Short Polyethylene Glycol Research Articles

Short polyethylene glycol chains densely bound to soft nanotube channels for inhibition of protein aggregation

Specific thermal dehydration/rehydration of short polyethylene glycol (PEG) chains densely bound to nanotube channels was useful for aggregation suppression and refolding acceleration of proteins.

Photophysical comparisons of PEGylated porphyrins, chlorins and bacteriochlorins in water

Synthesis of a bioconjugatable water-soluble (PEGylated) trans-AB-porphyrin enables photophysical comparisons (τS, kf, kic, kisc, Φf, Φic, Φisc) with analogous chlorins and bacteriochlorins in DMF and water.

Uncharged Helical Modular Polypeptide Hydrogels for Cellular Scaffolds.

Grafted synthetic polypeptides hold appeal for extending the range of biophysical properties achievable in synthetic extracellular matrix (ECM) hydrogels. Here, N-carboxyanhydride polypeptide, poly(γ-propargyl-l-glutamate) (PPLG) macromers were generated by fully grafting the "clickable" side chains with mixtures of short polyethylene glycol (PEG) chains terminated with inert (-OH) or reactive (maleimide and/or norbornene) groups, then reacting a fraction of these groups with an RGD cell attachment motif. A panel of synthetic hydrogels was then created by cross-linking the PPLG macromers with a 4-arm PEG star molecule. Compared to well-established PEG-only hydrogels, gels containing PPLG exhibited dramatically less dependence on swelling as a function of cross-link density. Further, PPLG-containing gels, which retain an α-helical chain conformation, were more effective than standard PEG gels in fostering attachment of a human mesenchymal stem cell (hMSC) line for a given concentration of RGD in the gel. These favorable properties of PPLG-containing PEG hydrogels suggest they may find broad use in synthetic ECM.

Computational Design of Oligopeptide Containing Poly(ethylene glycol) Brushes for Stimuli-Responsive Drug Delivery.

Stimuli-responsive biomaterials are used to facilitate drug and gene delivery by shielding the drug/gene during circulation times and selectively releasing the cargo at the desired target. Within stimuli-responsive materials, pH-responsive materials are exploited for delivery to specific organs, intracellular compartments, cancer cells, site of inflammation or infection as those sites are characterized by pH that is different from the blood pH. In this paper we use molecular dynamics (MD) simulations to design such pH-responsive biomaterials where the balance between the various intermolecular interactions (e.g., electrostatics, van der Waals) within the biomaterials allow biofunctional molecules to be reversibly shielded and exposed to the environment with change in pH. In our model the shielding aspect is imparted by a polyethylene glycol (PEG) brush and the pH-responsive component is a PEG-tethered oligopeptide that undergoes changes in conformations via protonation of residues upon changes in pH. Starting with a PEG-tethered peptide in a monodisperse short PEG brush, we first vary the composition and sequence of histidine (H), lysine (K), and glutamate (E) along the oligopeptide sequence to find the design parameters that maximize the shielding and exposure of the oligopeptide at pH ∼ 7.0 and pH < 7.0, respectively. Then, we probe the effect of the PEG brush on the conformations of the oligopeptides by simulating PEG-tethered peptide in a bimodal PEG brush containing short PEG and long PEG chains. We characterize the intermolecular interactions involving the PEG, peptide, and solvent that influence the shielded and exposed conformations of the oligopeptides at the two different pHs. In a short monodisperse PEG brush, with a longer PEG-tethered peptide containing large blocks of histidines that undergo change in protonation state as a response to pH change, placed between a protonated lysine and deprotonated glutamate, the PEG brush exhibits maximum shielding and exposure with pH change. This change from shielded to exposed state is driven by electrostatic repulsion upon H protonation. The presence of long PEG chains in a bimodal PEG brush leads to dominating PEG-peptide attractive interactions that reduces the contrast in shielded and exposed conformations of the PEG-tethered peptide upon protonation of histidines.

Synthesis and photochemical properties of PEGylated coumarin-caged ceramides for cell studies

Caged ceramide analogues (C6-, C16-, C18-, C22- and C24-Cer) have been prepared by introducing a hydrophilic coumarin-based cage bearing a short polyethylene glycol (PEG) chain. (6-Bromo-7-mTEGylated-coumarin-4-yl)methyl (Btc) caged ceramide showed efficient photo-uncaging to release the parent ceramide upon direct exposure to 350nm UV light; in contrast (7-mTEGylated-coumarin-4-yl)methyl (Tc) caged ceramide was photolysed more slowly. In preliminary experiments, Btc-caged ceramides were taken up by cells and their photolysis led to decreases in cell viability, but not to activation of caspase enzymes, suggesting that either reactive oxygen species or an alternate caspase-independent pathway may be responsible for the decreases in cell viability caused by photolysis of caged ceramides.

