Low Molecular Weight Polyethylene Glycol Research Articles

Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

Methotrexate (MTX) is one of the most common anticancer drugs used for chemotherapy so far. However some problems such as high toxicity and short plasma half-life, have limited its use. To overcome these limitations, conjugation with polymers such as polyethylene glycol (PEG) is one the efficient approaches which has been attempted in recent years. The aim of the present study is to synthesize esters of MTX with PEGs of different molecular weights and to characterize their physicochemical properties. Polymeric esters (MTX-PEGs) of MTX with low, medium and high molecular weight PEGs (750 D, 5000 D and 35000 D, respectively) were synthesized using dicyclohexylcarbodiimide (DCC) as coupling agent and triethylamine (TEA) as catalyst. The purification was carried out using preparative TLC. Purified esters were characterized by UV, IR and (1)H-NMR spectroscopy methods and their thermal behavior was studied by differential scanning calorimetry (DSC). Also, an isocratic HPLC method with three mobile phase systems was set to determine the partition coefficient of the esters (log P). Gel permeation chromatography (GPC) was utilized for molecular weight determination of esters, which proved 1 : 1 conjugation of drug with each polymer. The stability and solubility of esters were determined in different pH values. The spectroscopy results indicated that esteric bond between MTX and PEGs were formed. The sharp endothermic peaks for MTX-PEGs were obtained in DSC which are similar to pure polymers, whilst a wide peak was observed for MTX. The values of log P for MTX-PEGs (+4.3, obtained by HPLC method) were remarkably different from log P of MTX (-1.4, obtained by shake-flask method). The stability results showed a pH range of 3-4 and an optimum polymer mw of 5000 for maximum stability of esters. A parabolic profile obtained from solubility studies that indicated the more solubility of MTX in alkaline condition (pH>5) and MTX-PEGs in acidic conditions (pH<5). Based on our results, it is concluded that MTX-PEGs were formed on an equimolar ratio of MTX and PEGs. The higher log P observed for the esters indicated dramatic physicochemical differences between MTX and its PEG conjugates and the higher stability and solubility in acidic medium showed a promising approach to improve the drug delivery of the conjugates, specially MTX-PEG5000 in the future.

Substantiating in vivo magnetic brain tumor targeting of cationic iron oxide nanocarriers via adsorptive surface masking

Cationic magnetic nanoparticles are attractive as potential vehicles for tumor drug delivery due to their favorable interactions with both the tumor milieu and the therapeutic cargo. However, systemic delivery of these nanoparticles to the tumor site is compromised by their rapid plasma clearance. We developed a simple method for in vivo protection of cationic nanocarriers, using non-covalent surface masking with a conjugate of low molecular weight heparin and polyethylene glycol. Surface masking resulted in a 11-fold increase in plasma AUC and a 2-fold increase in the magnetic capture of systemically injected nanoparticles in orthotopic rodent brain tumors. Overall, the described methodology could expand the prospective applications for cationic magnetic nanoparticles in magnetically mediated gene/drug delivery.

Identification and quantification of polyethylene glycol types in polyethylene glycol methyl ether and polyethylene glycol vinyl ether

Quantitative determination of polyethylene glycol (PEG) impurities in two monofunctional polyglycol types, PEG methyl ether (M-PEG) and PEG vinyl ether (V-PEG), has been carried out by reversed-phase liquid chromatography with evaporative light scattering detection (ELSD). In addition to optimizing the resolution between PEG and monofunctional PEG peaks, the major focus has been to determine the molecular weights of PEG impurities in M-PEG and V-PEG of diverse molecular weights. The latter is achieved by examining liquid chromatography–mass spectrometry (LC–MS) mass spectra of both monofunctional PEG and PEG in several cases, and matching peak retention times with those of available PEG standards for all M-PEG and V-PEG sample types. This information is helpful in selecting the appropriate PEG standard to determine PEG content in each sample type. ELSD response factors for various PEG standards have also been compared. It has been found that PEG standards with molecular weights from 1000 Da to 8000 Da show responses that are within 10% of each other. However, a low molecular weight PEG such as PEG 400, provides approximately 30% less response compared to its higher molecular weight counterparts.

