Glycol Units Research Articles

The Effect of Chemical Structure of OEG Ligand Shells with Quaternary Ammonium Moiety on the Colloidal Stabilization, Cellular Uptake and Photothermal Stability of Gold Nanorods.

PurposePlasmonic photothermal cancer therapy by gold nanorods (GNRs) emerges as a promising tool for cancer treatment. The goal of this study was to design cationic oligoethylene glycol (OEG) compounds varying in hydrophobicity and molecular electrostatic potential as ligand shells of GNRs. Three series of ligands with different length of OEG chain (ethylene glycol units = 3, 4, 5) and variants of quaternary ammonium salts (QAS) as terminal functional group were synthesized and compared to a prototypical quaternary ammonium ligand with alkyl chain – (16-mercaptohexadecyl)trimethylammonium bromide (MTAB).MethodsStep-by-step research approach starting with the preparation of compounds characterized by NMR and HRMS spectra, GNRs ligand exchange evaluation through characterization of cytotoxicity and GNRs cellular uptake was used. A method quantifying the reshaping of GNRs was applied to determine the effect of ligand structure on the heat transport from GNRs under fs-laser irradiation.ResultsFourteen out of 18 synthesized OEG compounds successfully stabilized GNRs in the water. The colloidal stability of prepared GNRs in the cell culture medium decreased with the number of OEG units. In contrast, the cellular uptake of OEG+GNRs by HeLa cells increased with the length of OEG chain while the structure of the QAS group showed a minor role. Compared to MTAB, more hydrophilic OEG compounds exhibited nearly two order of magnitude lower cytotoxicity in free state and provided efficient cellular uptake of GNRs close to the level of MTAB. Regarding photothermal properties, OEG compounds evoked the photothermal reshaping of GNRs at lower peak fluence (14.8 mJ/cm2) of femtosecond laser irradiation than the alkanethiol MTAB.ConclusionOEG+GNRs appear to be optimal for clinical applications with systemic administration of NPs not-requiring irradiation at high laser intensity such as drug delivery and photothermal therapy inducing apoptosis.

Development of Water Solubility of 2-Phenylsulfanylhydroquinone Dimer Dye.

With the aim of developing a new fluorescence dye with enhanced photophysical properties, this study describes the modification of the 2-phenylsulfanylhydroquinone dimer to realize a new bioimaging molecule. The characteristics of the dimer were advanced by introducing tetraethylene glycol side chains to provide sufficient water solubility and a tether consisting of an N-hydroxysuccinimide-terminated C6-carbon chain to attach bioactive molecules. Two derivatives containing two or three tetraethylene glycol side chains were designed and prepared, and the latter showed sufficient water solubility for biochemical applications. Both compounds exhibited similar photophysical properties and blue fluorescence under UV light irradiation. The dye containing three tetraethylene glycol units reacted with bovine serum albumin in water to give fluorescent derivatives.

Effects of Appended Poly(ethylene glycol) on Electrochemical CO2 Reduction by an Iron Porphyrin Complex

Electrochemical carbon dioxide (CO2) reduction is a sustainable approach for transforming atmospheric CO2 into chemical feedstocks and fuels. To overcome the kinetic barriers of electrocatalytic CO2 reduction, catalysts with high selectivity, activity, and stability are needed. Here, we report an iron porphyrin complex, FePEGP, with a poly(ethylene glycol) unit in the second coordination sphere, as a highly selective and active electrocatalyst for the electrochemical reduction of CO2 to carbon monoxide (CO). Controlled-potential electrolysis using FePEGP showed a Faradaic efficiency of 98% and a current density of -7.8 mA/cm2 at -2.2 V versus Fc/Fc+ in acetonitrile using water as the proton source. The maximum turnover frequency was calculated to be 1.4 × 105 s-1 using foot-of-the-wave analysis. Distinct from most other catalysts, the kinetic isotope effect (KIE) study revealed that the protonation step of the Fe-CO2 adduct is not involved in the rate-limiting step. This model shows that the PEG unit as the secondary coordination sphere enhances the catalytic kinetics and thus is an effective design for electrocatalytic CO2 reduction.

