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Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications
Abstract
At first glance, the polymer known as poly(ethylene glycol) or PEG appears to be a simple molecule. It is a linear or branched, neutral polyether, available in a variety of MWs, and soluble in water and most organic solvents. Despite its apparent simplicity, {HO - {{\left( {C{H_2}C{H_2}O} \right)}_n} - C{H_2}C{H_2}OH} \hfill \\
{poly(ethylene\,glycol)} this molecule is the focus of much interest in the biotechnical and biomedical communities. Primarily this is because PEG is unusually effective at excluding other polymers from its presence when in an aqueous environment. This property translates into protein rejection, formation of two-phase systems with other polymers, nonimmunogenicity, and nonantigenicity. In addition, the polymer is nontoxic and does not harm active proteins or cells although it interacts with cell membranes. It is subject to ready chemical modification and attachment to other molecules and surfaces, and when attached to other molecules it has little effect on their chemistry but controls their solubility and increases their size. These properties, which are described in more detail below, have led to a variety of important biotechnical and biomedical applications, a summary of which is also presented below.
... Polymer-drug conjugation (Harris, 1992;Harris and Chess, 2003;Haag and Kratz, 2006;Pelegri-O'Day et al., 2014;Hoffman, 2016;Ekladious et al., 2019) was first described in the 1954 by German chemist, Horst Jatzkewitz, who demonstrated that covalent attachment of poly (vinyl pyrrolidone) to the psychoactive compound, mescaline, could be used to prolong its circulation and duration of action ( Figure 1A) (Jatzkewitz, 1954;Jatzkewitz, 1955;Luxenhofer, 2020). Yet despite its novelty and utility, Jatzkewitz's innovation went largely unnoticed until the mid 1970s when it was revived by Ringsdorf, Kopecek, and Duncan, among others, who championed the notion that these novel macromolecules could enhance the suboptimal activity of various pharmaceuticals (Ringsdorf, 1975). ...
... PEG's remarkable hydrophilicity, flexibility, inertness, and relative biocompatibility have found the polymer numerous uses beyond modulating drug circulation or activity and today it can be found near ubiquitously in both consumer products such as detergents, cosmetics, and car wax, as well as in industrial applications including electroplating, historical artifact preservation, and molded product production (Harris, 1992;Prime and Whitesides, 1993;Harris and Chess, 2003;Li et al., 2005;Jokerst et al., 2011). PEGylating has also been used to improve stability of contrast agents for in vivo fluorescence imaging, photodynamic therapy, and sonodynamic therapy (Ding et al., 2018;Chen et al., 2021;Xu et al., 2022). ...
... Given 1) the therapeutic impact of PEG on drug immunogenicity, 2) the possible increasing prevalence of preexisting and drug-induced PEG immunity, 3) the growing public need for safe and effective mRNA vaccines, and 4) our prevailing reliance on PEG for use in clinically approved nucleic acid and polymer-drug conjugate therapies (Schoenmaker et al., 2021), it is clear that the development and clinical validation of alternatives to (or derivatives of) PEG represents not only an unmet clinical need but also one with broad public health and national strategic interest. Indeed, the need for alternatives to PEG is a common refrain among those in the field (Harris, 1992), one as old as the first polymer-drug conjugate, Adagen; however, given the wide variety of potential candidate macromolecules such as polysaccharides, polyglycerols, and glycopolymers, (reviewed in detail elsewhere (Knop et al., 2010;Pelegri-O'Day et al., 2014;Bludau et al., 2017;Ekladious et al., 2019;Xu et al., 2022)), it begs the question as to why alternatives have yet to be approved (and studied post-approval) beyond poly(styrene co-maleic acid) (1993, Japan). Concerns over PEG immunogenicity have led some pharmaceutical companies to shy-away from or drop PEGylated products from their pipelines entirely (de Vrieze, 2020), thus the prospect of biopharma advancing clinically untested polymers through lengthy and expensive clinical trials is a difficult ask in the absence of a thoughtful incentive structure. ...
... : I In nt tr ro od du uc ct ti io on n 11 1.1 La thérapie génique 12 1.2 La thérapie génique anticancéreuse 13 18 Propriétés physico-chimiques 40 Utilisation chimique 41 Propriétés biologiques de biochimiques 42 Synthèse des mPEG-NH 2 44 46 Généralités 46 Structure des PEI 46 Physico-chimie des PEI 47 Capacité de transfection de l'ADN et des oligonucléotides 49 Ciblage des cellules 51 Caractères toxiques 52 Synthèse du L-PEI 53 3.1.2 Effets du mPEG-OH, et du L-PEI sur l'activité gélatinase 55 57 3 63 74 78 83 84 87 ...
... 3.3.1 Cinétique d'hydrolyse de substrat synthétique 87 3.3.2 Hydrolyse de ce substrat par les surnageants cellulaires 90 3.3.3 ...
... Les PEGs [87], sont utilisés à concentrations élevées pour précipiter des protéines, [86]. ...
Un peptide synthétique, substrat de gélatinases A (MMP2) et B (MMP9 a été introduit par synthèses chimiques diverses entre deux polymères : une poly(éthyleneimine), (L-PEI) et un poly(éthylène glycol)5000, (mPEG5000). La conception des produits est basée sur l’inhibition de la transfection cellulaire d’ADN lié au L-PEI, par le mPEG, lorsque le peptide incorporé n’est pas clivé par ces enzymes. Un taux plus important de transfection du gène de la luciférase, transporté par ces substrats, est obtenu avec les cellules HT1080 qu’avec les cellules B16 et 3T3, alors que pas ou peu de transfection est obtenue avec les molécules-témoins. Ces résultats sont en rapport avec les activités gélatinases des surnageants de ces cellules, permettant l’élimination du mPEG. Ils laissent envisager un ciblage de gènes thérapeutiques de cellules cancéreuses avec un vecteur synthétique.
... Polyethylene glycol (PEG) is a biocompatible, water-soluble and non-ionic polymer [1]. Because of its hydrophilic and non-toxic nature, PEG has been widely used in biomedical, pharmaceutical, cosmetic and food processing applications [1,2]. PEG has also been reported to show unique steric repulsion/exclusion property in aqueous environment due to its high flexibility and mobility with water [2]. ...
... Because of its hydrophilic and non-toxic nature, PEG has been widely used in biomedical, pharmaceutical, cosmetic and food processing applications [1,2]. PEG has also been reported to show unique steric repulsion/exclusion property in aqueous environment due to its high flexibility and mobility with water [2]. This property makes PEG to be uniquely suitable for reducing protein adsorption, cell uptake, cell stimulation and cell adhesion in body environment [1][2][3]. ...
... PEG has also been reported to show unique steric repulsion/exclusion property in aqueous environment due to its high flexibility and mobility with water [2]. This property makes PEG to be uniquely suitable for reducing protein adsorption, cell uptake, cell stimulation and cell adhesion in body environment [1][2][3]. PEG and its related polymers have been commonly used as hydrogels for drug delivery, cell delivery and tissue engineering [1,[4][5][6][7]. PEG is an FDAapproved biomedical polymeric material [3]. ...
Abstract Hydrophilic polymers are very useful in biomedical applications. In this study, biocompatible polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) polymers end‐capped with succinimidyl groups were either modified or synthesised and attached to polyvinylchloride surfaces. The modified surfaces were evaluated with cell adhesion and bacterial adhesion. 3T3 mouse fibroblast cells and three bacteria species were used to evaluate surface adhesion activity. Results showed that the modified surface exhibited significantly reduced 3T3 cell adhesion with a 50%–69% decrease for PEG and a 64%–81% for PVP, as compared to unmodified polyvinylchloride. The modified surface also showed significantly reduced bacterial attachment with 22%–78%, 18%–76% and 20%–75% decrease for PEG and 22%–76%, 18%–76% and 20%–73% for PVP to Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, respectively, as compared to unmodified polyvinylchloride. It seems that an appropriate chain length or molecular weight (neither the longest nor the shortest chain length) determines the lowest cell and bacterial adhesion in terms of PEG. On the other hand, a mixture of polymers with different chain lengths exhibited the lowest cell and bacterial adhesion in terms of PVP.
... TA B L E 1 Hydrodynamic radii of PEG solutions obtained by viscometry (0.1 M KCl) and solution conductivity as changed by PEG addition (20% w/w); adapted from refs. [18,19] insoluble in ethyl ether, hexane, and ethylene glycol [23]. As a result, the PEGs are frequently described as amphiphilic. ...
... PEGs are commercially available in a wide range of MWs and different sizes ( Table 1). The traditionally used PEGs are polydisperse; their MW and chain length are distributed in a certain relatively low range [23]. The monodispersed PEG products with defined discrete MWs are also available. ...
... The PEGs can be used for simple chemical modification of other molecules or surfaces. These attachments do not result in any significant changes in the chemistry of the molecules reacting with the polymers; however, their solubility and dimensions can be favorably altered [23]. PEGs are approved by the FDA for internal consumption and used extensively by pharmaceutical and cosmetic industries for drug compounding, personal care products, and other applications [23,24]. ...
Neutral water-soluble poly(ethylene glycol)s (PEGs) have been extensively explored in protein nanopore research for the past several decades. The principal use of PEGs is to investigate the membrane protein ion channel physical characteristics and transport properties. In addition, protein nanopores are used to study polymer-protein interactions and polymer physicochemical properties. In this review, we focus on the biophysical studies on probing protein ion channels with PEGs, specifically on nanopore sizing by PEG partitioning. We discuss the fluctuation analysis of ion channel currents in response to the PEGs moving within their confined geometries. The advantages, limitations, and recent developments of the approach are also addressed. This article is protected by copyright. All rights reserved.
... un changement de température, de force ionique ou de pH selon le composé) comme phase dispersée permet de favoriser la création des microsphères ou de billes (Millqvist-Fureby, 2014). Pour la phase continue, le polyéthylène glycol est intéressant car il possède un large volume d'exclusion envers les protéines et permet la coacervation des molécules de gélatine (Harris, 1992;Jizomoto, 1985). De plus, il est non toxique, biocompatible et permet de préserver l'activité biologique dans le cas d'encapsulation de substances actives comme des enzymes ou peptides. ...
... Comme cela a été détaillé dans le chapitre 1, paragraphe IV-3.a), le polyéthylène glycol a lui aussi la capacité d'induire une agrégation des molécules de gélatine pour donner des gouttelettes (Harris, 1992;Kong et al., 2011). Le polyéthylène glycol et la gélatine peuvent ainsi former deux phases distinctes grâce aux larges volumes d'exclusion du PEG et à l'absence sur le PEG de sites acides sur lesquels pourraient se fixer les protéines. ...
... (Bhat and Timasheff, 1992). Des concentrations plus importantes en PEG10 favorisent aussi le repliement de la protéine, permettant de former des billes de plus petit diamètre (Harris, 1992 En résumé, les paramètres choisis pour l'élaboration des billes utilisées pour la suite des travaux de cette thèse sont regroupés dans le Tableau 3-4. Ces conditions permettent la formation de billes dont le diamètre déterminé expérimentalement selon la méthode décrite au chapitre 2, paragraphe III-2.g) ...