Role of composite MnO2 cathode on electrochemical cells based on polymer electrolyte (PEO/NaClO3)

Thin-film sodium-ion-conducting polymer electrolyte based on polyethylene oxide (PEO) system was prepared by solvent casting method. The thin-film electrolytes were characterized by X-ray diffraction (XRD), infrared (IR), cyclic voltammetry (CV) and alternating current conductivity, and Wagner’s polarization method. The complexation of salt with PEO was confirmed by XRD and IR studies. The charge transport of these electrolytes is mainly due to ions, which was confirmed by the transference number experiment. The conductivity studies show that the conductivity value of PEO/NaClO3 complex increases with the increase of temperature as well as the addition of low molecular weight polyethylene glycol, dimethyl formamide, and propylene carbonate. The electrolyte stability and cell reversibility were analyzed by CV studies. Electrochemical cells have been fabricated with a common cell configuration Na|electrolyte|(MnO2 + I2 + C + electrolyte), and their discharge characteristic studies were made through a load 100 kΩ at room temperature. The measured open circuit voltage ranges from 2.80 to 2.54 V with short circuit current ranges from 667 to 1,000 μA and several other cell parameters were evaluated. Finally, the merit of the composite cathode is found with the comparison of the MnO2 cathode.

Effect of processing temperature on the bitumen/MDI-PEG reactivity

Reactive polymers are lately gaining acceptance to give added value to a residue of the crude oil refining process such as bitumen. The resulting material should display enhanced mechanical properties to be considered for advanced applications in construction. In the present paper, we report the effect of processing temperature on the reaction between bitumen compounds and an isocyanate-based reactive polymer, synthesized by reaction of polymeric MDI (4,4′-diphenylmethane diisocyanate) with a low molecular weight polyethylene-glycol (PEG). Rheokinetics experiments, viscosity measurements at 60 °C, atomic force microscopy (AFM) characterization, thin layer chromatography (TLC-FID) analysis and thermogravimetric studies (TGA) were performed on the reactive polymer and on samples of MDI-PEG modified bitumen containing 2 wt.% of the polymer. Results showed the existence of an optimum processing temperature arisen as a consequence of opposite effects: microstructural availability for the formation of a polymer–bitumen network, reaction ability and polymer thermal degradation. Consequently, this study aims to serve as a guideline for the refining and asphalt industries facing the stage of selecting the optimum processing parameters.

Partition of plasmid DNA in polymer–salt aqueous two-phase systems

The partition of plasmid DNA (pDNA) in polyethylene glycol (PEG)–phosphate aqueous two-phase systems (ATPS) is presented. A high molecular weight (HMW) and a low molecular weight (LMW) polymer, PEG-1450 and -300, were used in combination with di-potassium hydrogen phosphate. The experimental results demonstrated that the plasmid pTX0161 displays a varied partition behaviour in PEG–phosphate ATPS. In HMW PEG (PEG-1450–phosphate systems), pDNA partitioned to the bottom phase only. In LMW PEG (PEG-300–phosphate systems), pDNA partitioned to all of the phases with respect to the phase composition, system temperature and concentration of lysate used in the ATPS. In systems with volume ratios higher than one, pDNA was mainly recovered in the top phase. For volume ratios between 0.5 and 1, pDNA mainly partitioned to the interface. In systems with volume ratios below 0.5, most of the pDNA was recovered in the bottom phase. For temperatures between 4 and 25 °C, the partition to the top phase decreased whereas partition to the interface steadily increased. At 25 °C, over 80% of pDNA was recovered in the interface. The partition to the bottom phase increased steadily with increasing temperatures up to 40 °C and the partition to the interface decreased. At 20 °C, the recovery of pDNA in the interface gradually increased and reached a maximum at 60% (w/w) lysate with 80% recovery recorded. At 25 °C, over 80% of pDNA was recovered in the interface from lysate concentrations greater than 35% (w/w). At 30 °C, the top phase preference changed to an interface preference between 0 and 20% (w/w) lysate.

