Glycol Derivatives Research Articles

Development of a Liver‐Targeting Gold–PEG–Galactose Nanoparticle Platform and a Structure–Function Study

For the specific liver parenchymal cell delivery, a series of short heterobifunctional poly(ethylene glycol) (PEG) derivatives containing dimercapto and galactose (Gal) terminals is synthesized for the preparation of gold conjugates. The Gal density on the surface of all gold conjugates can be well controlled and the prepared gold conjugates are stable in various media, even in the presence of serum. For the liver targeting and reflectance imaging applications, the structure–function relationships of this platform, including the influence of the PEG molecular weight and the Gal ligand coverage of hybrid particles on the cytotoxicity and cellular recognition of tumor cells in vitro and on their liver‐targeting ability in small animals, are studied. Biocompatibility results show that HepG2 cells are more sensitive than HeLa cells to gold conjugates. Cellular uptake studies demonstrate that a lower PEG molecular weight, a higher Gal density, or a higher gold concentration can increase the cellular uptake efficiency of these hybrid particles in HepG2 cells when the other parameters are constant. The results reveal the importance of parameter modulation for the design and control of nanoprobes and the gold conjugates with short PEG chains and a high Gal density are a potential vector for active‐targeting therapy.

Synthesis of Poly(ethylene glycol) Derivatives

To expand the extent of conjugation with biologically active molecules (biopolymers, peptides, drugs, etc.) and biomaterial substrates, we synthesized a serial of poly (ethy1ene glycol) (PEG) derivatives (PEG-2000-NH2, MPEG-1200-NH2, and APEG-1200-NH2) in three efficient steps. The end groups were characterized by 1H NMR spectroscopy.

ADIBO-Based “Click” Chemistry for Diagnostic Peptide Micro-Array Fabrication: Physicochemical and Assay Characteristics

Several azide-derivatized and fluorescently-labeled peptides were immobilized on azadibenzocyclooctyne (ADIBO)-activated slide surfaces via a strain-promoted alkyne-azide cycloaddition (SPAAC) reaction revealing excellent immobilization kinetics, good spot homogeneities and reproducible fluorescence signal intensities. A myc-peptide micro-array immunoassay showed an antibody limit-of-detection (LOD) superior to a microtiter plate-based ELISA. Bovine serum albumin (BSA) and dextran covalently attached via “click” chemistry more efficiently reduced non-specific binding (NSB) of fluorescently-labeled IgG to the microarray surface in comparison to immobilized hexanoic acid and various types of polyethylene glycol (PEG) derivatives. Confirmation of these findings via further studies with other proteins and serum components could open up new possibilities for human sample and microarray platform-based molecular diagnostic tests.

Orthogonal Functionalisation of Upconverting NaYF4 Nanocrystals

A simple and straightforward method for the orthogonal functionalisation of upconverting NaYF4 nanocrystals (UCNCs)-doped withYb(3+) and Er(3+)-based on N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide/N-hydroxysuccinimide (EDC/NHS) selective reactions between two dyes and two different reactive groups present at the periphery of the upconverting nanocrystals is reported. Organic-soluble UCNCs of 10 and 50 nm in size are encapsulated efficiently in a 1:1 mixture of two commercial 3000 Da poly(ethylene glycol) derivatives with two different reactive groups (amino and carboxylic groups). The water-dispersible UCNCs are non-cytotoxic, stable in the physiological environment, and present free amine and carboxylic reactive groups on their periphery, allowing rapid, selective, and modular covalent conjugation to payloads through EDC/NHS reactions. PEG-encapsulated UCNCs with and without covalent conjugation to payloads are characterised in vitro through spectroscopic, dynamic light scattering, and electron microscopy measurements. Living cell analyses coupled with TEM measurements confirm the uptake and low cytotoxicity of the coated UCNCs. They are linked covalently to two different dyes, internalised by living cells, and analysed by confocal microscopy. The related colocalisation measurements prove the reactivity of both amines and carboxylic acids on the periphery of the nanocrystals. This approach demonstrates that it is possible to produce water-dispersible and cyto-compatible dual-functional UCNCs.