Ce travail de thèse a pour objectif l’élaboration de supports d’immobilisation d’enzymes bio sourcés en vue de la dégradation de micropolluants dans l’eau. Des billes de gélatine de diamètre moyen 1,9 mm ont été formées dans ce but par un procédé de goutte à goutte n’employant aucun solvant organique. La réticulation des billes par le glutaraldéhyde permet d’une part de limiter le gonflement de ce polymère dans l’eau et d’améliorer sa tenue mécanique en immersion, et d’autre part de créer des liaisons covalentes entre la gélatine et la laccase. Un plan d’expérience 2^4 a été réalisé afin d’identifier les paramètres influant sur l’efficacité du greffage.La dégradation de deux micropolluants par les billes activées a été étudiée en réacteur agité et dans un réacteur à lit fluidisé conçu pour ce projet. La tétracycline s’est montrée sensible à l’oxydation par les laccases greffées à la surface des billes. Divers paramètres ont été étudiés comme le pH de la solution, le débit de recirculation, ou l’addition d’oxygène dans le système. Le glyphosate s’est montré plus récalcitrant à l’action de la laccase seule à cause d’une structure plus complexe. L’ajout d’un médiateur d’oxydoréduction, l’ABTS, a néanmoins permis de faciliter son oxydation. La co-immobilisation du médiateur et du biocatalyseur sur les supports à base de gélatine a été étudiée, afin de limiter l’impact économique et environnemental du projet.
... Polyethylene glycol (PEG) is widely used in various industries such as medicine, chemical, oil, food and pharmaceutical industries. [1][2][3][4][5][6] Because most of applications of PEG occur in an aqueous environment, studying the interaction of PEG with water is of great interest. The hydration number -the amount of water molecules bound to PEG by strong hydrogen bonds between the oxygen atom of the PEG ether and the hydrogen atoms of the water molecules in solution, effectively characterizes this interaction. ...
... The calculated values of effective hydration numbers per monomer ( h n ) (where n is the degree of polymerization), determined by the proposed model using formula (5) and known viscometric data, [17] are presented in Table 1 and in Figure 2. The hydration numbers per monomer, determined by other authors by viscometry [11,17,19,20,30] are also shown there for comparison. ...
Due to the high solubility in water and the structural compatibility of polyethylene glycol with water molecules, it is a good model system for studying the mechanisms of interaction between water and biopolymers. The behavior of biopolymers in living organisms strongly depends on the hydration of macromolecules in the aquatic environment. In this work the effective hydration numbers of polyethylene glycols are determined using a new viscosity model developed for electrolytes and experimental data on the viscosity of dilute aqueous solutions of polyethylene glycols (300–35000). The calculated hydration numbers are in good agreement with the literature data and increase with increasing molecular mass of polyethylene glycol: as the molecular mass increases, starting from a molecular mass of 1000, the chain begins to fold in on itself, forming segment‐segment interactions, trapping additional, more loosely bound water between the segments. Based on the dependence of the intrinsic viscosity on the molecular mass according to the Mark‐Houwink equation, it is shown that PEGs are the flexible polymers and highly soluble in water.
... A large number of hydrogels based on natural polymers such as alginates (ALG), hyaluronic acid (HA), collagens, gelatins, chitosan, and cellulose have been used as printable materials in the treatment of wound healing [72,82,[95][96][97][98][99][100][101][102][103][104][105]. To facilitate and improve the resolution of 3D printing objects, synthetic biopolymers can be incorporated together with natural biopolymers and APIs [88,[106][107][108][109][110][111][112][113]. Table II summarizes the characteristics of the biopolymers and characteristics of the inks most commonly used in bioprinting/3D printing. ...
... Poly (ethylene glycol) diacrylate (PEGDA) is one of the best materials to use in stereolithographic 3D printing for biological applications because it is UV light curable. [108,109] Polyglycolic acid (PGA) y-PGA is a water-soluble polymer obtained by in natura microbial fermentation. It is non-toxic, biodegradable, and biocompatible. ...
Wound healing is a dynamic process which involves stages of hemostasis, inflammation, proliferation and remodeling. Any error in this process results in abnormal wound healing, generating financial burdens for health systems and even affecting the physical and mental health of the patient. Traditional dressings do not meet the complexities of ideal treatment in all types of wounds. For this reason, in the last decades, different materials for drug delivery and for the treatment of wounds have been proposed reaching novel level of standards, such as 3D printing techniques. The use of natural or synthetic polymers, and the correct design of these printed products loaded with cells and/or combined with active compounds, can generate an effective system for the treatment of wounds, improving the healing process and generating customized dressings according to the patient needs. This manuscript provides a comprehensive review of different types of 3D printing techniques, as well as its use in wound healing and its different stages, including the advantages and limitations of additive manufacturing and future perspectives.Graphical abstract
... Poly(ethylene glycol) (PEG) has been established as a key class of biocompatible hydrophilic polymer. Due to its high-water solubility and antifouling behavior in combination with efficient largescale production, this ''gold standard" has been extensively studied, particularly in the biomedical and cosmetic fields, where PEG and its derivatives are used as surfactants, cleansers, emulsifiers, or dispersing agents and as the most widely used polymers for drug delivery through so-called PEGylation [1][2][3][4][5]. ...
... After two more precipitations following the previous conditions, the pure block copolymer was obtained as a white solid after one week drying in vacuum oven (5.61 g, 89% yield). 1 Figure S1) SEC (DMA) Mn = 6.7 kg/mol (Ɖ 1.11) and PhOx (P) in the final copolymers. B stands for block and G for gradient copolymers. ...
Hypothesis
Poly(2-alkyl/aryl-oxazoline)s (PAOx) have seen a resurgence of interest in the new millennium due to their biocompatibility, low toxicity, and higher tunability compared to poly(ethylene glycol) (PEG). Due to the straightforward access to hydrophilic and hydrophobic PAOx, it was hypothesized that amphiphilic PAOx should be capable of stabilizing oil/water (O/W) interfaces. Furthermore, the control of their composition, chain length, and monomer distribution could suggest the formulation of tunable emulsions. Special emphasis was given to evaluate whether spontaneously formed amphiphilic gradient copolymer could stabilize O/W emulsions.
Experiments
We prepared a series of amphiphilic block and gradient copolymers based on 2-methyl-2-oxazoline and 2-phenyl-2-oxazoline with variable hydrophilic/lipophilic balance, degree of polymerization, and monomer distribution as basis to explore their ability to stabilize emulsions. Systematic granulometry, stability, and rheology studies were performed to characterize the final emulsions.
Findings
Remarkably, stable O/W emulsions are obtained with only 0.5 wt.% of copolymers. The finer emulsions stabilized by the most hydrophilic copoly(2-oxazoline)s allow an adjustment of their texture, as well as the concentration increase and oil content. Importantly, emulsion properties prepared with gradient copolymers show similar behavior compared with their block counterparts offering easy access to new biocompatible emulsifiers as these gradient copolymers are spontaneously formed by statistical copolymerization.
... Poly ethylene glycol (PEG) is a biocompatible polymer. PEG has pretty hydrophilicity and can reduce the adhesion of proteins, platelets, and bacteria (Elbert and Hubbell, 1998;Park et al., 1998;Chen et al., 2000;Kenausis et al., 2000;Razatos et al., 2000;Zhu et al., 2001;Harris, 2013). Then antiadhesion is due to the strong hydrophilicity of polyethylene glycol, which forms a water layer on the surface. ...
... Then antiadhesion is due to the strong hydrophilicity of polyethylene glycol, which forms a water layer on the surface. The layer can reduce the adsorption of proteins (Harder et al., 1998;Feldman et al., 1999;Harris, 2013). PEG can connect with different terminal functional groups to reduce the protein adhesion to different extents. ...
Most oral diseases originate from biofilms whose formation is originated from the adhesion of salivary proteins and pioneer bacteria. Therefore, antimicrobial materials are mainly based on bactericidal methods, most of which have drug resistance and toxicity. Natural antifouling surfaces inspire new antibacterial strategies. The super wettable surfaces of lotus leaves and fish scales prompt design of biomimetic oral materials covered or mixed with super wettable materials to prevent adhesion. Bioinspired slippery surfaces come from pitcher plants, whose porous surfaces are infiltrated with lubricating liquid to form superhydrophobic surfaces to reduce the contact with liquids. It is believed that these new methods could provide promising directions for oral antimicrobial practice, improving antimicrobial efficacy.
... Inter alia, research and application in drug, protein and gene delivery systems [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] self-assembled polymers [19][20][21][22][23], nanoreactors [24,25], bioimaging contrast agent carriers [26], anti-biofouling coatings [13,[27][28][29], sensors [30,31], tissue engineering [32][33][34] requires specifically designed polymers with suitable functionalities for appropriate bioconjugation and further biomedical application [35][36][37]. Among the plethora of synthetic polymers, poly(ethylene glycol) (PEG) remains the commercially available "gold standard" for biomedical application due to its high hydrophilicity combined with good solubility in organic solvents [38], low toxicity [39], and stealth behavior [40]. In addition, structural varieties such as star-PEG and a considerable diversity of end-group functionalization [38,[41][42][43] are commercially available. ...
... Among the plethora of synthetic polymers, poly(ethylene glycol) (PEG) remains the commercially available "gold standard" for biomedical application due to its high hydrophilicity combined with good solubility in organic solvents [38], low toxicity [39], and stealth behavior [40]. In addition, structural varieties such as star-PEG and a considerable diversity of end-group functionalization [38,[41][42][43] are commercially available. Despite PEG being generally regarded safe, antibodies against PEG [44][45][46][47] and some other limitations such as toxic side products [48,49], hypersensitivity [50,51], vacuolization [52][53][54] and accumulation in the body [40,54,55] were reported. ...
Here we introduce a post-polymerization modification method of an α-terminal functionalized poly-(N-methyl-glycine), also known as polysarcosine. We utilized 4-(methylthio)phenyl piperidine-4-carboxylate as an initiator for the ring-opening polymerization of N-methyl-glycine-N-carboxyanhydride followed by oxidation of the thioester group to yield an α-terminal reactive 4-(methylsulfonyl)phenyl piperidine-4-carboxylate polymer. This represents an activated carboxylic acid terminus, allowing straightforward modification with nucleophiles under mild reaction conditions and provides the possibility to introduce a wide variety of nucleophiles as exemplified using small molecules, fluorescent dyes and model proteins. The new initiator yielded polymers with well-defined molar mass, low dispersity and high end-group fidelity, as observed by gel permeation chromatography (GPC), nuclear magnetic resonance (NMR) spectroscopy and matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectroscopy. The introduced method could be of great interest for bioconjugation, but requires optimization, especially for protein conjugation.
This article is protected by copyright. All rights reserved
... Inter alia, research and application in drug, protein and gene delivery systems [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] self-assembled polymers [19][20][21][22][23], nanoreactors [24,25], bioimaging contrast agent carriers [26], anti-biofouling coatings [13,[27][28][29], sensors [30,31], tissue engineering [32][33][34] requires specifically designed polymers with suitable functionalities for appropriate bioconjugation and further biomedical application [35][36][37]. Among the plethora of synthetic polymers, poly(ethylene glycol) (PEG) remains the commercially available "gold standard "for biomedical application due to its high hydrophilicity combined with good solubility in organic solvents [38], low toxicity [39], and stealth behavior [40]. In addition, structural varieties such as star-PEG and a considerable diversity of endgroup functionalization [38,[41][42][43] are commercially available. ...
... Among the plethora of synthetic polymers, poly(ethylene glycol) (PEG) remains the commercially available "gold standard "for biomedical application due to its high hydrophilicity combined with good solubility in organic solvents [38], low toxicity [39], and stealth behavior [40]. In addition, structural varieties such as star-PEG and a considerable diversity of endgroup functionalization [38,[41][42][43] are commercially available. Despite PEG being generally regarded safe, antibodies against PEG [44][45][46][47] and some other limitations such as toxic side products [48,49], hypersensitivity [50,51], vacuolization [52][53][54] and accumulation in the body [40,54,55] were reported. ...