Vanillin based polymers: V. Poly(hydrovanilloin–urethane)

Renewable resources based hydrovanilloin [1,2- bis(4-hydroxy-3-methoxyphenyl)-1,2-ethanediol] was synthesized in 86% yield by electrochemical dimerization of vanillin in aqueous NaOH. This symmetrical bis-phenol monomer was then used for the preparation of urethane polymers by two different methods. In the first method a 1:2 mole ratio mixture of hydrovanilloin and diisocyanate was polymerized in DMF using 1,4-diazabicyclo[2,2,2]octane as the catalyst at 60°C, for 1 h to give poly(hydrovanilloin–urethane)s. In the second method diisocyanates were first reacted with polyethylene glycol-400 to give pre-polymers. Then prepolymers were reacted with equivalent amount of hydrovanilloin at 60°C for 4 days to produce poly(hydrovanilloin-ethylene glycol-urethane)s. The first method resulted hard poly(hydrovanilloin–urethane)s showing Tg values in the range of 121–172°C. The second method yielded softer poly(hydrovanilloin-ethylene glycol-urethane)s and these polymers failed to show distinct glass transition temperatures in the DSC analysis. However, poly(hydrovanilloin-ethylene glycol-urethane)s showed better thermal stabilities than polymers without polyethylene glycol units.

Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors.

CD4 mimics are small molecules that inhibit the interaction of gp120 with CD4. We have developed several CD4 mimics. Herein, hybrid molecules consisting of CD4 mimics with a long alkyl chain or a PEG unit attached through a self-cleavable linker were synthesized. In anti-HIV activity, modification with a PEG unit appeared to be more suitable than modification with a long alkyl chain. Thus, hybrid molecules of CD4 mimics, with PEG units attached through an uncleavable linker, were developed and showed high anti-HIV activity and low cytotoxicity. In investigation of pharmacokinetics in a rhesus macaque, a hybrid compound had a more effective PK profile than that of the parent compound, and intramuscular injection was a more useful administration route to maintain the high blood concentration of the CD4 mimic than intravenous injection. The presented hybrid molecules of CD4 mimics with a PEG unit would be practically useful when combined with a neutralizing antibody.

The Effect of Alkyl Spacers on the Mixed Ionic‐Electronic Conduction Properties of N‐Type Polymers

AbstractConjugated polymers with mixed ionic and electronic transport are essential for developing the complexity and function of electrochemical devices. Current n‐type materials have a narrow scope and low performance compared with their p‐type counterparts, requiring new molecular design strategies. This work presents two naphthalene diimide‐bithiophene (NDI‐T2) copolymers functionalized with hybrid alkyl‐glycol side chains, where the naphthalene diimide unit is segregated from the ethylene glycol (EG) units within the side chain by an alkyl spacer. Introduction of hydrophobic propyl and hexyl spacers is investigated as a strategy to minimize detrimental swelling close to the conjugated backbone and balance the mixed conduction properties of n‐type materials in aqueous electrolytes. It is found that both polymers functionalized with alkyl spacers outperform their analogue bearing EG‐only side chains in organic electrochemical transistors (OECTs). The presence of the alkyl spacers also leads to remarkable stability in OECTs, with no decrease in the ON current after 2 h of operation. Through this versatile side chain modification, this work provides a greater understanding of the structure‐property relationships required for n‐type OECT materials operating in aqueous media.

A simulation study for the treatment of Kuwait sour gas by membranes

Sour gas of the west fields of Kuwait is reported to have a concentration of 12 mol% carbon dioxide and 4 mol% hydrogen sulfide along with moistures. The gas is treated at the gathering center using amine and ethylene glycol units. However, the two processes are energy-intensive and work with solvents that necessitate proper disposal. On the other hand, polymeric membranes provide an energy-efficient solution for acid gas removal with gas dehydration in one step. A simulation study by UniSim was performed to determine if the cellulose acetate membranes are sufficient to treat 70,000 m3 h−1 of gas by producing a stream that meets the pipeline requirements. Results show that the membranes met the standards but the hydrocarbons recovery was extremely low. It was concluded that the sour gas should contain no more than 3.5 mol% of carbon dioxide and 0.15 mol% hydrogen sulfide to attain a hydrocarbons recovery of 97%.

