Design of Multivalent Galactoside Ligands and Their Binding to Hepatic Asialoglycoprotein Receptor

Zhang, Xiaoru; Jia, Ji-Long; Zhang, Rongjun; Xu, Min; Zhang, Shusheng

doi:10.1002/cjoc.200690197

Cited by 3 publications

(4 citation statements)

References 19 publications

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“…The inhibition by one GalNAc unit in the polymer was comparable to ASF and much greater than free GalNAc when compared with the GalNAc equivalent concentration of PMAGalNAc 62 chains. These data suggest that multivalent binding imparts higher receptor affinity, in accordance with previous findings on the effect of ligand valency on binding affinity to ASGPRs. ,,, Previous studies have used ligand-functionalized, radiolabeled proteins at 4 °C for measuring IC 50 values to show that biantennary and triantennary structures can have 3–4 orders of magnitude higher binding constants compared to monovalent structures. , Uptake studies of fluorescently labeled compounds at 37 °C (similar to our current study) have also shown a similar trend , with biantennary and triantennary ligands, even though the IC 50 values differ between these two approaches due to differences in experimental design. These data suggest that a serial arrangement of GalNAc in a block of 62 repeat units also provides high binding affinity due to the cluster glycoside effect (yielding 5 orders of magnitude higher affinity than free GalNAc) .…”

Section: Resultssupporting

confidence: 92%

“…These data suggest that multivalent binding imparts higher receptor affinity, in accordance with previous findings on the effect of ligand valency on binding affinity to ASGPRs. 50,51,65,66 Previous studies have used ligand-functionalized, radiolabeled proteins at 4 °C for measuring IC 50 values to show that biantennary and triantennary structures can have 3−4 orders of magnitude higher binding constants compared to monovalent structures. 50,54 Uptake studies of fluorescently labeled compounds at 37 °C (similar to our current study) have also shown a similar trend 51,66 with biantennary and triantennary ligands, even though the IC 50 values differ between these two approaches due to differences in experimental design.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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N-Acetylgalactosamine Block-co-Polycations Form Stable Polyplexes with Plasmids and Promote Liver-Targeted Delivery

et al. 2016

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The liver is an ideal target for nucleic acid therapeutic applications (i.e., siRNA, gene therapy, and genome editing) due to its ability to secrete proteins into the blood. In this work, we present the first synthesis of a novel monomer derived from N-acetyl-d-galactosamine (GalNAc) and its polymerization as a facile route to create multivalent delivery vehicles with exceptional targeting efficiency to asialoglycoprotein receptors (ASGPRs) on liver hepatocytes. A series of cationic diblock GalNAc glycopolymers composed of a GalNAc-derived block of fixed length (n = 62) and cationic 2-aminoethylmethacrylamide (AEMA) blocks of varying lengths (n = 19, 33, and 80) have been synthesized and characterized. In addition, nontargeted control polymers consisting of either glucose or polyethylene glycol-derived neutral blocks with an AEMA cationic block were also created and examined. All polymeric vehicles were able to bind and encapsulate plasmids (pDNA) into polymer-pDNA complexes (polyplexes). The GalNAc-derived polyplexes were colloidally stable and maintained their size over a period of 4 h in reduced-serum cell culture media. The GalNAc-derived homopolymer effectively inhibited the uptake of Cy5-labeled asialofetuin (a natural ligand of ASGPRs) by cultured hepatocyte (HepG2) cells at lower concentrations (IC50 = 20 nM) than monomeric GalNAc (IC50 = 1 mM) and asialofetuin (IC50 = 1 μM), suggesting highly enhanced ASGPR binding due to multivalency. These polymers also showed cell type-specific gene expression in cultured cells, with higher protein expression in ASGPR-presenting HepG2 than HeLa cells, which lack the receptor. Biodistribution studies in mice show higher accumulation of pDNA and GalNAc-derived polymers in the liver compared with the glucose-derived nontargeted control. This study demonstrates the first facile synthesis of a multivalent GalNAc-derived block copolymer architecture that promotes enhanced delivery to liver and offers insights to improve targeted nanomedicines for a variety of applications.