PEG blocking of single pores arising on phase transitions in unmodified lipid bilayers

Changes in ionic permeability of bilayer lipid membranes (BLM) from dipalmitoyl phosphatidylcholine at temperature of phase transition in 1 M LiCl solution in the presence of polyethyleneglycols (PEG) of various molecular masses are studied. The transition of ionic membrane channels from conducting to blocked nonconducting state using polymers makes it possible to calibrate lipid pores. It is shown that low-molecular weight glycerol and PEG with molecular weights of 300 and 600 decrease the amplitude of current fluctuations through the membrane, the decrease being proportional to the size of the polymer molecule incorporated. The addition of PEG with molecular masses of 1450, 2000, and 3350 decrease the current fluctuations to the basal noise level. The result is considered as a complete blockade of ion channel conductivity. In the presence of rather large polymers, such as PEG with molecular masses of 6000 and 20000, which are hardly incorporated in the pore, single current fluctuations occur again; however, their amplitudes are somewhat smaller than in the absence of PEG. It is assumed that a complete blockade of the conductivity of lipid ionic channels by PEG with molecular masses of 1450, 2000, and 3350 is due to dehydration of the pore gap and the conversion of the hydrophilic pore to a hydrophobic one.

Molecular Dynamics Studies of Polyethylene Oxide and Polyethylene Glycol: Hydrodynamic Radius and Shape Anisotropy

A revision (C35r) to the CHARMM ether force field is shown to reproduce experimentally observed conformational populations of dimethoxyethane. Molecular dynamics simulations of 9, 18, 27, and 36-mers of polyethylene oxide (PEO) and 27-mers of polyethylene glycol (PEG) in water based on C35r yield a persistence length λ = 3.7 Å, in quantitative agreement with experimentally obtained values of 3.7 Å for PEO and 3.8 Å for PEG; agreement with experimental values for hydrodynamic radii of comparably sized PEG is also excellent. The exponent υ relating the radius of gyration and molecular weight ( R g ∝ M w υ ) of PEO from the simulations equals 0.515 ± 0.023, consistent with experimental observations that low molecular weight PEG behaves as an ideal chain. The shape anisotropy of hydrated PEO is 2.59:1.44:1.00. The dimension of the middle length for each of the polymers nearly equals the hydrodynamic radius R h obtained from diffusion measurements in solution. This explains the correspondence of R h and R p, the pore radius of membrane channels: a polymer such as PEG diffuses with its long axis parallel to the membrane channel, and passes through the channel without substantial distortion.

Use of a MDI-functionalized reactive polymer for the manufacture of modified bitumen with enhanced properties for roofing applications

In this study, the suitability of a reactive polymer, synthesized by reaction of 4,4′-diphenylmethane diisocyanate (MDI) with a low molecular weight polyethylene-glycol (PEG), as a modifying agent for the manufacture of bitumen-based waterproof membranes, was evaluated. With that purpose, rheological and thermal analysis tests, and microstructural observations by AFM were carried out on different samples of modified bitumen having a MDI–PEG content ranging from 0 to 10wt.%, cured at room temperature for a period of time within 0–30 days. The results obtained demonstrate that the addition of the reactive polymer proposed in this work to bitumen is very suitable at high in-service temperatures, because a noticeable increase in the values of viscosity, at 60°C, of the resulting modified bitumen samples is observed on a time-scale of days. AFM observations, carried out at 50°C, evidenced that the reactive polymer MDI–PEG leads to a new microstructure, displaying a higher level of stiffness. Therefore, this polymer should be seriously taken into consideration as a modifier of bituminous coatings for the waterproofing industry.

