, Zhi-Ping Li, Peng-Ju Ye, Li Xiang, Dong-Xiu He, Xiang-Wen Tan, Cui-Yun Yu
A novel type of macromolecular prodrug delivery system is reported in this research. The N-galactosylated-chitosan-5-fluorouracil acetic acid conjugate (GC-FUA) based nanoparticle delivery system was evaluated in vitro and in vivo. Biocompatibility of GC-FUA-NPs was screened by BSA adsorption test and hemolysis activity examination in vitro. Cytotoxicity and cellular uptake study in HepG2 and A549 cells demonstrated that compared to free 5-Fu, the GC-FUA-NPs play great function in killing cancer cells for the cell endocytosis mediated by asialoglycoprotein receptor (ASGPR), which overexpresses on the cell surface...
November 2017: Drug Delivery
https://www.readbyqxmd.com/read/28194629/-68-ga-nota-galactosyl-human-serum-albumin-a-tracer-for-liver-function-imaging-with-improved-stability
#3
Roland Haubner, Andreas M Schmid, Andreas Maurer, Christine Rangger, Llanos Geraldo Roig, Bernd J Pichler, Irene J Virgolini
PURPOSE: Non-invasive techniques allowing quantitative determination of the functional liver mass are of great interest for patient management in a variety of clinical settings. Recently, we presented [(68)Ga]DTPA-GSA to target the hepatic asialoglycoprotein receptor for this purpose. Here, we introduce [(68)Ga]NOTA-GSA to improve metabolic stability of the radiopharmaceutical and compare the imaging properties with [(68)Ga]DTPA-GSA. PROCEDURES: Labeling of the compounds was carried out at room temperature using 1...
February 13, 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/28179943/synthesis-of-multi-lactose-appended-%C3%AE-cyclodextrin-and-its-cholesterol-lowering-effects-in-niemann-pick-type-c-disease-like-hepg2-cells
#4
Keiichi Motoyama, Rena Nishiyama, Yuki Maeda, Taishi Higashi, Yoichi Ishitsuka, Yuki Kondo, Tetsumi Irie, Takumi Era, Hidetoshi Arima
Niemann-Pick type C (NPC) disease, characterized by intracellular accumulation of unesterified cholesterol and other lipids owing to defects in two proteins NPC1 and NPC2, causes neurodegeneration and other fatal neurovisceral symptoms. Currently, treatment of NPC involves the use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). HP-β-CD is effective in the treatment of hepatosplenomegaly in NPC disease, albeit at a very high dose. One of the methods to reduce the required dose of HP-β-CD for treatment of NPC is to actively targeting hepatocytes with β-cyclodextrin (β-CD)...
2017: Beilstein Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28167263/asialoglycoprotein-receptor-targeted-liposomes-loaded-with-a-norcantharimide-derivative-for-hepatocyte-selective-targeting
#5
Xiaolin Liu, Mengting Han, Jiawen Xu, Sicong Geng, Yu Zhang, Xaohui Ye, Jingxin Gou, Tian Yin, Haibing He, Xing Tang
In order to overcome the shortcomings associated with the clinical application of norcantharidin (NCTD), including intense irritation and a short half-life, and to obtain a hepatocyte-selective liposome system with high encapsulation efficiency (EE) and low leakage, we synthesized a C14 alkyl chain norcantharimide derivative of NCTD (2-tetradecylhexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione, N-14NCTDA). Asialoglycoprotein receptor-targeted, galactosylated liposomes loaded with N-14NCTDA (GAL-Lipo) were prepared by the lipid film hydration method...
February 4, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28158620/characterizing-the-effect-of-galnac-and-phosphorothioate-backbone-on-binding-of-antisense-oligonucleotides-to-the-asialoglycoprotein-receptor
#6
Karsten Schmidt, Thazha P Prakash, Aaron J Donner, Garth A Kinberger, Hans J Gaus, Audrey Low, Michael E Østergaard, Melanie Bell, Eric E Swayze, Punit P Seth
No abstract text is available yet for this article.
February 3, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28155331/asialoglycoprotein-receptor-targeted-delivery-of-doxorubicin-nanoparticles-for-hepatocellular-carcinoma
#7
Sandhya Pranatharthiharan, Mitesh D Patel, Vinod C Malshe, Vaishali Pujari, Ajit Gorakshakar, Manisha Madkaikar, Kanjaksha Ghosh, Padma V Devarajan
We report asialoglycoprotein receptor (ASGPR)-targeted doxorubicin hydrochloride (Dox) nanoparticles (NPs) for hepatocellular carcinoma (HCC). Polyethylene sebacate (PES)-Gantrez® AN 119 Dox NPs of average size 220 nm with PDI < 0.62 and ∼20% Dox loading were prepared by modified nanoprecipitation. ASGPR ligands, pullulan (Pul), arabinogalactan (AGn), and the combination (Pul-AGn), were anchored by adsorption. Ligand anchoring enabled high liver uptake with a remarkable hepatocyte:nonparenchymal cell ratio of 85:15...