Impact of dynamic sub-populations within grafted chains on the protein binding and colloidal stability of PEGylated nanoparticles.

Polyethylene glycol grafting has played a central role in preparing the surfaces of nano-probes for biological interaction, to extend blood circulation times and to modulate protein recognition and cellular uptake. However, the role of PEG graft dynamics and conformation in determining surface recognition processes is poorly understood primarily due to the absence of a microscopic picture of the surface presentation of the polymer. Here a detailed NMR analysis reveals three types of dynamic ethylene glycol units on PEG-grafted SiO2 nanoparticles (NPs) of the type commonly evaluated as long-circulating theranostic nano-probes; a narrow fraction with fast dynamics associated with the chain ends; a broadened fraction spectrally overlapped with the former arising from those parts of the chain experiencing some dynamic restriction; and a fraction too broad to be observed in the spectrum arising from units closer to the surface/graft which undergo slow motion on the NMR timescale. We demonstrate that ethylene glycol units transition between fractions as a function of temperature, core size, PEG chain length and surface coverage and demonstrate how this distribution affects colloidal stability and protein uptake. The implications of the findings for biological application of grafted nanoparticles are discussed in the context of accepted models for surface ligand conformation.

Tunable branching and living character in ethylene polymerization using “polyethylene glycol sandwich” α-diimine nickel catalysts

The key effects of polyethylene glycol units as a unique secondary coordination sphere in α-diimine Ni(ii)-mediated ethylene polymerization are comprehensively disclosed.

Poly(Ethylene Glycol) Interacts with Hyaluronan in Aqueous Media.

We report here the first evidence for the interaction of poly(ethylene glycol) (PEG) with hyaluronan (HA) in aqueous solutions. PEG-HA complexes (Kapp = 45,000 ± 8000 M-1) contained about 3.3 ± 0.1 of ethylene glycol units per disaccharide of HA. The carboxyl of the D-glucuronic acid and the amide of the N-acetyl-D-glucosamine did not participate in PEG binding. Similar experiments performed with dextran and monosaccharides showed that multiple free primary hydroxyls regularly distributed along the polysaccharide chain are necessary for PEG binding. Another novelty of our study is contraction of HA upon PEG binding. The effect was observed with HA in solution or adsorbed on positively charged liposomes. The thickness of the HA layer on the liposomes decreased 2-fold upon PEG addition. HA compaction induced by PEG may underlie the changes in the plasma membrane properties and resealing of mechanical injuries induced by Pluronics.

Biosynthesis of Random-Homo Block Copolymer Poly[Glycolate-ran-3-Hydroxybutyrate (3HB)]-b-Poly(3HB) Using Sequence-Regulating Chimeric Polyhydroxyalkanoate Synthase in Escherichia coli.

Glycolate (GL)-containing polyhydroxyalkanoate (PHA) was synthesized in Escherichia coli expressing the engineered chimeric PHA synthase PhaCAR and coenzyme A transferase. The cells produced poly[GL-co-3-hydroxybutyrate (3HB)] with the supplementation of GL and 3HB, thus demonstrating that PhaCAR is the first known class I PHA synthase that is capable of incorporating GL units. The triad sequence analysis using 1H nuclear magnetic resonance indicated that the obtained polymer was composed of two distinct regions, a P(GL-ran-3HB) random segment and P(3HB) homopolymer segment. The random segment was estimated to contain a 71 mol% GL molar ratio, which was much greater than the value (15 mol%) previously achieved by using PhaC1PsSTQK. Differential scanning calorimetry analysis of the polymer films supported the presence of random copolymer and homopolymer phases. The solvent fractionation of the polymer indicated the presence of a covalent linkage between these segments. Therefore, it was concluded that PhaCAR synthesized a novel random-homo block copolymer, P(GL-ran-3HB)-b-P(3HB).