Theory and practice of combining coagulant fixation and microwave histoprocessing

The German, F. Blum, introduced formalin as a fixative in 1893. Formalin rapidly became popular for hardening and preserving gross human and animal specimens. As a result, microscopy for diagnostic pathology by combining paraffin embedding and formalin fixation was developed. Alcohol-based fixatives have coagulation of proteins as their main preservative effect. Because there is no cross-linking, immunostaining is not compromised, and DNA and RNA is not damaged. Ethyl alcohol was used by Dutch scientists of the 18th century, but was replaced by the cheaper formalin. Addition of low molecular weight polyethylene glycol (PEG) optimized the coagulant fixative, Kryofix. The polyethylene glycol prevents excessive hardening and enhances the speed of coagulation of proteins. Kryofix was used on a large scale for skin biopsies in Leiden between 1987 and 2001. DNA preservation by the formulated coagulant fixative, BoonFix, is related to the concentration of ethyl alcohol, PEG and acetic acid. BoonFix has been used since 2004 in Leiden for over 40,000 diagnostic skin biopsies and more than 100,000 cervical samples. A literature review and three decades of experience with coagulant, formalin-free fixatives in pathology suggest that when health authorities realize that formalin invalidates expensive tests, it might eventually be eliminated legislatively from diagnostic pathology. Finally, coagulant fixation is optimal for microwave histoprocessing where ethyl alcohol is followed by isopropanol.

Displacement flows of dilute polymer solutions in capillaries

The two-dimensional, free surface flow of a viscoelastic liquid being displaced in a capillary tube by gas injection is analyzed by both experiments and theory. The experiments consisted of flow visualization and measurement of mass displaced by a gas bubble in a capillary tube filled with a viscoelastic liquids. Various solutions of low molecular weight polyethylene glycol (PEG) and high molecular weight polyethylene oxide (PEO) in water were used in order to evaluate the effect of viscoelastic behavior on the flow. The rheological properties of the solutions were evaluated both in shear and predominantly extensional flows. The theoretical analysis consisted of solving the conservation equations, together with appropriate constitutive models, with the finite element method. Models of flows of high molecular weight polymer solution must rely on theories that can account for the different behavior of microstructured liquids in shear and extensional flow. Moreover, displacement flows involve a free surface, and the domain where the differential equations are posed is unknown a priori, being part of the solution. These two characteristics make the problem extremely complex. Here, the viscoelastic behavior of the liquid was described using three differential constitutive equations that approximate dilute and semi-dilute polymer solutions, namely Oldroyd-B, FENE-P and FENE-CR . Both the theoretical predictions and experimental measurements were obtained at values of the elasto-capillary number much higher than previously reported. At this limit, a new phenomenon is observed, the film thickness attached to the capillary wall reaches a plateau as the liquid becomes more elastic.

Preparation and characterization of poly(ethylene terephthalate) fabrics treated by blends of cellulose nanocrystals and polyethylene glycol

AbstractIn this study, the coating based on the blends of low molecular weight polyethylene glycol (PEG) and cellulose nano‐crystals (CNC) was introduced to immobilize on the surface of polyethylene terephthalate (PET) fabrics to modify the surface properties of fabrics, and to fabricate comfortable fabrics for formidable climate. Field‐emission scanning electron microscope, attenuated total reflectance Fourier transform infrared spectroscopy, and differential scanning calorimetry (DSC) were employed to study the topography, superficial ingredients, and thermal activity of the finished fabrics. The observation of field‐emission scanning electron microscope and attenuated total reflectance Fourier transform infrared spectroscopy confirmed that the surface of PET fabrics was covered by CNC/PEG1000/PEG600 coating. The transition onset temperature and phase change enthalpy of PET fabrics treated with CNC/PEG1000/PEG600 were at 7.06°C and 11.41 kJ/kg, respectively. Dimensional memory measurement demonstrated that the introduction of CNC caused the deformation percent to decrease by about 41% for PET fabrics covered with CNC/PEG1000/PEG600 coating. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007

Multiphase coexistence in colloidal dispersions of positively charged layered double hydroxides

Colloidal dispersions of Mg-Al (Mg/Al molar ratio 2:1) layered double hydroxide (LDH) have previously been found to exhibit an isotropic–nematic (I–N) phase transition [S.Y. Liu, J. Zhang, N. Wang, W.R. Liu, C.G. Zhang, D.J. Sun, Chem. Mater. 15 (2003) 3240–3241]. In the present paper, we show that an effective attraction induced by the addition of low molecular weight polyethylene glycol (PEG) enriches the phase behavior of Mg-Al LDH dispersions. At certain concentrations of LDH and PEG, multiphase coexistence is observed. The addition of PEG leads to the appearance of a four-phase equilibrium and even a five-phase equilibrium. We explain the experimental phenomena by the interplay between PEG-induced effective attraction, LDH particle polydispersity and sedimentation.