Here we introduce a post-polymerization modification method of an α-terminal functionalized poly-(N-methyl-glycine), also known as polysarcosine. We utilized 4-(methylthio)phenyl piperidine-4-carboxylate as an initiator for the ring-opening polymerization of N-methyl-glycine-N-carboxyanhydride followed by oxidation of the thioester group to yield an α-terminal reactive 4-(methylsulfonyl)phenyl piperidine-4-carboxylate polymer. This represents an activated carboxylic acid terminus, allowing straightforward modification with nucleophiles under mild reaction conditions and provides the possibility to introduce a wide variety of nucleophiles as exemplified using small molecules, fluorescent dyes and model proteins. The new initiator yielded polymers with well-defined molar mass, low dispersity and high end-group fidelity, as observed by gel permeation chromatography (GPC), nuclear magnetic resonance (NMR) spectroscopy and matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectroscopy. The introduced method could be of great interest for bioconjugation, but requires optimization, especially for protein conjugation.
... PEG-based surfactants are widely used in pharmaceutical industries, as household and cleaning products, food industries, agriculture and various biotechnology applications. [9][10][11][12][13][14] Their performance can be improved with the addition of different solvents. There have been numerous studies has been conducted regarding the properties of PEG in water. ...
Polyethylene glycol monododecanoate (PEGMD) is a widely used nonionic surfactant in the industry and this study aims to examine its physicochemical properties in water and organic solvents namely methanol, ethanol, and 2-propanol. Simulations were carried out via GROMACS simulation package. A multitude of tests were carried out to evaluate the dihedral angle distribution, radius of gyration, spatial density function (SDF) and solvent accessible surface areas (SAS) calculation. It was found that gyration radius shows that water has the highest degree of compactness followed by methanol, ethanol, and propanol. Dihedral angle distribution instead shows that PEGMD in water exists in three conformations i.e., gauche-, gauche + and trans states while in organic alcohols only in gauche- and gauche + states, albeit at differing population preferences, with methanol being almost equally distributed, ethanol preferring gauche + and propanol gauche-. SDF maps show an irregular, bean-shaped density distribution covering a single PEGMD molecule while the SAS revealed that surface area available for hydrophobic interaction in all four systems exceed that of hydrophilic systems at a ratio of 3:1. Reasons and explanations for the observations are discussed.
... In addition, the authors tried to covalently conjugate the QHREDGS peptide with a non-adhesive polyethylene glycol (PEG) hydrogel and showed the significant action of the peptide in enhancing cell adhesion to the hydrogel [124]. Using a PEG hydrogel for testing peptide adhesion is advantageous as PEG surfaces are repellent to the adsorption of non-specific proteins compared with the non-specific binding of other plastic culture surfaces [125]. Further investigations on the effect of QHREDGS peptide immobilization on maintaining the undifferentiated status after several cell passaging are required. ...
Peptides, short protein fragments, can emulate the functions of their full-length native counterparts. Peptides are considered potent recombinant protein alternatives due to their specificity, high stability, low production cost, and ability to be easily tailored and immobilized. Stem cell proliferation and differentiation processes are orchestrated by an intricate interaction between numerous growth factors and proteins and their target receptors and ligands. Various growth factors, functional proteins, and cellular matrix-derived peptides efficiently enhance stem cell adhesion, proliferation, and directed differentiation. For that, peptides can be immobilized on a culture plate or conjugated to scaffolds, such as hydrogels or synthetic matrices. In this review, we assess the applications of a variety of peptides in stem cell adhesion, culture, organoid assembly, proliferation, and differentiation, describing the shortcomings of recombinant proteins and their full-length counterparts. Furthermore, we discuss the challenges of peptide applications in stem cell culture and materials design, as well as provide a brief outlook on future directions to advance peptide applications in boosting stem cell quality and scalability for clinical applications in tissue regeneration.
... The polyethylene glycol (PEG), a synthetic polymer, is soluble in both aqueous and organic solvents, therefore it can interact with both the intra-and extra-cellular spaces, which provides an environment beneficial to cellular infiltration and growth (Harris 1992). It has been widely used in biomedical engineering, such as regeneration of nerves, articular cartilage and bladder tissue (Yamawaki, Taguchi et al., 2017). ...
Most injuries are accompanied by acute bleeding. Hemostasis is necessary to relieve pain and reduce mortality in these accidents. In recent years, the traditional hemostatic materials, including inorganic, protein-based, polysaccharide-based and synthetic materials have been widely used in the clinic. The most prominent of these are biodegradable collagen sponges (Helistat®, United States), gelatin sponges (Ethicon®, SURGIFOAM®, United States), chitosan (AllaQuixTM, ChitoSAMTM, United States), cellulose (Tabotamp®, SURGICEL®, United States), and the newly investigated extracellular matrix gels, etc. Although these materials have excellent hemostatic properties, they also have their advantages and disadvantages. In this review, the performance characteristics, hemostatic effects, applications and hemostatic mechanisms of various biomaterials mentioned above are presented, followed by several strategies to improve hemostasis, including modification of single materials, blending of multiple materials, design of self-assembled peptides and their hybrid materials. Finally, the exploration of more novel hemostatic biomaterials and relative coagulation mechanisms will be essential for future research on hemostatic methods.
... Fluctuations from Polymer Adsorption in Nanopores Resistive pulse sensing with nanopores has seen widespread use for studies of polymer transport, and poly-ethylene glycol (PEG) in particular has frequently been used as a model polymer for sensing with biological pores [32,116,117], due to its biocompatability and high solubility [118]. These studies have provided great insight both into the transport properties of the polymer and into details of the pore itself. ...
Channel transport is an important physical process, with relevance to diverse fields from cell biology to single molecule sensors, catalysts and filters. Given the ubiquitous nature of channel transport phenomena, achieving a deep understanding of their governing dynamics is ever more desirable. Experimental model systems provide powerful platforms to probe these dynamics. This thesis presents experimental investigations into the fundamental phenomena governing transport through confining channels, in particular the role of fluctuations in such processes. In sensing fields, fluctuations, or noise, are considered undesirable, however careful study of their spectral composition can yield deep insight into underlying physical mechanisms. To achieve a broad understanding over multiple length scales, two experimental models are exploited: the first centred on probing currents of ions through nanoscale glass pores and the second, the flow of colloidal particles through a microfluidic channel. Studies in nanopores begin with an investigation into the intrinsic fluctuations in the ionic current flowing through the pore. A careful study of the 1/f noise present at low frequencies shows that this regime is dominated by fluctuations in the surface current rather than bulk current. Building on this, fluctuations associated with polymer adsorption in the pores are considered. It is found that adsorption generates a characteristic change in current fluctuations which depends sensitively on experimental conditions. Careful analysis of the change in fluctuations yields information on the underlying shape of the adsorption potential on the scale of a single polymer. Next, to probe fluctuations in observable currents of particles, colloidal flow through microfluidic channels is studied using optical microscopy. By using colloids which sediment into a quasi-2D monolayer, the entire transport process can be visualised in detail. To characterise the system, the capture dynamics in two different microfluidic geometries is probed. The importance of long range behaviour to the capture process is demonstrated by showing that drastically different capture rates can be achieved even when conditions within the channel itself are held constant. Fluctuations in the colloidal currents through microchannels are then studied. We start with a model from classical electronics for shot noise in a system with a single characteristic transit time, which is then modified to account for a distribution of transit times, arising from the distribution of particle speeds within the channel. Excellent agreement is found between the spectra of fluctuations for measured currents and those predicted by the modified model, with the particle speed distribution representing the key input into the model. By presenting a series of studies in multiple experimental model systems, this work represents an advancement in the understanding of channel transport fluctuations, and demonstrates the untapped potential of fluctuations analysis as a method of probing physical processes at the micro- and nano-scale. Characterising these systems lays the groundwork for further studies of fluctuating transport in the future, opening the door to more detailed models of molecular transport, cellular processes, and all confined motion on the sub-micrometre scale.
... Iron oxide nanoparticles (IONPs) are physically and chemically inert materials, and present unique characteristics for niche applications such as imaging, biosensors, targeted drug and gene delivery, immunoassays, hyperthermia, magnetic resonance imaging, DNA and nucleic acid separation, pathogen detection, protein purification, etc. [1][2][3][4][5][6][7]. Their distinct properties such as superparamagnetic behavior, low toxicity, biocompatibility, and persistent magnetic properties have exemplified them as an ideal candidate for these applications [8,9]. ...
Here, we used experiments and Monte Carlo simulations (MC) to identify appropriate poly (ethylene) glycol (PEG) polymer molecular weight (Mw) as the coating agent for iron oxide nanoparticles (IONPs) resulting in individual particles in water. IONPs coated with PEG Mw’s ranging from 1500 to 6000 Da showed highly stable dispersions for more than a year. Transmission electron microscopy (TEM) results of the dispersions revealed that particles coated with lower PEG Mw were aggregated, which shifted to individual form with increasing PEG Mw used for coating. We find that this transformation is due to increased PEG layer shell thickness (from 1.47 to 6.46 nm) with increasing PEG Mw (from 1500 to 6000 Da), which imparted sufficient repulsive steric forces to overcome the attractive van der Waals and magnetic forces. To predict appropriate PEG Mw resulting individual IONPs in water, the number density distribution of different PEG Mw coated particles was determined using MC simulation which employs interparticle potentials between the interacting particles as a function of their interparticle distance. The predictions gave very good agreement with our’s and others’ experimental data. Thus, the study helps to identify a suitable polymer Mw as a coating agent, resulting in individual nanoparticle dispersion.
... Increasing the reaction temperature and time with high vacuum support to remove the byproduct (H 2 O), subsequently, the reaction equilibrium can be shifted toward the polymerization [21] . PEG is water soluble and one of the safest materials [22] employed in biomedical field. Therefore, it is often employed as a vital building block in several polymer based biomaterials. ...
A range of D-sorbitol/D-mannitol incorporated co-polymers were synthesized via solvent free enzyme catalyzed polycondensation with adipic acid and polyethylene glycol. In-vitro cytotoxic studies on breast cancer and fibroblast cell lines showed that the co-polymers are biocompatible up to 500 and 250 µg/mL, respectively. However, THP-1 and RAW 264.7 cell lines showed a dose dependent cytotoxicity. Furthermore, these co-polymers did not produce excessive cytokines (TNFα/IL-6) and chemokines (CXCL-5/CXCL-10) when interacting with THP-1 cells, thereby, not causing any inflammation. Whilst, the expression of IL-1b, CXCL-1 and IFNβ were upregulated. The results suggest that these co-polymers could be promising vaccine adjuvants.
... Introduction Polyethylene glycol (PEG) is commonly used as bio-compatible additive in bulk and on surfaces 1 . In the last decade, PEG and its monomer have been widely used as cryoprotectants of human Langmuir 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 embryonic stem cells (hES) cryopreservation, for example. ...
... These nonbranched PEG ligands have large exclusion volumes due to their high conformational entropy, and high resistance to biomolecules adsorption via steric repulsion. [59][60][61] Moreover, PEG modification is considered to be the best biocompatible material to mitigate QDs-induced adverse effects. [62][63][64] It forms a fencelike structure on the QD surface, which can effectively prevent the chemical degradation of QDs and the release of metal ions to the intracellular environment. ...
The use of synthetic nanomaterials as contrast agents, sensors, and drug delivery vehicles in biological research primarily requires effective approaches for intracellular delivery. Recently, the well-accepted microelectrophoresis technique has been reported to exhibit the ability to deliver nanomaterials, quantum dots (QDs) as an example, into live cells, but information about cell viability and intracellular fate of delivered nanomaterials is yet to be provided. Here we show that cell viability following microelectrophoresis of QDs is strongly correlated with the amount of delivered QDs, which can be finely controlled by tuning the ejection duration to maintain long-term cell survival. We reveal that microelectrophoretic delivered QDs distribute homogeneously and present pure Brownian diffusion inside the cytoplasm without endosomal entrapment, having great potential for the study of dynamic intracellular events. We validate that microelectrophoresis is a powerful technique for the effective intracellular delivery of QDs and potentially various functional nanomaterials in biological research.