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Section: Resultssupporting

confidence: 92%

Section: ■ Materials and Methodsmentioning

confidence: 99%

N-Acetylgalactosamine Block-co-Polycations Form Stable Polyplexes with Plasmids and Promote Liver-Targeted Delivery

et al. 2016

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“…To compare the self-assembly behavior of Bz - and Ac -protected glycopolymers, the corresponding monomers were designed first. As shown in Scheme , glycosylation donors Bz-1 and Ac-1 were prepared via three steps according the reaction conditions reported in the literature . After glycosylation reaction with the same acceptor S1 , the vinyl group was successfully coupled to Bz-1 and Ac-1 , generating new monomers Bz-2 and Ac-2 .…”

Section: Resultsmentioning

confidence: 99%

Deprotection-Induced Micellization of Glycopolymers: Control of Kinetics and Morphologies

Chen

Jiang

2015

Macromolecules

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In recent years, self-assembly of block or graft copolymers with sugar-containing component has drawn great attention. We just reported that protection−deprotection chemistry could initiate self-assembly of glycopolymers based on the high polarity change induced by the deprotection. Considering that the protection−deprotection is so common and its variety in glycochemistry, it is worth developing this finding into a new and general strategy of self-assembly of glyco-containing polymers. For this purpose, this article focuses on the kinetics and morphology control of the assemblies of glyco-block copolymers induced by the deprotection. Benzoyl (Bz) as the protective group was introduced, which has much lower deprotection rate than acetyl group (Ac) reported previously. Thus, the detailed kinetic study of the self-assembly of Bz copolymer by means of in situ light scattering and 1 H NMR, etc., became possible. The morphologies of all of the resultant assemblies were observed by cryo-TEM. Thus, we found that in the case of using an equivalent catalyst TBAOH, with the progress of deprotection of Bz, the copolymer follows three-stage assembly, i.e., fast initiation, steady growth, and then fission/reorganization into stable state. In most conditions, both Bz and Ac copolymers form stable vesicles, but the former is apparently larger than the latter. This is because that the slow deprotection of Bz makes the resultant assemblies assume structures closer to equilibrium, and the fast reaction of Ac makes the assemblies with more kinetic-trapped features.

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“…Unfortunately, some of these are moisture sensitive and thermally not very stable. To the best of our knowledge the derivatives of 4-(trans-4-n-alkylcyclohexyl)benzene is found to be more advantageous than benzoic acid phenyl esters, biphenyl derivatives, Schiff's base derivatives, etc, based on viscosity, temperature range of the mesophase and other physical properties [18][19][20]. Very recently, Tamaoki et al [21] and Wu [22,23] synthesized a series of novel dimer compounds containing cholesteryl and phenyl benzoate groups or azobenzene dimer in which the two mesogenic units were linked through dicarboxylic ester bonds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and properties of non‐symmetric liquid crystal dimers containing a cholesteryl moiety

et al. 2008

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2008) Synthesis and properties of non-symmetric liquid crystal dimers containing a cholesteryl moiety, Liquid Crystals, 35:1, 39-44, A series of non-symmetric liquid crystal dimers having cholesteryl and 4-trans-(4-nalkylcyclohexyl)phenoxy groups were synthesized by condensation of cholesteryl vbromoalkanoates with appropriate 4-trans-(4-n-alkylcyclohexyl)phenols. The structures and thermal phase behaviour of the dimers were characterized using IR, 1 H NMR and mass spectroscopy, elemental analysis, differential scanning calorimetry, polarizing optical microscopy and X-ray diffraction measurements. Their thermal phase behaviour is significantly different to that of other cholesterol-based liquid crystal dimers. All of these liquid crystal dimers exhibit low phase transition temperatures. The relationships between their properties and chemical structures of these new dimers are discussed.

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Design of Multivalent Galactoside Ligands and Their Binding to Hepatic Asialoglycoprotein Receptor

Cited by 3 publications

References 19 publications

N-Acetylgalactosamine Block-co-Polycations Form Stable Polyplexes with Plasmids and Promote Liver-Targeted Delivery

N-Acetylgalactosamine Block-co-Polycations Form Stable Polyplexes with Plasmids and Promote Liver-Targeted Delivery

Deprotection-Induced Micellization of Glycopolymers: Control of Kinetics and Morphologies

Synthesis and properties of non‐symmetric liquid crystal dimers containing a cholesteryl moiety

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