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Asialoglycoprotein receptor

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https://www.readbyqxmd.com/read/29456020/advanced-sirna-designs-further-improve-in-vivo-performance-of-galnac-sirna-conjugates
#1
Donald J Foster, Christopher R Brown, Sarfraz Shaikh, Casey Trapp, Mark K Schlegel, Kun Qian, Alfica Sehgal, Kallanthottathil G Rajeev, Vasant Jadhav, Muthiah Manoharan, Satya Kuchimanchi, Martin A Maier, Stuart Milstein
Significant progress has been made in the advancement of RNAi therapeutics by combining a synthetic triantennary N-acetylgalactosamine ligand targeting the asialoglycoprotein receptor with chemically modified small interfering RNA (siRNA) designs, including the recently described Enhanced Stabilization Chemistry. This strategy has demonstrated robust RNAi-mediated gene silencing in liver after subcutaneous administration across species, including human. Here we demonstrate that substantial efficacy improvements can be achieved through further refinement of siRNA chemistry, optimizing the positioning of 2'-deoxy-2'-fluoro and 2'-O-methyl ribosugar modifications across both strands of the double-stranded siRNA duplex to enhance stability without compromising intrinsic RNAi activity...
January 4, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29408311/carrier-free-nanodrug-by-co-assembly-of-chemotherapeutic-agent-and-photosensitizer-for-cancer-imaging-and-chemo-photo-combination-therapy
#2
Ruirui Zhao, Guirong Zheng, Lulu Fan, Zhichun Shen, Kai Jiang, Yan Guo, Jing-Wei Shao
Nanosized drug delivery systems (NDDS) with photothermal therapy (PTT) and photodynamic therapy (PDT) have been extensively exploited to improve the therapeutic performance and bio-safety of chemotherapeutic drugs in cancer. In this work, a carrier-free nanodrug was developed by co-assembly of the anti-cancer agent ursolic acid (UA), an asialoglycoprotein receptor (ASGPR), which can recognize the target molecule lactobionic acid (LA), and the near-infrared (NIR) probe dye indocyanine green (ICG) to form UA-LA-ICG NPs by a simple and green self-assembly approach...
February 5, 2018: Acta Biomaterialia
https://www.readbyqxmd.com/read/29404442/generation-of-safe-and-therapeutically-effective-human-induced-pluripotent-stem-cell-derived-hepatocyte-like-cells-for-regenerative-medicine
#3
Kazuo Takayama, Naoki Akita, Natsumi Mimura, Rina Akahira, Yukimasa Taniguchi, Makoto Ikeda, Fuminori Sakurai, Osamu Ohara, Tomohiro Morio, Kiyotoshi Sekiguchi, Hiroyuki Mizuguchi
Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells are expected to be applied for regenerative medicine. In this study, we attempted to generate safe and therapeutically effective human iPS-HLCs for hepatocyte transplantation. First, human iPS-HLCs were generated from a human leukocyte antigen-homozygous donor on the assumption that the allogenic transplantation might be carried out. Highly efficient hepatocyte differentiation was performed under a feeder-free condition using human recombinant laminin 111, laminin 511, and type IV collagen...
December 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29379913/the-synthesis-of-la-fe3o4-pda-peg-dox-for-photothermal-therapy-chemotherapy
#4
Yuhua Chen, Feng Zhang, Qian Wang, Huiming Lin, Ruihan Tong, Na An, Fengyu Qu
A facile methodology is presented to construct a multifunctional nanocomposite that integrates photothermal therapy and specific drug release into a single nanostructure. Firstly, magnetic Fe3O4@polydopamine core-shell nanoparticles (Fe3O4@PDA) were synthesized via a reversed-phase microemulsion approach. By varying the amount of DA, Fe3O4@PDA with a particle size of 28-38 nm can be obtained. To further ensure the monodispersity, biocompatibility and specific uptake, PEG and lactobionic acid (LA) were grafted onto Fe3O4@PDA (LA-Fe3O4@PDA-PEG), whose fast photothermal conversion is derived by the combination of Fe3O4 and PDA with high near infrared (NIR) absorption...
January 30, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/29353104/galactosylated-iodine-based-small-molecule-i-v-ct-contrast-agent-for-bile-duct-imaging
#5
Yeonjin Jung, Hee Sook Hwang, Kun Na
Computed tomography (CT) with contrast plays an important role as a clinical diagnostic tool but still has a limited diagnostic range. In this work, we developed a novel injectable iodine-based small molecule CT contrast agent, even can be used for bile duct diagnostics. The bile duct diagnosable CT contrast agent (BDICA) is synthesized with 5-amino-2,4,6-triiodoisophthaloyl dichloride (ATIPC), tromethamine and lactobionic acid (LBA) for asialoglycoprotein receptor (ASGPR) targeted delivery via receptor-mediated endocytosis and transport to the bile canaliculi...