The Suzuki cross‐coupling reaction in pure water catalyzed by ligandless palladium using polyethylene glycol derivatives as surfactant

The results of a ligandless Pd(OAc)2‐catalyzed Suzuki–Miyaura coupling experiment are presented. It was found that the use of polyethylene glycol phosphonium salts (PEG‐quat) as surfactant resulted in very rapid reactions of aryl halides with phenylboronic acids in pure water. Moreover, aryl chlorides such as 4‐nitrochlorobenezene reacted quantitatively with phenylboronic acid under optimized conditions. Copyright © 2013 John Wiley & Sons, Ltd.

Combined Electrostatic and Covalent Polymer Networks for Cell Microencapsulation

SummaryTwo types of hydrogel microspheres have been developed. Fast ionotropic gelation of sodium alginate (Na‐alg) in the presence of calcium ions was combined with slow covalent cross‐linking of poly(ethylene glycol) (PEG) derivatives. For the first type, the fast obtainable Ca‐alg hydrogel served as spherical matrix for the simultaneously occurring covalent cross‐linking of multi‐arm PEG derivative. A two‐component interpenetrating network was formed in one step upon extruding the mixture of the two polymers into the gelation bath. For the second type, heterobifunctional PEG was grafted onto Na‐alg prior to gelation. Upon extrusion of the polymer solution into the gelation bath, fast Ca‐alg formation ensured the spherical shape and was accompanied by cross‐linker‐free covalent cross‐linking of the PEG side chains. Thus, one‐component hydrogel microspheres resulted. We present the physical properties of the hydrogel microspheres and demonstrate the feasibility of cell microencapsulation for both types of polymer networks.

An easy access to asymmetrically substituted oligoethylene glycols from 18-crown-6

Abstract A new route for the preparation of multi-gram quantities of the heterobifunctional oligoethylene glycol (OEG) derivatives (n = 6, 7) is reported based on decyclization of 18-crown-6.

Synthesis of Substituted 3-Hydroxy-2-Furanone Derivatives via an Unusual Enolate Wittig Rearrangement/Alkylative Cyclization Sequence

Treatment of methyl O-(alkynylmethyl) glycolate derivatives with dialkylboron triflates and Hünig's base leads to the formation of highly substituted 3-hydroxy-2-furanone derivatives. The transformations appear to proceed via an unusual mechanism involving initial 2,3-Wittig rearrangement of a boron ester enolate followed by an alkylative cyclization reaction that leads to incorporation of an alkyl group from the boron reagent into the product.

A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from Aβ-induced toxicity. However, the effects of Aβ-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aβ levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG4-mediated behavioral improvement is not correlated with LTP, but with increased spinogenesis. The higher dendritic spine density reflects an increase in the number of functional synapses as determined by increased miniature EPSC (mEPSC) frequency without changes in presynaptic parameters or postsynaptic mEPSC amplitude. Additionally, BTA-EG4 requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG4 may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy.

Oral Delivery of Low Molecular Weight Heparin by Polyaminomethacrylate Coacervates