... These materials are designed to keep bacteria in a planktonic (swimming) state [43][44][45] and thus more susceptible to antibiotics and the host immune system 10 . Non-fouling, 'bio-passive' polymer brush surfaces, such as hydrophilic polyethylene glycol (PEG) are effective, but tend to fail after a period of days [46][47] . Slippery liquid infused porous surfaces (SLIPS) show highly-effective, long term anti-fouling properties but clinical performance is still unclear 48 . ...
... PAGs were proposed as lubricants and shale stabilizers in the 1980s [3] , and several WBDF formulations containing PAGs have been patented [4][5][6] . The PAGs may play multiple roles such as drill lubrication, bit balling prevention, loss circulation control and shale hydration inhibition when be used as additives in WBDF due to their low cost, chemical and thermal stability, as well as their biodegradable, non-toxic and non-corrosive characteristics [7][8] . As shale stabilizers, they have shown a better performance in the presence of KCl [9][10] . ...
The mechanism of the hydrophobized poly(ethylene glycol) (PEG)/K⁺ system inhibiting shale hydration was studied by laboratory experiment. The inhibition performance was evaluated through cuttings hot-rolling dispersion, bentonite inhibition and contact angle tests. The inhibition became stronger as contact angle and PEG concentration increased. A modified cuttings hot-rolling dispersion experiment suggested that these molecular systems did not act through the thermally activated mud emulsion (TAME) mechanism. The interaction of the PEG/K⁺ with clay samples was investigated through adsorption studies and by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). The adsorption isotherms showed that the presence of K⁺ increased the PEG affinity for the clay surface. This inhibition effect was accompanied by a reduction of the bentonite hydration with PEG adsorption, evidenced by FT-IR, TGA and differential thermogravimetric (DTG) curves. XRD patterns were conclusive in showing that the presence of K⁺ ions limited the expansion of the clay interlamellar region to only one PEG layer, and the terminal hydrophobic segments of the PEG chains turned out to be determinant in enhancement of the inhibitory efficiency. The cuttings hot-rolling dispersion was carried out on water-base drilling fluid with PEG/K⁺, which proved the inhibition performance of PEG/K⁺ in oil field drilling.
This chapter is dedicated to explaining the principle of PEGylation in the solubilization of nanocarriers for pharmaceutical and biomedical applications, in addition to the enhancement of the propensity of these carriers to solubilize drugs. The chapter introduces the general rationale for nanocarrier PEGylation with a specific focus on the topic of solubilization in addition to the solubility characteristics of PEG. PEGylated small molecular weight drugs and proteins are briefly introduced to emphasize the stages of pharmaceutical solubilization by PEGylation. Furthermore, protein PEGylation as a means to solubilize enzymes and proteins for facilitated nanoparticle production is highlighted. Proposed mechanisms and factors affecting the drug solubilization propensity of PEGylated nanocarriers are also explored. Illustrative examples and reviewed applications are included wherever appropriate.
The coating of the exterior of nanocarriers with polyethylene glycol (PEG; known as “PEGylation”), has emerged as one of the most widely adopted approaches to impart stealth properties to pharmaceutical nanocarrier systems. The PEGylation tactic offers a stealth barrier towards the adsorption of circulatory proteins owing to its hydrophilicity, elasticity, neutralization, and hydration properties. PEGylation dramatically provides sustained drug release benefits, reduces immune sensitivity, as well as improves the systemic circulation period, Overall, PEGylation effectively improves the therapeutic efficacy of the loaded therapeutic moiety in treating target cells and tissues. This chapter offers discussion on drug delivery nanosystems that are developed based on the principle of PEGylation strategy. Furthermore, a detailed account of the pharmaceutical and biomedical applications of PEGylated nanocarriers has also been presented in detail.
It is crucial to comprehend protein misfolding and aggregation in the domains of biomedicine, pharmaceuticals, and proteins. Amyloid fibrils are formed when proteins misfold and assemble, resulting in the debilitating illness known as “amyloidosis”. This work investigates lysozyme fibrillation with pluronics (F68 and F127). The effect of pluronics on protein aggregation and fibrillation has been studied mechanistically using a combination of calorimetric and spectroscopic techniques. TEM images and the ThT binding experiment were used to analyze the conformation of protein fibrils, and the results showed that pluronics accelerated the fibrillation process. When pluronics interact with protein at different stages of fibrillation, their pre- and postmicellar concentrations show a decrease in ΔHm° value as the time of incubation increases. This indicates the formation of amorphous aggregates due to which endothermic enthalpy is observed. As a consequence, it was investigated if these generated aggregates can also act as drug delivery vehicle; therefore, the work was carried out with 5-fluorouracil and cytarabine. The endothermic enthalpy of interaction suggests that hydrophobic interaction is more prevalent when cytarabine is employed with protein fibrils, whereas the electrostatic interaction is more prevalent when 5-fluorouracil is combined with it. The former drug, however, showed a greater adsorption than the latter on the surface of protein fibrils. It is therefore determined that 5-fluorouracil has relatively significant adsorption on fibril surfaces, whereas cytarabine has weak adsorption and is easily desorbed in cells. Consequently, the combination of LFF127 and 5-FU is lethal to malignant cells. The drug encapsulation and delivery aspect of protein fibrils/aggregates needs further exploration.
Polyethylene glycol (PEG) is a water soluble, non-ionic polymer with applications in drug delivery, protein precipitation, anti-biofouling, water-splitting, Li-ion batteries, and fuel cells. The interaction of PEG with water and electrolytes plays pivotal roles in such applications. Using interface-selective spectroscopy, heterodyne-detected vibrational sum frequency generation, and Raman difference spectroscopy with simultaneous curve fitting analysis, we show that water adopts different structures and orientations at the air/water–PEG interface, which depends on the molar mass of the PEG. At the air/water–PEG4000 (MW 4000u) interface, water is H-up oriented (i.e., water Hs are pointed away from the aqueous bulk) around 3200 cm⁻¹ and H-down oriented (i.e., water Hs are pointed toward the aqueous bulk) around 3470 cm⁻¹. Variation of the bulk concentration of PEG4000 does not change the dual orientation of interfacial water. The presence of an electrolyte (1.0M NaCl) selectively reduces the H-up oriented water without affecting the H-down oriented water at the air/water–PEG4000 interface. The selective reorganization of the interfacial water is assigned to the disruption of the asymmetric hydration around ether-oxygen of the surface-adsorbed PEG4000 by the Na⁺ ion of the electrolyte. Interestingly, in the case of low molar mass PEG (air/water–PEG200), the interfacial water neither shows the dual orientation nor is affected by 1.0M NaCl.
Nanocarriers in cancer treatment are important for transport and release of insoluble drugs. In this work, block thermo- and pH-responsive copolymers based on poly(di(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate) (PDO) and poly(2-(N,N-diethylamino)ethyl methacrylate) (PDEA) were tested. At pH 7.4 and 37 °C, the title polymers formed micelles which were used for the loading and release of diorganotin(IV) complexes (LSnR2), where L is a Schiff base ligand and R = n-butyl (LSnBu2) or cyclohexyl (LSnCy2). Results revealed that the PDO-b-PDE block copolymers could enhance the solubility of LSnR2(IV) compounds in PBS at pH = 7.4, resulting in good loading capacity (%DLC) and loading efficiency (%DLE), and better release performance (pH-dependent and T-dependent) than the free compound. In vitro cytotoxic activity was evaluated by the sulforhodamine B (SRB) assay against a normal cell line, African green monkey kidney fibroblast (COS-7) and seven human cancer cell lines prostate (PC-3), leukemia (K-562), colon (HCT-15), lung (SKLU-1), central nervous system glia (U-251), breast Strogen receptor-positive (MCF-7) and breast hormone-independent (MDA-MB-231). The non-loaded block copolymers were non-cytotoxic, but the loaded ones showed high cell growth inhibition against human cancer cell lines. Results confirmed that these temperature and pH-sensitive polymeric systems are excellent candidates for the loading and release of potential metallodrugs, such as LSnR2, against diverse types of cancers.
The unique physicochemical properties of PEG-400 were imparted to (L)-prolinamide to afford a homogeneous, solvent-free, recyclable organocatalyst for scalable enantioselective aldol reaction between acetone and benzaldehyde to afford (R)-4-hydroxy-4-phenylbutan-2-one. The reaction was scaled up to afford 41 g of ketol in 95% yield and an ee of 91% using 30 mol% catalyst, 10 mol% trifluoroacetic acid (TFA), and 135 equivalent moles of acetone with respect to benzaldehyde. The catalyst was recycled 4 times with no obvious loss of activity. The role of PEG is discussed at the molecular level. This type of catalyst may provide new possibilities for the so-far-thwarted attempts at large-scale application of proline organocatalysis to asymmetric aldol reactions.
Graphical Abstract
Polymer blend systems offer a versatile approach for tailoring the properties of polymer materials for specific applications. In this study, we investigated the compatibility of polybutylene terephthalate (PBT) and poly(ethylene glycol) (PEG) blends processed using a twin‐screw extruder, with the aim of enhancing their compatibility. Phthalic anhydride (PAn) and phthalic acid (PAc) were used as potential compatibilizers at different concentrations to improve interfacial interactions between PBT and PEG. Blend morphologies were characterized using scanning electron microscopy, which revealed improved interfacial compatibility and reduced phase separation with the incorporation of small amounts of PAn and PAc. Differential scanning calorimetry analysis indicated changes in the melting temperature (Tm) and glass transition temperature (Tg) of the blends owing to the compatibilizing effects of PAn and PAc. Dynamic mechanical analysis further corroborated the influence of the compatibilizers on the Tg and viscoelastic behavior. Thermogravimetric analysis demonstrated enhanced thermal stability with the addition of either PAn or PAc. Rheological measurements indicated an increase in complex viscosity with increasing compatibilizer content, indicating improved compatibility. The degradation point (Td) of PBT/PEG blend increased from 158 to 200 and 319°C with the incorporation of 5 phr PAn and 2 phr PAc, respectively. Mechanical properties, including tensile strength, Young's modulus, and Izod impact strength, were evaluated. For instance, the tensile strength of PBT/PEG blend was enhanced from 43.5 to 48.7 and 49.7 MPa by incorporating 5 phr PAn and 2 phr PAc, respectively. However, the impact strength of PBT/PEG blend increased from 3.0 to 4.3 and 4.2 kJ/m² with the addition of 1 phr PAn and 1 phr PAc, respectively. The findings demonstrated that adding 5 phr PAn or 2 phr PAc to the PBT/PEG blends was advantageous, achieving a harmony of performance benefits and compromises. Rheological observations contributed significantly to the mechanical and thermal properties. Overall, the study highlights the significance of utilizing PAn and PAc as effective compatibilizers for enhancing the properties of PBT/PEG blends, making them potential candidates for various applications.