January 12, 2018: Biomaterials
https://www.readbyqxmd.com/read/29246313/assessment-of-the-drug-interaction-potential-of-unconjugated-and-galnac3-conjugated-2-moe-asos
#6
Colby S Shemesh, Rosie Z Yu, Mark S Warren, Michael Liu, Mirza Jahic, Brandon Nichols, Noah Post, Song Lin, Daniel A Norris, Eunju Hurh, Jane Huang, Tanya Watanabe, Scott P Henry, Yanfeng Wang
Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides (2'-MOE-ASOs), including a single triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASO. Several investigations to describe the DDI potential of a 2'-MOE-ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored...
December 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29193962/cell-penetrating-polymers-containing-guanidinium-trigger-apoptosis-in-human-hepatocellular-carcinoma-cells-unless-conjugated-to-a-targeting-n-acetyl-galactosamine-block
#7
Zhe Tan, Yogesh K Dhande, Theresa M Reineke
A series of 3-guanidinopropyl methacrylamide (GPMA)-based polymeric gene delivery vehicles were developed via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers have been evaluated for their cellular internalization ability, transfection efficiency, and cytotoxicity. Two homopolymers: P(GPMA20), P(GPMA34), were synthesized to study the effect of guanidium polymer length on delivery efficiency and toxicity. In addition, an N-acetyl-d-galactosamine (GalNAc)-based hydrophilic block was incorporated to produce diblock polymers, which provides a neutral hydrophilic block that sterically protects plasmid-polymer complexes (polyplexes) from colloidal aggregation and aids polyplex targeting to hepatocytes via binding to asialoglycoprotein receptors (ASGPRs)...
December 1, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29192290/direct-conversion-of-human-fibroblasts-into-hepatocyte-like-cells-by-atf5-prox1-foxa2-foxa3-and-hnf4a-transduction
#8
Daiki Nakamori, Hiroki Akamine, Kazuo Takayama, Fuminori Sakurai, Hiroyuki Mizuguchi
Recently, it has been reported that human hepatocyte-like cells can be generated from fibroblasts by direct reprogramming technology. However, the conversion efficiency of human induced hepatocyte-like cells (hiHeps) is not high enough. In addition, comparative analysis with the existing models of hepatocytes, such as human iPS cell-derived hepatocyte-like cells and primary human hepatocytes, has not been sufficiently carried out. In this study, we screened hepatic transcription factors for efficient direct hepatic reprogramming and compared hepatic functions between hiHeps and other existing hepatocyte models...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29108133/targeted-delivery-of-mir-199a-3p-using-self-assembled-dipeptide-nanoparticles-efficiently-reduces-hepatocellular-carcinoma
#9
Aditi Varshney, Jiban J Panda, Avishek K Singh, Nitin Yadav, Chhagan Bihari, Subhrajit Biswas, Shiv K Sarin, Virander S Chauhan
Hepatocellular carcinoma (HCC) is an aggressive tumor with limited systemic and locoregional modalities of treatment. Although microRNA (miRNA) based therapies have significant potential, their targeted delivery remains a major challenge. miR-199a-3p functions as an important tumor suppressor in HCC, which regulates various cellular processes. Recently, peptide-based nanoparticles (NPs) have been developed to deliver oligonucleotides including miRNA. Here, we describe the synthesis and characterization of arginine α,β-dehydrophenylalanine (RΔF) nanoparticles for the selective delivery of miR-199a-3p to restore dysregulated gene expression in HCC...
November 6, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29107835/co-delivery-of-sorafenib-and-sivegf-based-on-mesoporous-silica-nanoparticles-for-asgpr-mediated-targeted-hcc-therapy
#10
Guirong Zheng, Ruirui Zhao, Aixiao Xu, Zhichun Shen, Xian Chen, Jingwei Shao
Combination with chemotherapeutic drug and gene therapy has been proven highly effective in suppressing tumor progression. Hence, an asialoglycoprotein receptor (ASGPR)-targeting nanodrug delivery system based on mesoporous silica (MSN) nanocarrier for co-delivery of sorafenib (SO) and vascular endothelial growth factor (VEGF) targeted siRNA (siVEGF) to hepatocellular carcinoma (HCC) was successfully designed and synthesized. The structure of nanoparticles was characterized by IR, particle size, zeta potential and N2 adsorption-desorption...