Oral bioavailability of low molecular weight heparin (LMWH) can be achieved by several advanced drug delivery approaches. Here, a new preparation method for coacervates (CAs) using non-toxic polyethylene glycol derivates was developed. LMWH were coacervated with polyaminomethacrylates (Eudragit® RL or RS) using polyethylene glycol (PEG) derivatives as non-toxic solvents. CAs were analyzed for their physicochemical properties and pharmacokinetic parameters were determined for different formulations in rabbits. CAs from both polymer types using various PEGs were of irregular shape and had particle sizes of around 40 μm, encapsulation efficiencies of >90%, and complete LMWH in vitro release was obtained within 2 h. In vivo, oral Absorption at doses of 300 IU/kg was rather low (F < 2.5%) while dose increase resulted in a maximum at 600 IU/kg (FRL: 6.0 ± 1.2%; FRS: 5.8 ± 2.5%) and 1,200 IU/kg did not result in higher bioavailability (FRL: 4.6 ± 0.4%; FRS: 4.1 ± 0.8%). CAs were applicable to various LMWH types where the oral availability decreased in the order fondaparinux>enoxaparin>nadroparin>certoparin depending mainly on the molecular weight. CAs prepared by an organic solvent-free method allowed the oral delivery of LMWHs. The therapeutic efficiency and the simple and solvent-free manufacturing process underlines the high potential of this new preparation method.

Syntheses of Biologically Non-Toxic ZnS:Mn Nanocrystals by Surface Capping with O-(2-aminoethyl)polyethylene Glycol and O-(2-carboxyethyl)polyethylene Glycol Molecules

, Mw = 10,000 g/mol) and O-(2-Carboxyethyl)polyethylene glycol(PEG-COOH, Mw = 10,000 g/mol) molecules. The modified PEG capped ZnS:Mn nanocrystal powders werethoroughly characterized by XRD, HR-TEM, EDXS, ICP-AES and FT-IR spectroscopy. The optical propertieswere also measured by UV/Vis and photoluminescence (PL) spectroscopies. The PL spectra showed broademission peaks at 600 nm with similar PL efficiencies of 7.68% (ZnS:Mn-PEG-NH2) and 9.18% (ZnS:Mn-PEG-COOH) respectively. The measured average particle sizes for the modified PEG capped ZnS:Mnnanocrystals by HR-TEM images were 5.6 nm (ZnS:Mn-PEG-NH2) and 6.4 nm (ZnS:Mn-PEG-COOH),which were also supported by Debye-Scherrer calculations. In addition, biological toxicity effects of thenanocrystals over the growth of wild type E. coli were investigated. They showed no biological toxicity toE. coli until very high concentration dosage of 1 mg/mL of the both nanocrystal samples.Key Words : ZnS:Mn nanocrystal, Polyethylene glycol derivatives capping, Water-dispersible nanocrystal,Biological toxicity IntroductionNanosized semiconductor materials have gained signi-ficant attention over the past decade.

Stability of polymer encapsulated quantum dots in cell culture media

The unique optical properties of Quantum Dots have attracted a great interest to use these nanomaterials in diverse biological applications. The synthesis of QDs by methods from the literature permits one to obtain nanocrystals coated by hydrophobic alkyl coordinating ligands and soluble in most of the cases in organic solvents. The ideal biocompatible QD must be homogeneously dispersed and colloidally stable in aqueous solvents, exhibit pH and salt stability, show low levels of nonspecific binding to biological components, maintain a high quantum yield, and have a small hydrodynamic diameter. Polymer encapsulation represents an excellent scaffold on which to build additional biological function, allowing for a wide range of grafting approaches for biological ligands. As these QD are functionalized with poly(ethylene)glycol (PEG) derivatives on their surface, they show long term stability without any significant change in the optical properties, and they are also highly stable in the most common buffer solutions such as Phosphate Buffer Saline (PBS) or borate. However, as biological studies are normally done in more complex biological media which contain a mixture of amino acids, salts, glucose and vitamins, it is essential to determine the stability of our synthesized QDs under these conditions before tackling biological studies.

Clickable Poly(ethylene glycol)‐Microsphere‐Based Cell Scaffolds

Clickable poly(ethylene glycol) (PEG) derivatives are used with two sequential aqueous two-phase systems to produce microsphere-based scaffolds for cell encapsulation. In the first step, sodium sulfate causes phase separation of the clickable PEG precursors and is followed by rapid geleation to form microspheres in the absence of organic solvent or surfactant. The microspheres are washed and then deswollen in dextran solutions in the presence of cells, producing tightly packed scaffolds that can be easily handled while also maintaining porosity. Endothelial cells included during microsphere scaffold formation show high viability. The clickable PEG-microsphere-based cell scaffolds open up new avenues for manipulating scaffold architecture as compared with simple bulk hydrogels.