Synthesis and Biological Evaluation of Novel Water-Soluble Poly-(ethylene glycol)-10-hydroxycamptothecin Conjugates

In order to improve the antitumor activity and water solubility of 10-hydroxycamptothecin (HCPT), a series of novel HCPT conjugates were designed and synthesized by conjugating polyethylene glycol (PEG) to the 10-hydroxyl group of HCPT via a valine spacer. The in vitro stability of these synthesized compounds was determined in pH 7.4 buffer at 37 °C, and the results showed that they released HCPT at different rates. All the compounds demonstrated significant antitumor activity in vitro against K562, HepG2 and HT-29 cells. Among them, compounds, 4a, 4d, 4e and 4f, exhibited 2–5 times higher potency than HCPT. The stability and antitumor activity of these conjugates were found to be closely related to the length of PEG and the linker type, conjugates with a relatively short PEG chain and carbamate linkages (compounds 4a and 4f) exhibited controlled release of HCPT and excellent antitumor in vitro activity.

α, ω-Cholesterol-functionalized low molecular weight polyethylene glycol as a novel modifier of cationic liposomes for gene delivery.

Here, three novel cholesterol (Ch)/low molecular weight polyethylene glycol (PEG) conjugates, termed α, ω-cholesterol-functionalized PEG (Ch2-PEGn), were successfully synthesized using three kinds of PEG with different average molecular weight (PEG600, PEG1000 and PEG2000). The purpose of the study was to investigate the potential application of novel cationic liposomes (Ch2-PEGn-CLs) containing Ch2-PEGn in gene delivery. The introduction of Ch2-PEGn affected both the particle size and zeta potential of cationic liposomes. Ch2-PEG2000 effectively compressed liposomal particles and Ch2-PEG2000-CLs were of the smallest size. Ch2-PEG1000 and Ch2-PEG2000 significantly decreased zeta potentials of Ch2-PEGn-CLs, while Ch2-PEG600 did not alter the zeta potential due to the short PEG chain. Moreover, the in vitro gene transfection efficiencies mediated by different Ch2-PEGn-CLs also differed, in which Ch2-PEG600-CLs achieved the strongest GFP expression than Ch2-PEG1000-CLs and Ch2-PEG2000-CLs in SKOV-3 cells. The gene delivery efficacy of Ch2-PEGn-CLs was further examined by addition of a targeting moiety (folate ligand) in both folate-receptor (FR) overexpressing SKOV-3 cells and A549 cells with low expression of FR. For Ch2-PEG1000-CLs and Ch2-PEG2000-CLs, higher molar ratios of folate ligand resulted in enhanced transfection efficacies, but Ch2-PEG600-CLs had no similar in contrast. Additionally, MTT assay proved the reduced cytotoxicities of cationic liposomes after modification by Ch2-PEGn. These findings provide important insights into the effects of Ch2-PEGn on cationic liposomes for delivering genes, which would be beneficial for the development of Ch2-PEGn-CLs-based gene delivery system.

Controlling the orientations of gold nanorods inside highly packed 2D arrays.

Gold nanorods (AuNRs) were assembled into highly packed two dimensional (2D) arrays with different structures by the Langmuir-Blodgett (LB) technique. The structure of the 2D arrays (the width of the arrays, the surface area and the shape of circular voids) was controlled by varying the applied surface pressure in the LB trough. Due to the shape anisotropy of AuNRs, both end-to-end (EE) and side-by-side (SS) assembly were observed depending on the chain length of a polyethylene glycol (PEG) polymer functionalized with their surfaces. Short chain PEG encouraged the SS assembly of the AuNRs, while the SS and EE assemblies were obtained in case of using the long chain PEG. Numerical calculation of the potential energy between two nanorods as a function of separation and orientation yielded good predictions of the optimum separation distance between the nanorods and their orientations inside the arrays. Due to the alignment of the AuNRs inside the arrays, optical measurements of the arrays showed a strong longitudinal localized surface plasmon resonance (LSPR) peak when excited by polarized light along the axis of the majority of the rods. When the polarization angle was rotated by 90 degrees, the intensity of the high energy transverse LSPR peak was increased. The measured LSPR spectrum of the arrays was confirmed by discrete dipole approximation (DDA) calculations, which was used to simulate both the LSPR spectrum and the plasmon field distribution.