October 28, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29080883/-lactose-based-glycoconjugates-with-variable-spacers-for-design-of-liver-targeted-liposomes
#11
A S Nosova, O O Koloskova, I P Shilovskiy, Yu L Sebyakin, M R Khaitov
Asialoglycoprotein receptors are highly abundant on the hepatocyte surface and have specific binding sites for blood serum glycoproteins. Such discovery resulted in development of liver-targeted drug delivery systems because modification of the liposomal surface by carbohydrate derivatives results in an increase of endocytosis, which facilitates selective uptake of such systems by hepatocytes. In this study we have synthesized novel lactose derivatives containing a palmitic hydrophobic domain. They were used for modification of the liposome surface...
October 2017: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
https://www.readbyqxmd.com/read/29069408/asialoglycoprotein-receptor-1-mediates-productive-uptake-of-n-acetylgalactosamine-conjugated-and-unconjugated-phosphorothioate-antisense-oligonucleotides-into-liver-hepatocytes
#12
Michael Tanowitz, Lisa Hettrick, Alexey Revenko, Garth A Kinberger, Thazha P Prakash, Punit P Seth
Antisense oligonucleotide (ASO) therapeutics show tremendous promise for the treatment of previously intractable human diseases but to exert their effects on cellular RNA processing they must first cross the plasma membrane by endocytosis. The conjugation of ASOs to a receptor ligand can dramatically increase their entry into certain cells and tissues, as demonstrated by the implementation of N -acetylgalactosamine (GalNAc)-conjugated ASOs for Asialoglycoprotein Receptor (ASGR)-mediated uptake into liver hepatocytes...
October 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29063370/pathways-of-production-and-delivery-of-hepatocyte-exosomes
#13
Li Chen, Ruju Chen, Sherri Kemper, David R Brigstock
Hepatocyte exosomes (Exo(Hep)) are proposed to mediate physiological or pathophysiological signaling in a variety of hepatic target cells. Exo(Hep) were purified from the medium of primary mouse hepatocytes or AML12 cells and characterized as ~100 nm nanovesicles that were positive for proteins commonly found in exosomes (CD9, CD81, flotillin) or hepatocytes (asialoglycoprotein receptor). Ethanol treatment of hepatocytes caused increased Exo(Hep) release and increased cellular mRNA expression of components involved in intracellular vesicle trafficking (Rab 5a,b,c, Rab 7a, Rab 27a,b) or exosome biogenesis via the ESCRT (HGS, Alix, STAM1, TSG101, VTA1, YKT6) or ceramide (nSmase2) pathways...
October 23, 2017: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/29059528/glycosylated-raft-polymers-with-varying-peg-linkers-produce-different-sirna-uptake-gene-silencing-and-toxicity-profiles
#14
Elizabeth G L Williams, Oliver Earl Hutt, Tracey M Hinton, Sophie C Larnaudie, Tam Le, James M MacDonald, Pathiraja Gunatillake, San H Thang, Peter J Duggan
Achieving efficient and targeted delivery of short interfering (siRNA) is an important research challenge to overcome to render highly promising siRNA therapies clinically successful. Challenges exist in designing synthetic carriers for these RNAi constructs that provide protection against serum degradation, extended blood retention times, effective cellular uptake through a variety of uptake mechanisms, endosomal escape and efficient cargo release. These challenges have resulted in a significant body of research, and led to many important findings about the chemical composition and structural layout of the delivery vector for optimal gene silencing...
October 23, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/29057592/the-role-of-sialic-acids-in-the-immune-recognition-of-xenografts
#15
REVIEW
Beth M French, Selin Sendil, Richard N Pierson, Agnes M Azimzadeh
Presentation of sialic acid (Sia) varies among different tissues and organs within each species, and between species. This diversity has biologically important consequences regarding the recognition of cells by "xeno" antibodies (Neu5Gc vs Neu5Ac). Sia also plays a central role in inflammation by influencing binding of the asialoglycoprotein receptor 1 (ASGR-1), Siglec-1 (Sialoadhesin), and cellular interactions mediated by the selectin, integrin, and galectin receptor families. This review will focus on what is known about basic Sia structure and function in association with xenotransplantation, how changes in sialylation may occur in this context (through desialylation or changes in sialyltransferases), and how this fundamental pathway modulates adhesive and cell activation pathways that appear to be particularly crucial to homeostasis and inflammation for xenografts...