Tunable LCST/UCST-Type Polypeptoids and Their Structure-Property Relationship.

Bioinspired thermoresponsive polymeric materials with tunable phase-transition behaviors are highly desirable for biomedical applications. Here, we reported a facile approach for the synthesis of both lower critical solution temperature (LCST) and upper critical solution temperature (UCST) types of thermoresponsive polypeptoids with tunable phase-transition temperature in the range of 29--55 °C. The introduction of alkyl groups and ethylene glycol (EG) units results in a controlled phase-transition behavior under fairly mild conditions. A very sharp transition (ΔT ≤ 1.5 °C) is observed by simply adjusting pH and the alkyl chain length. In particular, the carboxyl-containing polypeptoids display designable UCST behavior, which can be finely tuned in both water and methanol. All these features make the obtained polymers beneficial for practical applications. More interestingly, we demonstrate that the hydrophilic EG group behaves as an excellent regulator to tune the UCST behavior, while the hydrophobic alkyl residues show remarkable capability to regulate the LCST behavior of the system. We hope that such systematic structure-property studies will enable the design of smart polymer materials to meet the specific needs of future applications.

Exploring the Potential of Benzene-1,3,5-tricarboxamide Supramolecular Polymers as Biomaterials.

The fast dynamics occurring in natural processes increases the difficulty of creating biomaterials capable of mimicking Nature. Within synthetic biomaterials, water-soluble supramolecular polymers show great potential in mimicking the dynamic behavior of these natural processes. In particular, benzene-1,3,5-tricaboxamide (BTA)-based supramolecular polymers have shown to be highly dynamic through the exchange of monomers within and between fibers, but their suitability as biomaterials has not been yet explored. Herein we systematically study the interactions of BTA supramolecular polymers bearing either tetraethylene glycol or mannose units at the periphery with different biological entities. When BTA fibers were incubated with bovine serum albumin (BSA), the protein conformation was only affected by the fibers containing tetraethylene glycol at the periphery (BTA-OEG4). Coarse-grained molecular simulations showed that BSA interacted with BTA-OEG4 fibers rather than with BTA-OEG4 monomers that are present in solution or that may exchange out of the fibers. Microscopy studies revealed that, in the presence of BSA, BTA-OEG4 retained their fiber conformation although their length was slightly shortened. When further incubated with fetal bovine serum (FBS), both long and short fibers were visualized in solution. Nevertheless, in the hydrogel state, the rheological properties were remarkably preserved. Further studies on the cellular compatibility of all the BTA assemblies and mixtures thereof were performed in four different cell lines. A low cytotoxic effect at most concentrations was observed, confirming the suitability of utilizing functional BTA supramolecular polymers as dynamic biomaterials.

Self-assembly of dextran – b – deoxycholic acid polyester copolymers: Copolymer composition and self-assembly procedure tune the aggregate size and morphology

Self-assembly potential of new amphiphilic block copolymers containing dextran (Mn 4500, 8000, 15,000) and a semi-rigid deoxycholic acid-oligoethyleneglycol polyester (Mn 2500–8800, 2 or 4 ethyleneglycol units), was evaluated as a function of copolymer composition and self-assembly procedure, using dynamic light scattering and transmission electron microscopy. Addition of copolymer solution to water provided small star-like micelles (∼ 100 nm), while addition of water to copolymer solution led to various morphologies and sizes (60−600 nm), depending on polymer composition. Worm-like micelles were obtained from a copolymer containing dextran with Mn 4500 and 66 wt% polyester, and vesicles were formed by copolymers prepared from dextran with Mn 8000 and containing 46 wt% polyester. Presence of a longer oligoethyleneglycol decreased the size of micelles and vesicles due to an enhanced flexibility of the polyester hydrophobic block. The results allow the selection of the most appropriate parameters to obtain the desired aggregate characteristics.

Synthesis of Network Polymers by Means of Addition Reactions of Multifunctional-Amine and Poly(ethylene glycol) Diglycidyl Ether or Diacrylate Compounds.