Characterisation of the polyethylene glycol impregnation of the Swedish warship Vasa and one of the Danish Skuldelev Viking ships

The Swedish 17th century warship Vasa and the Danish Skuldelev Viking ships from the 11th century were impregnated with polyethylene glycol (PEG) in the 1960s. The molecular weight, amount and integrity of this PEG were investigated at a range of depths below the wood surface. Large amounts of PEG could be extracted from degraded parts of the ships but hardly any from sound parts. Mass spectrometry showed that PEG 4000 is present only in the surface layers of the wood, PEG 1500 and PEG 600 are present at all depths of the wood that has been treated with it. Low molecular weight PEG was detected in one of the Skuldelev ships by mass spectrometry and Size Exclusion Chromatography (SEC), it is argued that this is due to degradation of PEG 4000. SEC also showed that PEG 600 is the major PEG component in the Vasa which makes this particular object sensitive to changes in air humidity since PEG 600 is hygroscopic.

Rheology and microstructure of MDI–PEG reactive prepolymer-modified bitumen

This paper deals with the use of a new bitumen modifier, a reactive prepolymer, based on the reaction of 4,4′-diphenylmethane diisocyanate (MDI) and a low molecular weight polyethylene glycol (PEG). The rheological and thermal behaviours of modified bitumen containing a low MDI–PEG concentration, as well as its morphology, have been studied. A relatively low amount of MDI–PEG (0.5 to 1.5% wt.) yields a significant improvement in the modified bitumen rheological properties, mainly in the high in-service temperature region. In this range of temperature, the rheological properties are clearly affected by curing time at room temperature. These results indicate that chemical changes, due to the reaction of MDI isocyanate groups with the most polar groups (–OH; –NH) of asphaltenes and resins, are produced. Thus, new chemical structures, non-visible by optical microscopy, slowly develop in MDI–PEG modified bitumen when samples are cured at room temperature.

Morphologies of calcium carbonate crystallites grown from aqueous solutions containing polyethylene glycol

AbstractCalcium Carbonate has been precipitated from aqueous solutions containing different concentrations and different molecular weight of Polyethylene Glycol (PEG). The precipitations were analyzed by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT‐IR) and X‐ray diffraction (XRD). The results demonstrated that PEG has profound influence on the nucleation and crystal growth of CaCO3, under condition of low PEG6000 (refer to PEG MW=6000) concentration, it favored the formation of calcite, while high PEG6000 concentration promoted vaterite formation. Additionally, low molecular weight PEG can stabilize vaterite phase. (© 2006 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

The role of elasticity in the formation of electrospun fibers

The role of fluid elasticity in the formation of fibers from polymer solution by electrospinning is investigated. Model solutions with different degrees of elasticity were prepared by blending small amounts of high molecular weight polyethylene oxide (PEO) with concentrated aqueous solutions of low molecular weight polyethylene glycol (PEG). The elastic properties of these solutions, such as extensional viscosity and the longest relaxation time, were measured using the capillary breakup extensional rheometer (CaBER). The formation of beads-on-string and uniform fiber morphologies during electrospinning was observed for a series of solutions having the same polymer concentration, surface tension, zero shear viscosity, and conductivity but different degrees of elasticity. A high degree of elasticity is observed to arrest the breakup of the jet into droplets by the Rayleigh instability and in some cases to suppress the instability altogether. We examine the susceptibility of the jet to the Rayleigh instability in two ways. First, a Deborah number, defined as the ratio of the fluid relaxation time to the instability growth time, is shown to correlate with the arrest of droplet breakup, giving rise to electrospinning rather than electrospraying. Second, a critical value of elastic stress in the jet, expressed as a function of jet radius and capillary number, is shown to indicate complete suppression of the Rayleigh instability and the transition from ‘beads-on-string’ to uniform fiber morphology.