Oligonucleotides conjugated with short chemically defined polyethylene glycol chains are efficient antisense agents

Ligand conjugation is an attractive approach to rationally modify the poor pharmacokinetic behavior and cellular uptake properties of antisense oligonucleotides. Polyethylene glycol (PEG) attachment is a method to increase solubility of oligonucleotides and prevent the rapid elimination, thus increasing tissue distribution. On the other hand, the attachment of long PEG chains negatively influences the pharmacodynamic effect by reducing the hybridization efficiency. We examined the use of short PEG ligands on the in vitro effect of antisense agents. Circular dichroism showed that the tethering of PEG12-chains to phosphodiester and phosphorothioate oligonucleotides had no influence on their secondary structure and did not reduce the affinity to the counter strand. In an in vitro tumor model, a luciferase reporter assay indicated unchanged gene silencing activity compared to unmodified compounds, and even slightly superior target down regulation was found after treatment with a phosphorothioate modified conjugate.

Thioctic acid derivatives as building blocks to incorporate DNA oligonucleotides onto gold nanoparticles.

Oligonucleotide gold nanoparticle conjugates are being used as diagnostic tools and gene silencing experiments. Thiol-chemistry is mostly used to functionalize gold nanoparticles with oligonucleotides and to incorporate DNA or RNA molecules onto gold surfaces. However, the stability of such nucleic acid–gold nanoparticle conjugates in certain conditions may be a limitation due to premature break of the thiol-gold bonds followed by aggregation processes. Here, we describe a straightforward synthesis of oligonucleotides carrying thioctic acid moiety based on the use of several thioctic acid-l-threoninol derivatives containing different spacers, including triglycine, short polyethyleneglycol, or aliphatic spacers. The novel thioctic-oligonucleotides were used for the functionalization of gold nanoparticles and the surface coverage and stability of the resulting thioctic-oligonucleotide gold nanoparticles were assessed. In all cases gold nanoparticles functionalized with thioctic-oligonucleotides had higher loadings and higher stability in the presence of thiols than gold nanoparticles prepared with commercially available thiol-oligonucleotides. Furthermore, the thioctic derivative carrying the triglycine linker is sensitive to cathepsin B present in endosomes. In this way this derivative may be interesting for the cellular delivery of therapeutic oligonucleotides as these results provides the basis for a potential endosomal escape.

Biodegradable iodinated polydisulfides as contrast agents for CT angiography

Current clinical CT contrast agents are mainly small molecular iodinated compounds, which often suffer from short blood pool retention for more comprehensive cardiovascular CT imaging and may cause contrast-induced nephropathy. In this work, we prepared polydisulfides containing a traditional iodinated CT contrast agent in order to optimize the pharmacokinetics of the agent and improve its safety. Initially acting as a macromolecular agent and achieving sharp blood vessel delineation, the polydisulfides can be reduced by endogenous thiols via disulfide–thiol exchange reaction to oligomers that can be readily excreted via renal filtration. Short polyethylene glycol (PEG) chain was also introduced to the polymers to further modify the in vivo properties of the agents. Strong and prolonged vascular enhancement has been generated with two new agents in mice (5–10 times higher blood pool enhancement than iodixanol). The polydisulfide agents gradually degraded and excreted via renal filtration. The gradual excretion process could prevent contrast-induced nephropathy. These results suggest that the biodegradable macromolecular CT contrast agents are promising safe and effective blood contrast agents for CT angiography and image-guided interventions.

Minibody-indocyanine green based activatable optical imaging probes: the role of short polyethylene glycol linkers.

Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific membrane antigen (PSMA-MB) and conjugated with an activatable fluorophore, indocyanine green (ICG), was designed to fluoresce only after binding to cell-surface PSMA. To further reduce background signal, short polyethylene glycol (PEG) linkers were employed to improve the covalent bonding ratio of ICG. New PSMA-MBs conjugated with bifunctional ICG derivatives specifically visualized PSMA-positive tumor xenografts in mice bearing both PSMA-positive and -negative tumors within 6 h postinjection. The addition of short PEG linkers significantly improved TBRs; however, it did not significantly alter the biodistribution. Thus, minibody-ICG conjugates could be a good alternative to IgG-ICG in the optical cancer imaging for further clinical applications.

A multifunctional amphiphilic polymer as a platform for surface-functionalizing metallic and other inorganic nanostructures.