November 2017: Xenotransplantation
https://www.readbyqxmd.com/read/29040465/the-fut2-secretor-variant-p-trp154ter-influences-serum-vitamin-b12-concentration-via-holo-haptocorrin-but-not-holo-transcobalamin-and-is-associated-with-haptocorrin-glycosylation
#16
Aneliya Velkova, Jennifer E L Diaz, Faith Pangilinan, Anne M Molloy, James L Mills, Barry Shane, Erica Sanchez, Conal Cunningham, Helen McNulty, Cheryl D Cropp, Joan E Bailey-Wilson, Alexander F Wilson, Lawrence C Brody
Vitamin B12 deficiency is common in older individuals. Circulating vitamin B12 concentration can be used to diagnose deficiency but this test has substantial false positive and false negative rates. We conducted genome-wide association studies (GWAS) in which we resolved total serum vitamin B12 into the fractions bound to transcobalamin and haptocorrin: two carrier proteins with very different biological properties. We replicated reported associations between total circulating vitamin B12 concentrations and a common null variant in FUT2...
October 12, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28988716/evaluation-of-galnac-sirna-conjugate-activity-in-pre-clinical-animal-models-with-reduced-asialoglycoprotein-receptor-expression
#17
Jennifer L S Willoughby, Amy Chan, Alfica Sehgal, James S Butler, Jayaprakash K Nair, Tim Racie, Svetlana Shulga-Morskaya, Tuyen Nguyen, Kun Qian, Kristina Yucius, Klaus Charisse, Theo J C van Berkel, Muthiah Manoharan, Kallanthottathil G Rajeev, Martin A Maier, Vasant Jadhav, Tracy S Zimmermann
The hepatocyte-specific asialoglycoprotein receptor (ASGPR) is an ideal candidate for targeted drug delivery to the liver due to its high capacity for substrate clearance from circulation together with its well-conserved expression and function across species. The development of GalNAc-siRNA conjugates, in which a synthetic triantennary N-acetylgalactosamine-based ligand is conjugated to chemically modified siRNA, has enabled efficient, ASGPR-mediated delivery to hepatocytes. To investigate the potential impact of variations in receptor expression on the efficiency of GalNAc-siRNA conjugate delivery, we evaluated the pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates in multiple pre-clinical models with reduced receptor expression...
September 7, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28987883/galnac-bio-functionalization-of-nanoparticles-assembled-by-electrostatic-interactions-improves-sirna-targeting-to-the-liver
#18
Efrat Korin, Tzlil Bejerano, Smadar Cohen
RNA interference (RNAi) has the potential to reversibly silence any gene with high efficiency and specificity. To fulfill the clinical potential of RNAi, delivery vehicles are required to transport the short interfering RNA (siRNA) to the site of action in the cells of target tissues. Here, we describe the features of novel liver-targeted siRNA nanoparticles (NPs), co-assembled due to the complexation of alginate sulfate (AlgS) with siRNA, mediated by calcium ions bridges (AlgS-Ca(2+)-siRNA NPs) and then bioconjugation of a targeting ligand onto the AlgS upon the NP surface...
October 4, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28982888/accurate-estimation-of-functional-liver-volume-using-gd-eob-dtpa-mri-compared-to-mdct-99m-tc-spect-fusion-imaging
#19
COMPARATIVE STUDY
Yuji Morine, Chinbold Enkhbold, Satoru Imura, Tetsuya Ikemoto, Syuichi Iwahashi, Y U Saito, Shinichiro Yamada, Tohru Utsunomiya, Mitsuo Shimada
BACKGROUND/AIM: We assessed the utility of dynamic magnetic resonance imaging (MRI) with gadoxetate-ethoxybenzyl-diethylenetriamine penta-aceticpenta-acetic acid (Gd-EOB-DTPA) (EOB-MRI) for estimating functional liver volume compared to (99m)Tc-galactosyl albumin single-photon-emission computed tomography ((99m)Tc-GSA SPECT). PATIENTS AND METHODS: Regional functional liver volume (left lateral, medial, right anterior, right posterior) of 58 hepatectomized patients was assessed using EOB-MRI and (99m)Tc-GSA SPECT, and compared to the actual liver volume with MDCT-3D volumetry...
October 2017: Anticancer Research
https://www.readbyqxmd.com/read/28952928/generation-of-an-asgr1-homozygous-mutant-human-embryonic-stem-cell-line-wae001-a-6-using-crispr-cas9
#20
Yingying Xu, Yuhang Wu, Dongsheng Guo, Ge Gao, Keyu Lai, Fan Yang, Kepin Wang, Han Wu, Liangxue Lai, Jialiang Li, Kecheng Xu, Yin-Xiong Li
The gene asialoglycoprotein receptor 1 (ASGR1) encodes a subunit of the asialoglycoprotein receptor. Here we report the generation of a human embryonic stem cell line WAe001-A-6 harbouring homozygous ASGR1 mutations using CRISPR/Cas9. The mutation involves a 37bp deletion, resulting in a frame shift. The homozygous knockout WA01 cell line maintains a normal karyotype, typical stem cell morphology, pluripotency and differentiation potential in vitro.
July 2017: Stem Cell Research
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