Addition reactions of multi-functional amine, polyethylene imine (PEI) or diethylenetriamine (DETA), and poly(ethylene glycol) diglycidyl ether (PEGDE) or poly(ethylene glycol) diacrylate (PEGDA), have been investigated to obtain network polymers in H2O, dimethyl sulfoxide (DMSO), and ethanol (EtOH). Ring opening addition reaction of the multi-functional amine and PEGDE in H2O at room temperature or in DMSO at 90 °C using triphenylphosphine as a catalyst yielded gels. Aza-Michael addition reaction of the multi-functional amine and PEGDA in DMSO or EtOH at room temperature also yielded corresponding gels. Compression test of the gels obtained with PEI showed higher Young’s modulus than those with DETA. The reactions of the multi-functional amine and low molecular weight PEGDA in EtOH under the specific conditions yielded porous polymers induced by phase separation during the network formation. The morphology of the porous polymers could be controlled by the reaction conditions, especially monomer concentration and feed ratio of the multi-functional amine to PEGDA of the reaction system. The porous structure was formed by connected spheres or a co-continuous monolithic structure. The porous polymers were unbreakable by compression, and their Young’s modulus increased with the increase in the monomer concentration of the reaction systems. The porous polymers absorbed various solvents derived from high affinity between the polyethylene glycol units in the network structure and the solvents.

Insight into the mechanism of cytotoxicity of membrane-permeant psoralenic Kv1.3 channel inhibitors by chemical dissection of a novel member of the family

The potassium channel Kv1.3, involved in several important pathologies, is the target of a family of psoralen-based drugs whose mechanism of action is not fully understood. Here we provide evidence for a physical interaction of the mitochondria-located Kv1.3 (mtKv1.3) and Complex I of the respiratory chain and show that this proximity underlies the death-inducing ability of psoralenic Kv1.3 inhibitors. The effects of PAP-1-MHEG (PAP-1, a Kv1.3 inhibitor, with six monomeric ethylene glycol units attached to the phenyl ring of PAP-1), a more soluble novel derivative of PAP-1 and of its various portions on mitochondrial physiology indicate that the psoralenic moiety of PAP-1 bound to mtKv1.3 facilitates the diversion of electrons from Complex I to molecular oxygen. The resulting massive production of toxic Reactive Oxygen Species leads to death of cancer cells expressing Kv1.3. In vivo, PAP-1-MHEG significantly decreased melanoma volume. In summary, PAP-1-MHEG offers insights into the mechanisms of cytotoxicity of this family of compounds and may represent a valuable clinical tool.

Abstract 2885: Discovery of a tripeptide-based camptothecin drug-linker for antibody-drug conjugates with potent antitumor activity and a broad therapeutic window

Abstract In efforts to bring forward antibody-drug conjugate (ADC) technologies that complement vedotin and enable new clinical-stage ADCs, we have investigated compounds that interact with topoisomerase 1, an enzyme involved in the unwinding of DNA. In connection with this, we developed a highly active and well-tolerated camptothecin drug-linker technology, in which the lead molecule consists of 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT) attached to a protease-cleavable valine-lysine-glycine (VKG) tripeptide linker unit. A hydrophilic and discrete polyethylene glycol unit was included to improve the properties of the drug-linker, enabling high ADC drug-loading, and reducing the propensity for aggregation. A VKG-AMDCPT ADC, with 8 drug-linkers/mAb (DAR8), displayed a pharmacokinetic profile coincident with parental unconjugated antibody, with a high degree of stability against retro-Michael reaction deconjugation. ADCs based on the VKG-AMDCPT were broadly active against cancer cells in vitro, and in mouse xenograft models, giving tumor regressions and complete responses with a single ≤3 mg/kg dose. These included both solid and hematologic tumor models, and models of bystander killing activity and multidrug resistance. A non-binding DAR8 ADC was well-tolerated in rats at 60 mg/kg, q7dx4. The VKG-AMDCPT drug-linker can be prepared from available materials in eight high-yielding steps, and this drug-linker is being employed in the anti-CD30 ADC, SGN-CD30C; an investigational new drug application is planned for 2020. Citation Format: Ryan Lyski, Lauren Bou, Margo Zaval, Kim Emmerton, Nicole Okeley, Jessica Simmons, Francisco Zapata, David Ortiz, Erica McKinney, David Meyer, Maureen Ryan, Peter Senter, Scott Jeffrey. Discovery of a tripeptide-based camptothecin drug-linker for antibody-drug conjugates with potent antitumor activity and a broad therapeutic window [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2885.