We designed a new set of polymer ligands that combine multiple metal-coordinating groups and short polyethylene glycol (PEG) moieties in the same structure. The ligand design relies on the controlled grafting of a large number of amine-terminated histamines and PEG short chains onto a poly(isobutylene-alt-maleic anhydride) backbone, via a one-step nucleophilic addition reaction. This addition reaction is highly efficient, can be carried out in organic media and does not require additional reagents. We show that when imidazole groups are used the resulting polymer ligand can strongly ligate onto metal nanostructures such as nanoparticles (NPs) and nanorods (NRs) made of gold cores. The resulting polymer-coated NPs and NRs exhibit good colloidal stability to pH changes and added electrolytes. This constitutes a departure from the use of thiol-based ligands to coordinate on Au surfaces. The present chemical approach also opens up additional opportunities for designing hydrophilic and reactive platforms where the polymer coating can be adjusted to various metal and metal oxide surfaces by simply modifying or combining the addition reaction with other metal coordinating groups. These could include iron oxide NPs and semiconductor QDs. These polymer-capped NPs and NRs can be used to develop biologically-active platforms with potential use for drug delivery and sensing.

Synthesis and characterization of aliphatic segmented poly(ether amide urethane)s through a non-isocyanate route

Two nylon-6 oligomers with polymerization degrees (DP or n) of 6.82 and 4.52 terminated with H2N- and HO-groups (H2N–PAn–OHs) were prepared from caprolactam with ethanolamine via ring-opening polymerization at different molar ratios, and transformed into HO-terminated nylon-6 oligomers (HO–PAn–OHs) through reaction with excess caprolactone. Melt polycondensation of the HO–PAn–OHs, with 1,6-bis(hydroxyethyloxy carbonyl amino)hexane (BHCH) and polyethylene glycols (PEGs), was performed at 170 °C under normal pressure and at 180 °C under reduced pressure of 3 mmHg at different periods. A series of novel aliphatic thermoplastic poly(ether amide urethane)s with different short nylon-6 and PEG segments (s-PEAUs) was prepared. The obtained s-PEAUs were characterized by gel permeation chromatography, FTIR, 1H-NMR, 2D 1H–1H COSY NMR, differential scanning calorimetry, thermogravimetric analysis, wide-angle X-ray scattering, and tensile tests. The s-PEAUs exhibited an Mn up to 18 400, an Mw up to 48 900, Tm between 145.94 °C and 177.86 °C, initial decomposition temperature of over 253.39 °C, and tensile strength up to 30.03 MPa with elongation at break of 286.8%. Some urea linkages were formed during transurethane polycondensation.

Binding characteristics between polyethylene glycol (PEG) and proteins in aqueous solution.

Polymer-protein interactions are crucial for determining the activity of both polymer and protein for many bio-related applications. Poly(ethylene glycol) (PEG) as a well-known antifouling material is often coated on surfaces to form highly solvated brushes, which exhibit excellent protein-repellent properties. However, unlike surface-induced antifouling effects, little is known about the intrinsic PEG-protein interactions in aqueous solution, which is an important yet neglected problem. Here, we investigate the interactions between PEG and proteins in aqueous solution using fluorescence spectroscopy, atomic force microscopy (AFM), and nuclear magnetic resonance (NMR). Two important characteristics, molecular weight of PEG and mass ratio of PEG : protein, are examined to determine the effect of each on PEG-protein interactions as well as binding characteristics between PEG and proteins. In contrast to too long and too short PEG chains, collective results have shown that PEG with optimal molecular weight (MW) is more capable of interacting with proteins, which induces the conformational change of proteins through more stable binding sites and stronger interactions with long chain PEG. Enhanced PEG-protein interactions are likely due to the change of hydrophilicity to amphiphilicity of PEG with increasing MWPEG. In contrast to almost none or weak interactions of PEG surfaces with proteins, this work provides new evidence to demonstrate the existence of interactions between PEG and proteins in aqueous solution, which is important not only for better understanding of the structure-activity relationship of PEG both in solution and on surfaces, but also for the rational design of new PEG-based materials for specific applications.