Polyethylene glycol (PEG), a water-soluble non-ionic polymer, finds diverse applications from Li-ion batteries to drug delivery. The effectiveness of PEG in these contexts hinges on water’s behavior at PEG/water interfaces. Employing heterodyne-detected vibrational sum frequency generation and Raman spectroscopy along with a novel analytical approach, termed difference spectroscopy with simultaneous curve-fitting analysis, we observed that water exhibits both “hydrogen-up” and “hydrogen-down” orientations at PEG(≥400u)/water interfaces. As the molar mass of PEG increases, the contribution of the strongly hydrogen-bonded and H-up-oriented water rises. We propose that the PEG-affected interfacial water originates from the asymmetrical hydration of the surface-adsorbed PEG, as evidenced by the resemblance between the water spectra in the hydration shell of PEG and those at the PEG/water interface. These findings elucidate the molecular mechanism underlying PEG’s catalytic role in water splitting at membrane interfaces.
Biomimetic materials are able to mimic the structure and functional properties of native tissues especially natural oral tissues. They have attracted growing attention for their potential to achieve configurable and functional reconstruction in oral medicine. Though tremendous progress has been made regarding biomimetic materials, significant challenges still remain in terms of controversy on the mechanism of tooth tissue regeneration, lack of options for manufacturing such materials and insufficiency of in vivo experimental tests in related fields. In this review, the biomimetic materials used in oral medicine are summarized systematically, including tooth defect, tooth loss, periodontal diseases and maxillofacial bone defect. Various theoretical foundations of biomimetic materials research are reviewed, introducing the current and pertinent results. The benefits and limitations of these materials are summed up at the same time. Finally, challenges and potential of this field are discussed. This review provides the framework and support for further research in addition to giving a generally novel and fundamental basis for the utilization of biomimetic materials in the future.
This study focuses on developing surface coatings with excellent antifouling properties, crucial for applications in the medical, biological, and technical fields, for materials and devices in direct contact with living tissues and bodily fluids such as blood. Our approach combines thermoresponsive poly(2‐alkyl‐2‐oxazoline)s, known for their inherent protein‐repellent characteristics, with established antifouling motifs based on betaines. The polymer framework was constructed from various monomer types, including a novel benzophenone‐modified 2‐oxazoline for photocrosslinking and an azide‐functionalized 2‐oxazoline, allowing subsequent modification with alkyne‐substituted antifouling motifs through copper(I)‐catalyzed azide‐alkyne cycloaddition. From these polymers surface‐attached networks were created on benzophenone‐modified gold substrates via photocrosslinking, resulting in hydrogel coatings with several micrometers thickness when swollen with aqueous media. Given that poly(2‐alkyl‐2‐oxazoline)s can exhibit a lower critical solution temperature in water, we compared their temperature‐dependent solubility to the swelling behavior of the surface‐attached hydrogels upon thermal stimulation. The antifouling performance of these hydrogel coatings in contact with human blood plasma was further evaluated by surface plasmon resonance and optical waveguide spectroscopy. All surfaces demonstrated extremely low retention of blood plasma components, even with undiluted plasma. Notably, hydrogel layers with sulfobetaine moieties allowed efficient penetration by plasma components, which could then be easily removed by rinsing with buffer.
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Neonatal Formulary bridges a gap between a standard formulary (stating doses, indications, etc.) and a standard neonatal textbook by expanding information about the conditions for which each drug is used. Much of drug use during pregnancy, lactation, and in neonates and young infants is ‘off license’ (i.e. using licensed drugs but for an indication that is outside the licensed use—in many cases simply because the studies and the licensing application did not include data about neonatal use). The book offers information to allow practitioners to make informed choices whether to use such a drug or not by presenting data from published studies to support such a use. Part 1 concentrates on drug prescribing and drug administration, presenting general information on drug storage, drug licensing, and drug prescribing. It also explains to the reader why the metabolism of drugs differs in premature and sick infants and why the practice of extrapolating doses from adult studies is wrong. Patient safety, excipients, and therapies that affect drug metabolism (such as therapeutic hypothermia) are also covered. Part 2 consists of drug monographs for over 250 drugs that may find use in the neonatal population but which nonetheless may also find use outside the neonatal unit. Each monograph is divided into sections covering use, pharmacology, treatment, drug interactions, or other administration information, supply, and administration, and references. The monographs also contain links to Cochrane Database of Systematic Reviews and national guidelines supported by bodies such as the National Institute for Health and Care Excellence or the Royal Colleges. Part 3 contains brief notes on a range of additional drugs and groups of drugs that are often taken by mothers during pregnancy, labour, or during breast feeding where effects on either the fetus or infant can be seen. This information will help to provide safe and effective prescribing of drugs to all mothers and their babies.
Nanotechnology allows to develop new approaches for the diagnosis and treatment of cancer. In particular, formulations are developed specifically for the diagnosis purpose. This chapter reviews the development of polymeric theranostic formulations such as polymeric gold nanoparticles, polymeric superparamagnetic nanoparticles, quantum dots-loaded polymeric nanoparticles, dendrimer-loaded polymeric nanoparticles, polymeric micelles, and carbon nanotubes with polymeric nanoparticles. These systems are effective in the treatment of brain cancer, lung cancer, breast cancer, and ovarian cancer.
This chapter discusses current developments concerning recent advances and applications of biomolecule‐responsive hydrogels in medicine via emphasizing this research area with novel literature studies. The discussion is categorized into three main types, namely, glucose‐responsive hydrogels, protein‐responsive hydrogel, and nucleic acid‐responsive hydrogels. The chapter describes their potential applications in drug delivery, cell and cancer research, regenerative medicine and biosensor, and presents some problems as well as the new directions on future developments. Enzyme‐responsive hydrogels are used in the fabrication of degradable biomaterials and native extracellular matrices. Although the ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and the natural nucleic acid‐responsive hydrogels provide the advantages of biocompatibility, they are not stable against temperature and enzymatic cleavage. Peptide nucleic acid, serving as a synthetic nucleic acid not only solved these issues but also indicated stronger binding properties than RNA and DNA.
One of the important electrochemical techniques used to investigate corrosion is electrochemical impedance spectroscopy (EIS). It complements the potentiodynamic polarization (PDP) and linear polarization (LP) techniques used in corrosion studies and is nondestructive. EIS can be used to determine the appropriate potential scan rate to be used in PDP and LP and validate the results. After a brief introduction to EIS, experimental aspects and analysis, specifically to characterize corrosion, are described. Applications of EIS in metal corrosion in a variety of environments are illustrated. Coatings are often employed to protect a surface from corrosion. The effectiveness of coating in enhancing the corrosion resistance is frequently evaluated using EIS. Several circuits used to model the impedance data using equivalent electrical circuits are described. The identification of the circuit elements with the physical components or the processes is also explained. The future scope of the application of EIS to corrosion is outlined, and the main advantages and limitations of this technique are summarized.KeywordsElectrochemical impedance spectroscopyEquivalent electrical circuitPolarization resistance
Graphene oxide (GO), the oxygenated counterpart of one atom thick graphene sheets, has been applied in various biotechnologies such as biosensor, cellular imaging nano-probe, drug delivery, and so on, due to its extremely large surface area, ease of chemical functionalization, good biocompatibility, and biostability. The use of GO brings outs its dispersion behavior along with its ideal mechanical properties. Nano-hydroxyapatite (n-HAP) is a bioactive calcium phosphate ceramic [Ca10(PO4)6(–OH)2] with chemical and crystallographic similarity to that of apatite phases present in bones. The fragile nature of n-HAP prevents its use as load-bearing implants. On the other hand, polyethylene glycol (PEG) earns its fame because of its high structure flexibility, biocompatibility, amphilicity devoid of any steric hindrances, and high hydration capacity. PEG is electrically neutral at all pH with high active functional terminal and is inert in biological environment. In biomedical applications, PEG confers anti-biofouling effect in-vivo and also improves upon the drug targeting and bioavailability besides anti-biofouling. GO and n-HAP composites were deposited on implant materials along with polymers using various coating techniques. This article focuses on electrophoretic deposition and dip coating techniques which can be used to develop hybrid GO-bioceramic deposits on stainless steels and Ti alloys for orthopedic applications along with study of its corrosion behavior. The obtained hybrid-coated samples have been characterized using atomic force microscopy (AFM), FT-IR, optical microscopy, contact angle, porosity, X-ray diffraction spectroscopy, and electrochemical measurements.Graphical Abstract
KeywordsGraphene oxide (GO)Nano-hydroxyapatite (n-HAP)Polyethylene glycol (PEG)Ti alloyElectrophoretic depositionSpin and dip coatingCorrosion resistance
Tissue engineering is a multidisciplinary field that focuses on creating functional tissue through the combination of biomimetic scaffolds, a cell source, and biochemical/physiochemical cues. Stem cells are often used as the cell source due to their multipotent properties and autologous sourcing; however, the combination of physical and chemical cues that regulate their behavior creates challenges in reproducibly directing them to a specific fate. Hydrogel biomaterials are widely explored as tissue scaffolds due to their innate biomimetic properties and tailorability. For these constructs to be successful, properties such as surface chemistry and spatial configuration, stiffness, and degradability of the biomaterial used for the scaffold framework should be analogous to the natural environment of the tissue they are repairing/replacing. This is imperative, as cues from the surrounding extracellular matrix (ECM) influence stem cell behavior and direct cell differentiation to a specific lineage. Hydrogels offer great promise as tools to control stem cell fate, as researchers can modulate the degradation rates, mechanical properties, swelling behavior, and chemical properties of the biomaterial scaffold to mimic the instructive cues of the native ECM. Discussion of the advantages and challenges of utilizing hydrogel biomaterials as the basis of tissue scaffolds is reviewed herein, as well as specific examples of hydrogels in tissue engineering and advances in hydrogel research to achieve desired cell phenotypes.
The metal oxide nanoparticles (NPs), zinc oxide (ZnO) and nickel oxide (NiO) were synthesized using Sterculia foetida (S.foetida) leaf extract by solution combustion method. The Poly(glutaric acid-co-ethylene glycol-co-acrylic acid)(GEA) hydrogel was prepared using three different monomers such as glutaric acid (G), ethylene glycol (E) and acrylic acid (A). The zinc oxide (ZnO) and nickel oxide (NiO) nanoparticles were introduced into GEA hydrogel and the polymer nanocomposites GEA-ZnO and GEA-NiO were obtained. The UV-visible spectroscopy (UV) peak observed at 275 nm and 360 nm for GEA-ZnO and GEA-NiO polymer nanocomposites. The Fourier Transform Infrared (FT-IR) spectral data obtained at 414cm⁻¹ confirmed the presence of nanoparticles in the hydrogel. The size of the nanoparticles were confirmed through Scanning Electron Microscopy (SEM) and Transmission Electron Microscope (TEM) analysis. The size of the zinc oxide nanoparticles (ZnO NPs) introduced in GEA-ZnO polymer nanocomposite was 30 to 35 nm and the size of nickel oxide nanoparticles (NiO NPs) introduced in GEA-NiO nanocomposite was 27 to 33 nm. The percentage of zinc oxide (ZnO) and nickel oxide (NiO) were reported in Energy Dispersive X-ray Analysis (EDAX) spectrum.Where the percentage of zinc (Zn) is 2.22% and nickel (Ni) is 2.7%.The thermal stability of the nanoparticles in the hydrogel was assessed by Thermo gravimetric analysis (TGA). Beyond 450οC there was no change in the Thermo Gravimetric Analysis (TGA) peak of GEA-NiO polymer nanocomposite and found with nil weight loss. The antibacterial activity was performed using Staphylococcus aureus (s.aureus)and Bacillus subtilis (B.subtilis) gram positive bacterial strains and Escherchia coli (E.coli) and Klebsiella pneumoniae (K.pneumoniae) gram negative bacterial strains. The gram positive bacteria showed highest antibacterial activity than gram negative bacteria at highest concentration 100 μg/ml towards polymer nanocomposites.