Hydrophilic nanofibrous structure of polylactide; fabrication and cell affinity

Microstructure and architecture of the scaffolds along with the surface chemistry exert profound effect on biological activity (cell distribution, proliferation, and differentiation). For the biological activity, scaffolds in tissue engineering have been widely designed. The objective of this study was to develop hydrophilic nanofibrous structure of polylactides (PLLA) polymer in the form of nonwoven mat by electrospinning technique, and further evaluate the fibroblast NIH3T3 cell proliferation, morphology, and cell-matrix interaction. Hydrophilicity of the PLLA fibers was improved by adding small fraction of low molecular weight polyethylene glycol (PEG) into the electrospinning solution. Four different ratio types (100/0, 80/20, 70/30, and 50/50) of PLLA/PEG electrospun matrices were fabricated, and the pore characteristics, tensile properties, contact angle, and hydrolytic degradation were observed. Furthermore, scanning electron microscope (SEM) and fluorescence actin staining images were used for micro-observation of cell-matrix interaction and cell morphology. It was found that the electrospun mat of PLLA/PEG (80/20), composed of fibers with diameters in the range 540-850 nm, majority of pore diameter less than 100 microm, tensile strength 8 MPa, elongation 150%, porosity more than 90%, and improved hydrophilicity with slow hydrolytic degradation, is favorable for biological activity of NIH3T3 fibroblast cell. Based on these results, the correct composition of PLLA and PEG in the porous electrospun matrix (i.e., PLLA/PEG (80/20)) will be a better candidate rather than other compositions of PLLA/PEG as well as hydrophobic PLLA for application in tissue engineering.

Synthesis and characterization of a novel alginate–poly(ethylene glycol) graft copolymer

Sodium alginate grafted with low molecular weight polyethylene glycol (PEG) was prepared by reacting a mono-carboxyl terminated PEG with a sodium alginate modified by inserting a given amount of amine functionalities. The coupling between PEG and alginate was carried out using carbodiimide chemistry in aqueous solutions. Significant reduction of the molecular weight of alginate is recorded, as expected from literature reports. The chosen strategy allowed to graft significant amounts of PEG saving the carboxylic functionalities of alginate, necessary for the cross-linking of the polysaccharide. The chemical structure and chemical–physical properties of alginate derivatives were characterized by FTIR, 1H and 13C NMR, DSC, TGA and wide angle X-ray analysis.

Activity of acetone-treated Chromobacterium viscosum lipase in AOT reverse micelles in the presence of low molecular weight polyethylene glycol

The activity of Chromobacterium viscosum lipase (glycerol-ester hydrolase, EC 3.1.1.3) entrapped in AOT/isooctane/water reverse micelles was significantly enhanced by pretreatment with acetone, using the hydrolysis of olive oil as a model reaction. The activity of acetone treated lipase was further enhanced when low molecular weight polyethylene glycol (PEG 400) was introduced into AOT reverse micelles. To know the effects of acetone treatment on the lipase activity in simple AOT and mixed AOT/PEG 400 reverse micelles, the influence of various parameters, such as W 0 (molar ratio of water to surfactant), pH, surfactant concentration, ionic strength and reaction temperature were investigated and compared with those for native lipase in simple AOT reverse micelles. The optimal activities of treated lipase in AOT reverse micelles with and without PEG 400 were 2.0 and 1.6 times higher respectively than that of native lipase in AOT reverse micelles. A kinetic model that considers substrate adsorption equilibrium between the bulk phase of organic solvent and the micellar phase was successfully used to understand the improvement of the lipase activity. The Michaelis constant ( K m) and substrate adsorption equilibrium constant (K ad ) were obviously reduced compared with those for native lipase in AOT reverse micelles. The stability of the lipase in reverse micelles was also studied, and the values of half-life time ( t 1/2) were determined from residual activity profiles.