The interaction nature between hollow silica-based porous ionic liquids and CO2: A DFT study

Carbon dioxide (CO2) is one of the main factors leading to the greenhouse effect, so the capture of CO2 gas is currently a hot spot of research. Hollow silica-based porous ionic liquids (HS-liquids) are porous liquids containing cavities that are not only fluid but also have a high specific surface area and were used for the capture of CO2. However, the mechanism of CO2 absorption by HS-liquids has not been studied. In this work, the mechanism of CO2 absorption by HS-liquids was systematic studied by density functional theory (DFT). First, five possible models for absorbing CO2 in HS-liquids were constructed and optimized. The interaction energies between HS-liquids and CO2 at different sites were obtained. Moreover, the effects of HS-liquids with different degrees of polymerization of polyethylene glycol and different alkyl chain lengths on CO2 absorption were also investigated. Results show that the strongest absorption site locates near the polyethylene glycol unit. Then, the electrostatic potential (ESP) and reduced density gradient (RDG) methods were employed to further understand the interaction nature between them. The results show that hydrogen bonding dominates the weak interaction between the HS-liquid and CO2.

Novel thermoresponsive homopolymers of poly[oligo(ethylene glycol) (acyloxy) methacrylate]s: LCST-type transition in water and UCST-type transition in alcohols

The study of thermoresponsive homopolymers has attracted great attention due to their broad application value. Herein, a series of novel thermoresponsive homopolymers of poly[oligo(ethylene glycol) (acyloxy) methacrylate]s containing oligo(ethylene glycol) (OEG) units and substituent groups of ester have been designed and prepared by RAFT polymerization. The solution properties of these polymers have been investigated in detail, which indicate that most of them exhibit lower critical solution temperature (LCST) in water and upper critical solution temperature (UCST) in alcohols, and their LCST-type or UCST-type cloud point temperature (TCPL or TCPU) is closely related to the OEG units and ester groups. Furthermore, the parameters affecting the thermoresponse of these polymers including polymerization degree (DP) and concentration have also been investigated. The present work not only discovers a series of novel thermoresponsive polymers, but also has certain guiding significance on the understanding of molecular structure and thermoresponsive property relationships, which is useful for the design of new thermosensitive polymers.

Engineered Ovalbumin Nanoparticles for Cancer Immunotherapy

AbstractOvalbumin (OVA) is a protein antigen that is widely used for eliciting cellular and humoral immune responses in cancer immunotherapy. As an alternative to solute OVA, engineering approach is developed herein towards protein nanoparticles (pNPs) based on reactive electrospraying. The resulting pNPs are comprised of polymerized OVA, where individual OVA molecules are chemically linked via poly(ethylene glycol) (PEG) units. Controlling the PEG/OVA ratio allows for fine‐tuning of critical physical properties, such as particle size, elasticity, and, at the molecular level, mesh size. As the PEG/OVA ratio decreased, OVA pNPs are more effectively processed by dendritic cells, resulting in higher OT‐I CD8+ cells proliferation in vitro. Moreover, pNPs with lower PEG/OVA ratios elicit enhanced lymphatic drainage in vivo and increased uptake by lymph node macrophages, dendritic cells, and B cells, while 500 nm OVA pNPs show poor draining lymph nodes delivery. In addition, pNPs with lower PEG/OVA ratios result in higher anti‐OVA antibody titers in vivo, suggesting improved humoral immune responses. Importantly, OVA pNPs result in significantly increased median survival relative to solute OVA antigen in a mouse model of B16F10‐OVA melanoma. This work demonstrates that precisely engineered OVA pNPs can improve the overall anti‐tumor response compared to solute antigen.