November 2017: Drug Delivery
https://www.readbyqxmd.com/read/28129130/clinical-proof-of-concept-for-a-novel-hepatocyte-targeting-galnac-sirna-conjugate
#8
Tracy S Zimmermann, Verena Karsten, Amy Chan, Joseph Chiesa, Malcolm Boyce, Brian R Bettencourt, Renta Hutabarat, Saraswathy Nochur, Akshay Vaishnaw, Jared Gollob
Advancement of RNAi-based therapeutics depends on effective delivery to the site of protein synthesis. Although intravenously administered, multi-component delivery vehicles have enabled small interfering RNA (siRNA) delivery and progression into clinical development, advances of single-component, systemic siRNA delivery have been challenging. In pre-clinical models, attachment of a triantennary N-acetylgalactosamine (GalNAc) ligand to an siRNA mediates hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28110040/doxorubicin-and-paclitaxel-co-bound-lactosylated-albumin-nanoparticles-having-targetability-to-hepatocellular-carcinoma
#9
Le Quang Thao, Changkyu Lee, Bomi Kim, Sungin Lee, Tae Hwan Kim, Jong Oh Kim, Eun Seong Lee, Kyung Taek Oh, Han-Gon Choi, Sun Dong Yoo, Yu Seok Youn
Anticancer drug targeting to liver asialoglycoprotein receptors (ASGPR) is viewed as a good approach for hepatocellular carcinoma (HCC) treatment. Lactose residue is a promising ASGPR ligand due to its high receptor affinity. Herein, we introduce doxorubicin and paclitaxel co-bound lactosylated albumin (Lac-BSA) nanoparticles (Dox/Pac Lac-BSA NPs) with good liver targetability. Lac-BSA was synthesized by conjugating lactobionic acid to naïve BSA then characterized by mass spectrometry. Dox/Pac Lac-BSA NPs were fabricated utilizing high-pressure homogenization and evaporation with Nab(®) (nanoparticle albumin bound) technology...
January 17, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28100779/intramembrane-proteolysis-of-astrotactins
#10
Hao Chang, Philip M Smallwood, John Williams, Jeremy Nathans
Astrotactins are vertebrate-specific membrane proteins implicated in neuron-glia interactions during central nervous system development and in hair follicle polarity during skin development. By studying epitope-tagged derivatives of mouse Astrotactin2 (Astn2) produced in transfected cells, we determined that the amino- and carboxy-termini reside in the extracellular space and are initially linked by two transmembrane segments and a single cytoplasmic domain. We further show that Astn2 undergoes proteolytic cleavage in the second transmembrane domain (TM2) and that a disulfide bond holds the resulting two fragments together...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28095357/establishment-of-a-fluorescence-based-method-to-evaluate-endocytosis-of-desialylated-glycoproteins-in-vitro
#11
Cheng Luo, Song Chen, Na Xu, Wen Bo Sai, Wei Zhao, Ying Chun Li, Xiao Jing Hu, Hong Tian, Xiang Dong Gao, Wen Bing Yao
Insufficient sialylation can result in rapid clearance of therapeutic glycoproteins by intracellular degradation, which is mainly mediated by asialoglycoprotein receptors (ASGPRs) on hepatic cells. In contrast, for glycoproteins, a long half-life is often related to high level of terminal sialic acid. These could be extremely important for insufficient sialylated biomedicines in clinic, and development of therapeutic glycoproteins in laboratory. However, how the desialylated glycoproteins are removed and how to evaluate the ASGPRs mediated endocytosis in vitro needs further investigate...
January 14, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28092276/asialoglycoprotein-receptors-as-important-mediators-of-plasma-lipids-and-atherosclerosis
#12
Suleiman A Igdoura
PURPOSE OF REVIEW: This review seeks to describe the role of the asialoglycoprotein receptor (ASGR) in modulating non-HDL lipoprotein levels, platelet numbers and atherosclerosis. RECENT FINDINGS: Genetics studies have revealed that ASGR haplodeficiency provides protection from atherosclerosis. The potential interactions of ASGR with LDL receptor may regulate the rate of LDL uptake and as a result may lower plasma non-HDL cholesterol. ASGR clears senescent platelets and induces the expression of hepatic thrombopoietin...
January 13, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28063265/pegylation-potentiates-hepatoma-cell-targeted-liposome-mediated-in-vitro-gene-delivery-via-the-asialoglycoprotein-receptor
#13
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
https://www.readbyqxmd.com/read/28038747/efficient-delivery-of-paclitaxel-into-asgpr-over-expressed-cancer-cells-using-reversibly-stabilized-multifunctional-pullulan-nanoparticles
#14
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
https://www.readbyqxmd.com/read/28035433/development-of-t-cells-carrying-two-complementary-chimeric-antigen-receptors-against-glypican-3-and-asialoglycoprotein-receptor-1-for-the-treatment-of-hepatocellular-carcinoma
#15
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
https://www.readbyqxmd.com/read/28011954/new-cationically-modified-pullulan-attenuates-atherogenesis-and-influences-lipid-metabolism-in-apoe-knockout-mice
#16
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
https://www.readbyqxmd.com/read/27988010/pamam-pullulan-conjugates-as-targeted-gene-carriers-for-liver-cell
#17
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
https://www.readbyqxmd.com/read/27966887/well-defined-multivalent-ligands-for-hepatocytes-targeting-via-asialoglycoprotein-receptor
#18
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
https://www.readbyqxmd.com/read/27942238/targeted-transplantation-of-mitochondria-to-hepatocytes
#19
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
https://www.readbyqxmd.com/read/27941121/a-novel-copolymer-based-functional-spect-mr-imaging-agent-for-asialoglycoprotein-receptor-targeting
#20
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
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