We have prepared a series of ampholytic polymer films, using a self-initiated photografting and photopolymerization (SI-PGP) method to sequentially polymerize first anionic (deuterated methacrylic acid (dMAA)) and thereafter cationic (2-aminoethyl methacrylate (AEMA)) monomers to investigate the SI-PGP grafting process. Dry films were investigated by ellipsometry, X-ray, and neutron reflectometry, and their swelling was followed over a pH range from 4.5 to 10.5 with spectroscopic ellipsometry. The deuterated monomer allows us to separate the distributions of the two components by neutron reflectometry. Growth of both polymers proceeds via grafting of solution-polymerized fragments to the surface, and also the second layer is primarily grafted to the substrate and not as a continuation of the existing chains. The polymer films are stratified, with one layer of near 1:1 composition and the other layer enriched in one component and located either above or below the former layer. The ellipsometry results show swelling transitions at low and high pH but with no systematic variation in the pH values where these transitions occur. The results suggest that grafting density in SI-PGP-prepared homopolymers could be increased via repeated polymerization steps, but that this process does not necessarily increase the average chain length.
New squalene receptors bearing open-chain polyether ligands (SQ-diEG, SQ-triEG, SQ-tetraEG) were synthesised. The stoichiometries and association constants (Ka) for the interactions between these squalene receptors and representative alkaline earth metal ions (Mg²⁺, Ca²⁺, and Ba²⁺) were determined in solution. Fluorescence spectral studies revealed that the squalene receptors self-associate with critical vesicle concentrations at 25 °C of 2.2 × 10⁻⁵ M for SQ-diEG, 2.3 × 10⁻⁵ M for SQ-triEG, and 2.5 × 10⁻⁵ M for SQ-tetraEG. The self-assembly behaviour was probed using laser diffraction particle size-based analyses and scanning electron microscopy. A decrease in the SQ-tetraEG vesicle size was readily induced by the addition of alkaline earth metal ions, confirmed by cryogenic transmission electron microscopy.
The mechanism of separation methods, for example, liquid chromatography, is realized through rapid multiple adsorption‐desorption steps leading to the dynamic equilibrium state in a mixture of molecules with different partition coefficients. Sorting of colloidal particles, including protein complexes, cells, and viruses, is limited due to a high energy barrier, up to millions kT, required to detach particles from the interface, which is in dramatic contrast to a few kT for small molecules. Such a strong interaction renders particle adsorption quasi‐irreversible. The dynamic adsorption‐desorption equilibrium is approached very slowly, if ever attainable. This limitation is alleviated with a local oscillating repulsive mechanical force generated at the microstructured stimuli‐responsive polymer interface to switch between adsorption and mechanical‐force‐facilitated desorption of the particles. Such a dynamic regime enables the separation of colloidal mixtures based on the particle‐polymer interface affinity, and it could find use in research, diagnostics, and industrial‐scale label‐free sorting of highly asymmetric mixtures of colloids and cells.
The mechanism of separation methods, e.g. liquid chromatography, is realized through rapid multiple adsorption-desorption steps leading to the dynamic equilibrium state in a mixture of molecules with different partition coefficients. Sorting of colloidal particles, including protein complexes, cells, and viruses, is limited due to a high energy barrier, up to millions kT , required to detach particles from the interface, which is in dramatic contrast to a few kT for small molecules. Such a strong interaction renders particle adsorption quasi-irreversible. The dynamic adsorption-desorption equilibrium is approached very slowly, if ever attainable. This limitation is alleviated with a local oscillating repulsive mechanical force generated at the microstructured stimuli-responsive polymer interface to switch between adsorption and mechanical-force-facilitated desorption of the particles. Such a dynamic regime enables the separation of colloidal mixtures based on the particle-polymer interface affinity, and it could find use in research, diagnostics, and industrial-scale label-free sorting of highly asymmetric mixtures of colloids and cells.
Self-regulated “smart” insulin administration system that mimic pancreatic endocrine function would be highly desirable for diabetes management. Here, a glucose-responsive continuous insulin delivery system is developed, where novel polyhedral oligosilsesquioxane (POSS) modified with 3‐aminophenylboronic acid (APBA) were used to encapsulate insulin (insulin entrapment efficiency: 73.2%) to prepare a fast response, high stability, good distribution, and excellent biocompatible system. Due to the strong hydrophobicity of POSS, the POSS moiety is located at the core in aqueous solution and combines with the boronic group of APBA and the diol generated in PEG-insulin to form a nanomicelle structure, that is, nanoparticles naturally. Micelles self‐assembled from these molecules possess glucose‐responsiveness at varying glucose concentrations. The interaction of the PBA and diol containing insulin via boronate ester bond and its interchange with glucose was investigated by FT-IR, 1H NMR and XPS. Furthermore, the successful glucose-triggered release of insulin from the POSS-APBA micelles was investigated at neutral pH. A linear graph was plotted with the measured released insulin vs glucose concentrations, with a linear correlation coefficient (R2) value close to 1. Circular dichroism (CD) spectroscopy analysis was performed to measure insulin activity by comparing secondary structures of insulin, PEG-Insulin, and POSS-APBA@insulin. When confirming intracellular apoptosis signaling, cleaved caspase 3 and caspase 9 were not increased by 640 μg/ml POSS-APBA and POSS-APBA@insulin in HeLa, HDF and HUVE cells. Application in the biomedical field for controlled delivery of insulin appear to be promising.
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In this study, three PEG-maleated rosin polyesters were produced by reacting between maleated rosin and PEG with different molecular weights and served as surfactants. The surface characteristics of these PEG-maleated rosin polyesters were detected. The conformational transition and adsorption characteristics of these polyesters were analyzed with the reorientation theory on the water–air surface. The surfactant mole fraction at the water–air surface increased as surfactant concentration increased, while the solvent mole fraction was decreased. The amount of surfactant on the water–air surface at state 1 with a maximal molar area appeared one unimodal in distribution and that at state 2 occupying a minimal molar area appeared a sigmoid distribution with П growth. The calculated adsorption free energy from CMC value is lower than calculated micellization energy obtained from molecular area at state 2 indicates the polyethylene glycol-maleated rosin polyesters firstly spread on the water–air surface and then aggregated into micelles. The results lay a foundation for better understand the adsorption and self-assembly processes.
Graphical abstract
The adsorption characteristics and conformational transition of three PEG-maleated rosin polyesters were investigated.
Paper title: Adsorption Characteristics and Conformational Transition of Polyethylene Glycol-maleated Rosin Polyesters on the Water–Air Surface
Polydiacetylene (PDA) vesicles provide useful stimuli-responsive behavior as well as by the modular structure afford a means for the design of sensing and delivery systems with tunable target specificity. To reduce inherent non-specific interaction with either anionic or cationic formulations of polydiacetylene vesicles, we explored the use of various lengths of poly(ethylene glycol) (PEG) amphiphiles for integration and polymerization within PDA vesicles. Our results established that as little as 1% of polyethylene glycol amphiphile integration into anionic vesicles was sufficient to significantly reduce non-specific association with mammalian cells. Similarly integrating a low percent of PEG amphiphile content within cationic vesicles could also significantly reduce non-specific cell association, and moreover reduced cytotoxicity. These results may be prove useful in augmenting PDA vesicles formulations for reduced non-specific interaction which is of particularly interest to enhancing selectivity in vesicles designed with integrated targeting moieties for sensing and drug delivery applications.
Protein therapeutics have gained momentum in recent years and become a pillar in treating many diseases and the only choice in several ailments. Protein therapeutics are highly specific, tunable, and less toxic than conventional small drug molecules. However, reaping the full benefits of therapeutic proteins in the clinics is often hindered by issues of immunogenicity and short half‐life due essentially to fast renal clearance and enzymatic degradation. Advances in polymer chemistry and protein engineering allowed overcoming some of these limitations. Strategies to prolong the half‐life of proteins rely on increasing their size and stability and/or fusing them to endogenous proteins (albumin, Fc fragment of antibody) to hijack physiological pathways involved in protein recycling. On the downside, these modifications might alter therapeutic proteins structure and function. Therefore, a compromise between half‐life and activity is sought. This review covers half‐life extension strategies using natural and synthetic polymers as well as fusion to other proteins and sheds light on genetic engineering strategies and chemical and enzymatic reactions to achieve this goal. Promising strategies and successful applications in the clinics are highlighted. In the past decades, breakthroughs in protein engineering strategies have revolutionized the development of long‐acting medicines. Conjugation of polymers, polypeptides, Fc antibody fragments or human serum albumin to a parent therapeutic protein increases its half‐life and modulates protein biological activity.
Covalent conjugation of superoxide dismutase and catalase with polyethylene glycol (PEG) increases the circulatory half-lives of these enzymes from less than 10 min to 40 h, reduces immunogenicity, and decreases sensitivity to proteolysis. Because PEG has surface active properties and can induce cell fusion, we hypothesized that PEG conjugation could enhance cell binding and association of normally membrane-impermeable enzymes. Incubation of cultured porcine aortic endothelial cells with 125I-PEG-catalase or 125I-PEG-superoxide dismutase produced a linear, concentration-dependent increase in cellular enzyme activity and radioactivity. Fluorescently labeled PEG-superoxide dismutase incubated with endothelial cells showed a vesicular localization. Mechanical injury to cell monolayers, which is known to stimulate endocytosis, further increased the uptake of fluorescent PEG-superoxide dismutase. Endothelial cell cultures incubated with PEG-superoxide dismutase and PEG-catalase for 24 h and then extensively washed were protected from the damaging effects of reactive oxygen species derived from exogenous xanthine oxidase as judged by two criteria: decreased release of intracellular 51Cr-labeled proteins and free radical-induced changes in membrane fluidity, measured by electron paramagnetic resonance spectroscopy of endothelial membrane proteins covalently labeled with 4-maleimido-2,2,6,6-tetramethylpiperidinooxyl. Addition of PEG and PEG-conjugated enzymes perturbed the spin-label binding environment, indicative of producing an increase in plasma membrane fluidity. Thus, PEG conjugation to superoxide dismutase and catalase enhances cell association of these enzymes in a manner which increases cellular enzyme activities and provides prolonged protection from partially reduced oxygen species.
Derivatives of poly(ethylene glycol) (PEG) are of importance in a variety of applications. Often it is difficult to determine the identity of the end groups and the purity of these derivatives. In the present work we show that proton NMR spectra of PEGs dissolved in deuterated dimethyl sulfoxide (but not other solvents) reveal a hydroxyl peak at 4.56 (±0.02) ppm, which does not shift or broaden with variation in concentration of the PEG, water, or impurities and which is well separated from the large backbone resonance. The hydroxyl resonance in other solvents does not show this independence, and thus it is difficult to locate and utilize. The PEG hydroxyl resonance for samples in dimethyl sulfoxide is, therefore, well suited for quantifying percent substitution and molecular weight of PEG and derivatives. Use of this method is illustrated.
Methoxypolyethylene glycols of 1900 and 5000 daltons have been attached covalently to bovine serum albumin using cyanuric chloride as the coupling agent. When sufficient polymer is attached, the modified bovine serum albumin appears to lose its immunogenicity in the rabbit and, on intramuscular or intravenous injection, elicits antibodies neither to itself nor to native bovine serum albumin. It does not react with antibodies raised against native bovine serum albumin. Bovine serum albumin to which methoxypolyethylene glycol has been attached exhibits a blood circulating life in the rabbit rather similar to native bovine serum albumin, except that it is not removed from circulation by the eventual development of antibodies. Modified bovine serum albumins which had been iodinated with 125I, or prepared with [14C]cyanuric chloride, were injected intravenously in rabbits. Both labels appeared almost quantitatively in the urine after 30 days. The modified bovine serum albumins showed substantial changes in properties, such as solubility, electrophoretic mobility in acrylamide gel, ion exchange chromatography, and sedimentation, as compared with the unmodified protein.