Cellular uptake, intracellular trafficking, and antitumor efficacy of doxorubicin-loaded reduction-sensitive micelles

Reduction-sensitive micelles were prepared from monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16), an amphiphilic poly(ethylene glycol) derivative containing a disulfide bond. The micelles were then used for the intracellular delivery of the anticancer drug doxorubicin (DOX) into tumor cells, and the cellular uptake mechanisms of the micelles were determined. To serve as a control, monomethoxy-poly(ethylene glycol)-C-C-hexadecyl (mPEG-C-C-C16) with an analogous structure but without a disulfide bond was also prepared. The polymer could self-assemble into micelles in an aqueous solution and be loaded with high-content DOX. In vitro release studies revealed that DOX-loaded mPEG-S-S-C16 micelles released DOX faster than DOX-loaded mPEG-C-C-C16 micelles in the presence of dithiothreitol (DTT), but showed similar release rates in the absence of DTT. MTT assay demonstrated significantly enhanced cytotoxicity of DOX-loaded mPEG-S-S-C16 micelles against the human cervical cancer cells (HeLa) compared with DOX-loaded mPEG-C-C-C16 micelles, but there was no significant difference in the cytotoxicity between the two DOX-loaded micelles against the african green monkey SV40-transformed kidney fibroblast cells (COS-7). Confocal laser scanning microscopy observation and flow cytometry analyses indicated that DOX-loaded mPEG-S-S-C16 micelles were efficiently internalized into HeLa cells, released DOX into the cytoplasm, and entered the nuclei. By contrast, in the case of DOX-loaded mPEG-C-C-C16 micelles, little DOX was found in the nuclei. Endocytosis inhibition results proved that both mPEG-S-S-C16 and mPEG-C-C-C16 micelles entered the HeLa cells mainly through the clathrin-mediated endocytosis pathway, and caveolae-mediated endocytosis was involved to a small extent. These results indicated that the different behaviors of cell uptake between reduction-sensitive and -insensitive micelles may occur after the micelles were internalized into the cells, but not during endocytosis, and the potential of this reduction-sensitive polymer for the effective intracellular delivery of anticancer drugs.

Oral insulin delivery in rats by nanoparticles prepared with non-toxic solvents

Nanoparticles (NPs) have shown a certain potential to overcome the drawbacks of oral peptide delivery in the gastrointestinal tract such as low peptide stability and permeability. The preparation of insulin loaded NPs was carried out with Eudragit RL or RS dissolved in different non-toxic polyethylene glycol (PEG) derivatives. The use of these non-toxic solvents allowed the design of an one step NP preparation method where insulin retained its full biological activity as it was proven in vitro and in vivo. The insulin trapping NPs were in a size range of around 150-250 nm and exhibited a pH-dependent release. The type of solvent did not distinctly influence the particle properties or insulin stability but modified significantly the performance in vivo in rats, NPs prepared with glycofurol led to a bioavailability of F=1.4 ± 1.0% after oral administration while NPs prepared with PEG 300 were hardly efficient (F=0.3 ± 0.5%). In all cases t(max) was shifted to 2h compared to 1h after subcutaneous insulin solution. In general, we believe that the method presented here is a promising way to encapsulate sensitive drugs, especially for the production of peptide loaded NPs.