H2O2/UV-C and Photo-Fenton treatment of a nonylphenol polyethoxylate in synthetic freshwater: Follow-up of degradation products, acute toxicity and genotoxicity

H2O2/UV-C and Photo-Fenton treatment of a nonylphenol polyethoxylate surfactant was investigated in synthetic freshwater. H2O2/UV-C treatment outperformed Photo-Fenton treatment in terms of mother pollutant abatement kinetics as well as overall organic carbon removal efficiencies. Short polyethoxy-chain nonylphenol polyethoxylates, polyethylene glycols, formic acid, acetic acid and formaldehyde were identified as the common degradation products of the nonionic surfactant. Monocarboxylated polyethylene glycols and oxalic acid were detected during H2O2/UV-C oxidation, whereas a degradation product resulting from the hydroxyl radical attack of the tertiary alkyl chain and the aromatic ring was detected during Photo-Fenton treatment. Based on the liquid chromatography–mass spectrometry results, it was suggested that the polyethoxy chain of the surfactant was more susceptible to degradation with the H2O2/UV-C treatment process, while the alkyl chain and aromatic ring were more prone to Photo-Fenton oxidation. Acute toxicity analysis employing the photobacteria Vibrio fischeri indicated that the inhibitory effect of the surfactant increased from 10% to 30% and 19% during the early stages of H2O2/UV-C and Photo-Fenton treatment, respectively. At the end of the treatment period, the inhibitory effect of the surfactant dropped back to less than 10%. According to the umu-genotoxicity test conducted with Salmonella typhimurium TA1535/pSK1002 strain, the genotoxic effect followed an increasing trend during the course of H2O2/UV-C treatment. A positive correlation was evident between the intensity of the nonylphenol monoethoxylate product ion and the genotoxic effect observed during H2O2/UV-C treatment. The genotoxic effect of Photo-Fenton-treated degradation products appeared to be relatively low as compared with those of H2O2/UV-C treatment.

Strong fluorescence emission from PEGylated hyperbranched poly(amido amine)

Hyperbranched poly(amido amine)s (HPAA) show weak photoluminescence, however, they have shown strong emission after short polyethylene glycol (PEG) chains have been linked onto HPAA macromolecule via Michael addition reaction. These PEGylated hyperbranched poly(amido amine)s show low cytotoxicity and potential application in cell imaging.

Synthesis and anionic ring-opening polymerization of crown-ether-like macrocyclic dilactones: An alternative route to peg-containing polyesters PEG-containing polyesters and related networks

Linear aliphatic polyesters whose structure is made of short polyethylene glycol (PEG) segments connected along the chain by malonate units were synthesized from two PEG-containing macrolactones: 15,15-dimethyl-1,4,7,10,13-pentaoxacyclohexadecane-14,16-dione (1) and 5,8,11,14,17-pentaoxaspiro[2,15]octadecane-4,18-dione (2). Anionic ring-opening polymerization conditions using either thiophenolates or a p-nitrophenolate as initiators yielded poly(ether-ester)s of low to moderate molecular weights, with broad molecular weight distributions. When the monomer also contains an activated cyclopropane unit of the cyclopropane-1,1-dicarboxylate type (such as in 2) and harsher polymerization conditions are used (higher temperatures and bulkier counterions), opening of the cyclopropyl ring can compete with the dilactone polymerization, providing access to crosslinked materials.

ChemInform Abstract: Silver Coordination Polymers with Isonicotinic Acid Derived Short Polyethylene Glycol — Synthesis, Structures, Anion Effect and Solution Behavior

AbstractReview: 36 refs.

Activatable fluorescent cys-diabody conjugated with indocyanine green derivative: consideration of fluorescent catabolite kinetics on molecular imaging

Antibody fragments including diabodies have more desirable pharmacokinetic characteristics than whole antibodies. An activatable optical imaging probe based on a cys-diabody targeting prostate-specific membrane antigen conjugated with the near-infrared fluorophore, indocyanine green (ICG), was designed such that it can only be activated when bound to the tumor, leading to high signal-to-background ratios. We employed short polyethylene glycol (PEG) linkers between the ICG and the reactive functional group (Sulfo-OSu group), resulting in covalent conjugation of ICG to the cys-diabody, which led to lower dissociation of ICG from cys-diabody early after injection, reducing hepatic uptake. However, unexpectedly, high and long-term fluorescence was observed in the kidneys, liver, and blood pool more than 1 h after injection of the cys-diabody PEG-ICG conjugate. A biodistribution study using I125-labeled cys-diabody-ICG showed immediate uptake in the kidneys followed by a rapid decrease, while gastric activity increased due to released radioiodine during rapid cys-diabody-ICG catabolism in the kidneys. To avoid this catabolic pathway, it would be preferable to use antibody fragments large enough not to be filtered through glomerulus or to conjugate the fragments with fluorescent dyes that are readily excreted into urine when cleaved from the cys-diabody to achieve high tumor-specific detection.