A simple, rapid and high-yielding method for the synthesis of oligonucleotides by the phosphotriesters approach Is described.
The use of polyethylene glycol (PEG) as soluble polymeric support preserves some convenient features of the solid-phase synthesis
with
new interesting advantages.Short oligonucleotides in hundred milligrams scale can be obtained from few grams of functionalised
PEG.
Recombinant human interleukin 2 purified from Escherichia coli has limited solubility at neutral pH and a short circulatory half-life. This recombinant interleukin 2 was chemically modified by an active ester of polyethylene glycol. The modified interleukin 2 was purified by hydrophobic interaction chromatography and characterized by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and isoelectric focusing. This conjugate was compared to unmodified recombinant interleukin 2 in vitro and in vivo. Covalent attachment of the hydrophilic polymer polyethylene glycol enhanced the solubility of interleukin 2, decreased its plasma clearance, and increased its antitumor potency in the Meth A murine sarcoma model.
Polyethylene glycols (PEG’s) and their derivatives are finding a rapidly expanding range of chemical, biomedical, and industrial applications resulting from their low cost and useful properties such as solubility in aqueous and organic solvents, metal complexing ability, biological compatibility, and ease of chemical modification. The linear polymers have been employed as soluble matrices for liquid-phase peptide synthesis,2 ligands for water-soluble transition metal complexes,3 drug carriers,4 water-soluble cell fusion agents.5 Other reasons for the current interest in PEG’s include their reduction of enzyme immunogenicity,6 and their utility in aqueous two-phase polymer cell separations (phase partitioning).7
The effects of polyethylene-glycol (PEG) substitution on protein activity, us ing alkaline phosphatase as a model, have been studied. Such variables as PEG molecular weight, degree of substitution, and PEG mono- and di-functionality have been examined. Modification with the monomethyl ether of PEG 1900 (M- PEG-1900) does not alter enzyme activity until greater than 40% of the protein lysine groups are substituted, at which point increasing the degree of modifica tion gives increasing deactivation. Substitution with M-PEG-5000 gives more deactivation than does substitution with M-PEG-1900. Interestingly, modifica tion with PEG itself gives active protein conjugates in which there is little de pendence on molecular weight or degree of substitution.
Interspecific and intergeneric fusions of plant protoplasts were induced by polyethylene glycol (PEG) 1540 or 4000. The frequency of heterokaryocyte formation (or rate of fusion) was much higher when PEG was eluted with a high pH-high Ca2+ solution or a salt solution than when it was eluted with a protoplast culture medium. The frequency of heterokaryocyte formation was also affected by the types of enzymes used for wall degradation, duration of enzyme incubation and molality of the PEG solutions.
The maximum frequency of heterokaryocyte formation was 23% for V. hajastana Grossh.-soybean (Glycine max L.) and barley (Hordeum vulgare L.)-soybean, 35% for pea (Pisum sativum L.)-soybean, 20% for pea-V. hajastana, 14% for corn (Zea mays L.)-soybean and 10% for V. villosa Roth-V. hajastana.
40% of the barley-soybean, corn-soybean and pea-soybean heterokaryocytes divided at least once. Some divided many times and formed clusters of up to 100 cells in 2 weeks. The heterokaryocytes of soybean-V. hajastana, V. villosa-V. hajastana also divided. Of the PEG-treated protoplasts of N. langsdorffii and N. glauca 13.5% developed into tumor-like calli. The morphology of these calli was very much like that of the tumors produced on amphidiploid plants of N. langsdorffii x glauca.
Nuclear staining indicated that heterokaryocytes of V. hajastana-soybean, pea-soybean, corn-soybean and barley-soybean could undergo mitosis. Nuclear divisions in a heterokaryocyte were usually synchronized or almost synchronized. Nuclear fusion and true hybrid formation usually occurred during the first mitotic division after protoplast fusion. A hybrid of barley-soybean in third cell division was observed. The frequency of heterokaryocytes which underwent nuclear fusion has not been determined. Multipole formation and chimeral cell colonies were also observed.
In gel chromatographic experiments using Sephadex G-200, human serum albumin has been chromatographed in eluents containing neutral polymers. Each of the four types of polymers studied; dextran, polyethyleneglycol, polyvinylalcohol, and Ficoll, was tested at several concentrations. Albumin is eluted later as the polymer concentration in the eluent is increased. This is ascribed to an activity increase of the protein in the mobile polymer phase that is due mainly to steric exclusion. When the exclusion properties of the gel phase are known one can calculate the exclusion of the test substance from the liquid polymer phase. Measurements made by this method agree well with data derived from solubility studies of the exclusion of albumin from dextran solutions. They agree exactly with the exclusion measurements on dextran gels. The method should be useful in studies of the exclusion properties and the molecular parameters of polymer solutions.
The literature data on the use of poly(ethylene glycol) (PEG) in biochemistry and molecular biology are analysed from the standpoint of the physical chemistry of polymers. The exclusion properties of PEG, used as a factor influencing the rate of enzymatic reactions, the intra- and intermolecular transitions in polymers, and biopolymer precipitation and crystallisation processes are examined. The suitability of three-component PEG–dextran–water mixtures for the purification and separation of mixtures of biopolymers and for analytical purposes as well as the possibility of using functional derivatives of PEG in immunological research and for the immobilisation of enzymes are discussed. A special section is devoted to the synthesis of PEG derivatives containing different functional groups at the ends of the polymer chain. The surface-active properties of PEG are examined.
The bibliography includes 78 references.
Aqueous systems with two soluble polymers often phase-separate into two isotropic solutions. We investigate the molecular mechanism leading to this phase separation. It is concluded that the important factor is the direct molecular interaction between the monomeric units of two polymers, which should be effectively repulsive for phase separation to occur. Previously it has also been suggested that the size and shape of the entire polymer molecules are important factors, but our analysis does not support this view.
Proteins can be modified chemically by attaching synthetic or natural macromolecules to the surface of the protein molecule. In some cases, this manipulation of protein modification with polymers can eliminate some drawbacks of native proteins and improve thier properties. These are important aspects for future application in the use of protein drugs and catalysts in bioreactors. Poly(ethylene glycol) (PEG) with a history of plasma expander, being nonimmunogenic, amphipathic and nontoxic, has been applied to various enzymes as a superior agent for modification. This report is focused on our recent work with poly(ethylene glycol)-protein conjugates and their potential medical aplications.
One hundred and one rats were administered either D, α-tocopheryl succinate plus polyethylene glycol (PEG), PEG, or saline 30 min prior to or 5 min after moderate fluid percussion brain injury. Mortality rates, performance on beam balance and beam-walking tasks, and body weight were assessed daily for 10 days. With preinjury administration, mortality rate was reduced from 31% with saline to 9% with PEG and 9% with D, α-tocopheryl succinate plus PEG. With postinjury administration, mortality rate was reduced from 36% with saline to 20% with PEG and to 10% with the D, α tocopheryl succinate plus PEG combination. With administration prior to injury, PEG and D, α-tocopheryl succinate plus PEG reduced the deficits seen on beam balance testing on days 1-3 after injury. On beam walking, PEG and D, α tocopheryl succinate plus PEG reduced deficits compared to those in saline-injected animals on days 1 and 2 and on day 1 after injury, respectively. A strongly protective effect of PEG and of D, α-tocopheryl succinate plus PEG was seen with preinjury administration. With postinjury administration, D, α-tocopheryl succinate plus PEG reduced deficits on beam balance testing compared to animals receiving both saline and PEG on days 1-3 after injury. On beam-walking latencies, D, α-tocopheryl succinate plus PEG reduced deficits on days 1 and 2 after injury compared to saline and to PEG. Both PEG and D, α-tocopheryl succinate plus PEG reduced weight loss after injury compared to saline. The protective effects of these agents and their relatively low toxicity and high lipid solubility give them potential for the treatment of human head injury.
This book presents papers given at a symposium of the American Chemical Society. Topics covered include: Aromatic substitution in condensation polymerization catalyzed by solid-liquid phase transfer; Triphase catalysis in organometallic anion chemistry; and Multisite phase-transfer catalysts.
POLYETHYLENE glycol is now widely used for concentrating protein
solutions by dialysis. We have used the material of molecular weight
15,000 (L. Light and Co., Ltd., Colnbrook, England) and have found that
it penetrates dialysis sacs to an appreciable extent.
In recent years, derivatives of polyethylene glycol (PEG) have proven valuable in a variety of diverse chemical and biological endeavors. Such applications include peptide synthesis, phase transfer catalysis, pharmaceutical modification, protein and cell purifications, polymer-bound reagents, and binding assays. Because of the great deal of interest surrounding this subject, this review will describe generally applicable laboratory methods for preparing PEG derivatives from the parent PEG. We have largely restricted discussion to this starting material because most research laboratories interested in applications are not equipped to handle complex ethylene oxide polymerizations used in large-scale industrial preparations and because PEG and some of its ethers and esters are the only commonly available polymeric starting materials. For the purpose of this review, PEG is defined as those polyoxyethylenes having hydroxyl endgroups and a molecular weight of 20,000 daltons or less.
Vapor pressures at 25°C are reported for binary aqueous solutions containing 5-40 wt % poly(ethylene glycol) (PEG) 3350 or PEG 8000 or Dextran T-70 or Dextan T-500. 'Effective' osmotic second virial coefficients are calculated from vapor-pressure data at concentrations below 15 wt %. These are somewhat larger than second virial coefficients obtained from low-angle laser-light-scattering (LALLS) measurements at high dilution, indicating contributions from higher order interactions. Vapor-pressure data are used together with osmotic second virial coefficients measured by LALLS to fit an 'effective' third virial coefficient for each binary system. Chemical potentials obtained from vapor-pressure and LALLS data are used to predict liquid-liquid equilibria (LLE) for aqueous ternary systems containing PEG and dextran. Predicted and measured LLE are in good agreement.
The partitionings of five proteins - lysozyme, chymotrypsinogen, ovalbumin, human serum albumin, and bovine serum albumin - in two phase systems made from poly(vinyl methyl ether) (PVME) and poly(ethylene oxide) (PEO) were examined as functions of the compositions of the systems. Chymotrypsinogen partitioning was also examined as a function of PEO molecular weight. Experimental data for the partition coefficients were compared with values calculated from the lattice model of J.N. Baskir et al. Calculations were in good agreement with the experiments over the range of conditions investigated. Estimated phase polymer concentrations near the proteins were generally lower than those in the bulk, indicating that partitioning is primarily governed by steric repulsion of the protein from the phase polymers.
Analytical particle microelectrophoresis was used to evaluate the effectiveness of various coatings for control of the electroosmotic fluid flow that hinders electrophoretic processes. Mobilities of 2-μm-diameter glass and polystyrene latex spheres, exhibiting both negative and zero effective surface charge, were measured in 2-mm-diameter quartz capillaries filled with NaCl solutions within the pH range of 3.5 to 7.8. Covalent coating of capillary inner surfaces with poly(ethylene glycol) caused a reduction in the degree of electroosmotic flow which was related to the poly(ethylene glycol) molecular weight. Poly(ethylene glycol) coatings of 5000 molecular weight, or higher, greatly reduced electroosmosis within the selected pH range, were stable for long periods of time, and appeared to be more effective than dextran, methylcellulose, or silane coatings. Because of these characteristics, poly(ethylene glycol) coatings should be of considerable use for improving various electrophoretic processes as well as in the production of standard particles exhibiting controlled electrophoretic mobilities.