Supramolecular structures of uracil-functionalized PEG with multi-diamidopyridine POSS through complementary hydrogen bonding interactions

In this study, we synthesized (i) a multi-diamidopyridine-functionalized polyhedral oligomeric silsesquioxane (MD-POSS) through nucleophilic substitution and click 1,3-cycloaddition reactions and (ii) both mono- and bis-uracil (U)-functionalized poly(ethylene glycol) derivatives (U–PEG and U–PEG–U, respectively) through Michael additions of U to acryloyl-functionalized PEG oligomers. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that supramolecular structures self-assembled from mixtures of MD-POSS and U–PEG and from MD-POSS and U–PEG–U. Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy confirmed the presence of multiple hydrogen bonding interactions between the diaminopyridine groups of MD-POSS and the U groups of U–PEG and U–PEG–U. Because of these strong reversible intermolecular multiple hydrogen bonds, the POSS-based polymer-like supramolecular materials exhibited improved thermal properties upon increasing the MD-POSS content.

Synthesis of Linear Poly(ethylene glycol) Derivatives Based on Tripodal

Synthesis of Linear Poly(ethylene glycol) Derivatives Based on Tripodal

Self-Assembly of Bile Acid–PEG Conjugates in Aqueous Solutions

Thermoresponsive characteristics of oligo(ethylene glycol) derivatives of lithocholic acid (LCA) depend on the hydrophilic/hydrophobic balance of the compounds. Below a threshold temperature (∼30 °C), one of the derivatives, LCA(EG(4))(2), self-assembles in water into hollow nanotubes that form thixotropic gels at high concentrations. Two concentration regimes were observed in the plateau moduli (G(0) ∼ G'). At high concentrations, the mobility of the nanotubes is restricted at the ordered microdomains acting as cross-links. In semidilute aqueous solutions, the linkers between the aggregated domains in the fragile gel rupture easily, and this effect depends strongly on dilution. Organic hydrophobic additives perturb the self-assembling process, leading to changes in the two transition temperatures and poorer mechanical properties of the gel.

Generation and Recovery of &amp;beta;-cell Spheroids From Step-growth PEG-peptide Hydrogels

Hydrogels are hydrophilic crosslinked polymers that provide a three-dimensional microenvironment with tissue-like elasticity and high permeability for culturing therapeutically relevant cells or tissues. Hydrogels prepared from poly(ethylene glycol) (PEG) derivatives are increasingly used for a variety of tissue engineering applications, in part due to their tunable and cytocompatible properties. In this protocol, we utilized thiol-ene step-growth photopolymerizations to fabricate PEG-peptide hydrogels for encapsulating pancreatic MIN6 b-cells. The gels were formed by 4-arm PEG-norbornene (PEG4NB) macromer and a chymotrypsin-sensitive peptide crosslinker (CGGYC). The hydrophilic and non-fouling nature of PEG offers a cytocompatible microenvironment for cell survival and proliferation in 3D, while the use of chymotrypsin-sensitive peptide sequence (CGGY↓C, arrow indicates enzyme cleavage site, while terminal cysteine residues were added for thiol-ene crosslinking) permits rapid recovery of cell constructs forming within the hydrogel. The following protocol elaborates techniques for: (1) Encapsulation of MIN6 β-cells in thiol-ene hydrogels; (2) Qualitative and quantitative cell viability assays to determine cell survival and proliferation; (3) Recovery of cell spheroids using chymotrypsin-mediated gel erosion; and (4) Structural and functional analysis of the recovered spheroids.

Synthesis and self-assembly of a DNA-conjugated poly(propylene glycol) derivative

Due to several characteristic features of DNA (e.g., genetic coding transfer and nanoscaled accuracy or so), DNA based compounds have been recently highlighted in a variety of research fields, including physics, chemistry, engineering or so. To date, they have been expanded into a hybrid form conjugated with conventional polymer groups. Such synthetic hybrid conjugates can be organized into multi-dimensional nanoor micro-structures; rod, sheet, and spherical shaped nanomaterials [1]. In this study, we showed a novel block copolymer composed of DNA and poly(propylene glycol) (PPG) (designated as DNA-b-PPG) for the self-assembled construction into three-dimensional vesicular structures.