Polyethylene glycol (PEG) was used as a carrier polymer for the attachment, via end groups, of drugs such as penicillin V, aspirin, amphetamine, quinidine and atropine. For this purpose, methods were developed for the functionalization of PEG; PEG-NH2, PEG-COOH and PEG-NCO were prepared. Use was made of dicyclohexyl carbodiimide together with 4-dimethylamino pyridine or 1-hydroxybenzotriazole for the coupling reactions.
WE report new findings on the chemically-induced fusion of hen
erythrocytes and discuss possible ways in which the lipid and
protein/glycoprotein components of membranes may behave during the
process of membrane fusion. Our observations are consistent with Poste
and Allison's1 idea that the aggregation of intrinsic
membrane proteins is important in membrane fusion but we suggest that
fusion may occur in regions of perturbed lipid bilayer which are thus
denuded of intramembranous particles.
Polyethylene glycol (PEG) is known to promote fusion of plant protoplasts. Various adaptations of this treatment to mammalian, including human, cell cultures are reported here. PEG is very effective in producing hybrids capable of indefinite multiplication even in cases, such as early passage human skin fibroblasts and lymphocytes, known to be highly recalcitrant to other treatments.
Well-defined liposome systems have previously established the influence of size, surface charge lipid composition and surface ligands, on in vivo fate and behaviour of model compounds entrapped in liposomes. In the present study, preformed liposomes which quantitatively retain aqueous markers were covalenty coupled via dipalmitoylphosphatidyl-ethanolamine, to the hydrophilic polymer, monomethoxypoly(ethylene glycol) (MPEG 5000). Such liposomes retain the coating in the presence of plasma, and appear to adsorb plasma components more slowly than liposomes without the polymer, shown using an aqueous two-phase partitioning technique. MPEG-coupled liposomes were cleared from the blood circulation up to 30% more slowly than liposomes without MPEG after intravenous administration to mice, despite the unmodified liposomes being of a composition and size shown previously to favour achievement of maximum half-life. It is suggested that the polymer acts as a surface barrier to plasma factors which otherwise bind to liposomes in the blood and accelerate vesicle removal.
Dioleoyl-N-(monomethoxy polyethyleneglycol succinyl)-phosphatidylethanolamine (PEG-PE) (mol. wt. of PEG = 5000), an amphipathic polymer, can be incorporated into the liposome membrane and significantly prolong the blood circulation time of the liposome. As little as 3.7 mol% of PEG-PE in liposome resulted in maximal enhancement of liposome circulation time. However, this activity of PEG-PE was only seen with relatively small liposomes (d less than or equal to 200 nm); larger liposomes containing PEG-PE showed an unusually high level (approx. 35% injected dose) of accumulation in the spleen. We have tested whether the small, PEG-PE containing liposomes are suitable for immuno targeting by incorporating a lung-specific monoclonal antibody on the liposome surface. While another amphiphile, ganglioside GM1, which is well known for its activity to prolong the liposome circulation time, significantly enhanced the lung binding of the immunoliposomes, PEG-PE incorporation of immunoliposomes resulted in a low level of target binding. To test if the reduced target binding is due to a steric barrier effect of the surface PEG polymer, we have incorporated a small amount of N-biotinaminocaproylphosphatidylethanolamine into the PEG-PE containing liposomes and examined the liposome agglutination induced by the addition of streptavidin. As little as 0.72 mol% PEG-PE in these liposomes completely abolished agglutination. In contrast, incorporation of GM1 in liposomes only reduced the rate, but not the extent, of liposome agglutination. These results strongly support the hypothesis that PEG-PE prolongs liposome circulation time by providing a strong steric barrier which prevents close contact with another liposome or cell. Since GM1 provides only a weak steric barrier effect, its activity to prolong the liposome circulation time must involve another yet unknown mechanism.
We are able to morphologically fuse the severed halves of an invertebrate-myelinated axon by application of polyethylene glycol (PEG) to closely apposed cut ends. Morphological fusion of the medial giant axon (MGA) of the earthworm Lumbricus terrestris is defined as axoplasmic and axolemmal continuity in serial longitudinal sections of MGAs taken through the fusion site as viewed with light or electron microscopes. Morphological continuity is also shown by the transfer of Lucifer yellow dye between apposed MGA segments fused with PEG, but not between apposed MGA segments in normal or hypotonic saline without PEG application. PEG-induced MGA fusion rates can be as high as 80-100% with an appropriate choice of PEG concentration and molecular mass, tight apposition and careful alignment of the cut ends, and treatment with hypotonic salines containing reduced calcium and increased magnesium. A variant of this technique might produce rapid repair of severed mammalian-myelinated axons.
The mechanism of poly(ethylene glycol)-induced fusion of phospholipid vesicles was studied based on the "osmophobic association" theory which was recently proposed both theoretically [Ito, T., Yamazaki, M., & Ohnishi, S. (1989) Biochemistry 28, 5626-5630] and also experimentally [Yamazaki, M., Ohnishi, S., & Ito, T. (1989) Biochemistry 28, 3710-3715]. Osmophobic association and fusion were detected by measuring the light scattering of the vesicle suspension; the former was detected from the increase in light scattering induced by the addition of PEG, and the latter was from the irreversibility of the increase in light scattering. Threshold concentrations of PEG were required not only for osmophobic association but also for fusion. The threshold concentration for fusion depended on the molecular weight of PEG and also on the electrostatic repulsive interaction between phospholipid vesicles, which was manipulated by the use of vesicles with negative surface charge; increasing the molecular weight of PEG lowered the threshold concentration, and increasing the electrostatic repulsive interaction raised it. In addition, a transient leakage of internal contents from the vesicles was observed at the concentration that caused fusion. When the surface charge of the vesicle was varied, the threshold for fusion coincided with that for osmophobic association, provided that the latter exceeded 22 wt % of PEG 6000. However, when the threshold for osmophobic association was less than 22 wt %, the threshold for fusion remained approximately 22 wt %, irrespective of the difference in the threshold for osmophobic association.(ABSTRACT TRUNCATED AT 250 WORDS)
New phase supports for liquid-liquid partition chromatography, using aqueous poly(ethyleneglycol)-dextran systems have been developed by grafting linear polyacrylamide chains on to premanufactured chromatographic supports carrying primary or secondary aliphatic hydroxyl functions on their surface. Columns prepared from such supports have a higher binding capacity for the dextran-rich stationary phase and much higher performances than columns prepared from cellulose, the previously used phase support for this system. Test separations of DNA restriction fragments, ranging from 11 base pairs to 3829 base pairs, document a high resolution for DNA fragments larger than 200 base pairs.
A method to evaluate in blood free superoxide dismutase (SOD) and SOD covalently bound to monomethoxypolyethylene glycol (MPEG-5000) is reported. The method takes advantage of gel filtration and cationic exchange chromatography to remove substances present in plasma which can interfere with the SOD enzymatic assay. Using this methodology, it was demonstrated that, contrary to free SOD, MPEG-SOD, when added to blood, was not completely recovered in plasma. Binding of MPEG-SOD to blood cell components takes place involving interactions of MPEG chains with cell membranes.
The present studies were undertaken to investigate the enzymology of a fatal toxic syndrome that resulted from the absorption and subsequent oxidation of polyethylene glycol (PEG). The presence of organic acids of PEG in the blood of poisoned patients and in an animal model suggested that the metabolism of PEG involved sequential oxidations by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. A key question concerned the ability of ADH to initiate this pathway for oxidation of PEG. In the present studies the oxidation of PEG homologues by ADH was characterized. The polymer homologues of ethylene glycol from n = 1 to n = 8 were used as substrates. ADH catalyzed the oxidation of each of these PEGs. The oxidation of PEG was inhibited by the ADH inhibitor 4-methylpyrazole. With the exception of diethylene glycol, the Km decreased as the homologue number increased, and the Vmax decreased progressively through the series. The concentrations of PEG in the blood of poisoned humans and animals were 0.06 to 0.8 Km of ADH for all the PEG homologues above the triethylene glycol. These investigations establish ADH as a candidate enzyme for mammalian metabolism of PEG and thus suggest that specific inhibitors of ADH may prove to be useful as tools to treat PEG poisoning.
Fusion of synaptic vesicles with the surface membrane of the nerve terminal is a key step in synaptic transmission, which normally requires the entry of calcium ions into the cell. We report that this fusion and the subsequent liberation of transmitter can also be induced by the fusogenic substances DMSO (dimethyl sulfoxide) and PEG (poly(ethylene glycol)). Calcium ions and DMSO exhibit a synergistic effect in the fusion of synaptic vesicles with the axolemma, resembling their action on fusion phenomena in liposomes.
Previous work has shown that polyethylene glycol (PEG)-bound antibodies can be used as affinity ligands in PEG-dextran two-phase systems to provide selective partitioning of cells to the PEG-rich phase. In the present work we show that immunoaffinity partitioning can be simplified by use of PEG-modified Protein A which complexes with unmodified antibody and cells and shifts their partitioning into the PEG-rich phase, thus eliminating the need to prepare a PEG-modified antibody for each cell type. In addition, we provide a more rigorous test of the original technique with PEG-bound antibodies by showing that it is effective at shifting the partitioning of either cell type of a mixture of two cell populations.
Severed medial giant axons in crayfish can be rejoined in vitro with polyethylene glycol (PEG) to produce axoplasmic continuity and through transmission of action potentials. Severed axon-like processes of a mammalian neuroblastoma/glioma cell line seem to be rejoined to the cell body using PEG in tissue culture. Our data suggest that PEG might be used to rejoin severed axons in vivo in various organisms.
We treated two children who had adenosine deaminase deficiency and severe combined immunodeficiency disease by injecting bovine adenosine deaminase modified by conjugation with polyethylene glycol. The modified enzyme was rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses of approximately 15 U per kilogram of body weight maintained plasma adenosine deaminase activity at two to three times the level of erythrocyte adenosine deaminase activity in normal subjects. The principal biochemical consequences of adenosine deaminase deficiency were almost completely reversed. In erythrocytes, adenosine nucleotides increased and deoxyadenosine nucleotides decreased to less than 0.5 percent of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of the cellular immune function of each patient showed marked improvement, along with an increase in circulating T lymphocytes. Clinical improvement was indicated by absence of infection and resumption of weight gain. We conclude that from the standpoints of efficacy, convenience, and safety, polyethylene glycol-modified adenosine deaminase is preferable to red-cell transfusion as a treatment for adenosine deaminase deficiency. Patients with other inherited metabolic diseases in which accumulated metabolites equilibrate with plasma could benefit from treatment with the appropriate polyethylene glycol-modified enzyme.
By the use of fractional precipitation with high molecular weight nonionic polymers, immune globulins of marked homogeneity were isolated in high yield from either whole serum or commercial samples of immunoglobulins. The isolated fractions were characterized by immunochemical and ultracentrifugal analyses. When the pH was varied from 4.9 to 8.6 and the ionic strength from 0.1 to 2.0, little effect on the precipitation of the immunoglobulins was noted. The immunochemical studies indicated that this fractionation technique is not effective in separating the γG, γM, and γA activities present in the γ-globulins isolated from whole serum or in commercial immunoglobulin preparations.Preliminary experiments indicate that this technique may be used for the isolation of other serum proteins, especially albumin and the α-globulins. In these instances, however, it is important that ionic strength and pH be controlled.The mechanism for the precipitation of serum proteins by PEG has not been established, but it is suggested that the precipitation involves a local dehydration and consequent change in the dielectric constant of the medium immediately surrounding the protein molecules.It would appear that the high-polymer precipitation technique may be an effective and simple method for the isolation of serum proteins with preservation of much of their native properties.
. Intermediate- and high-purity antibaemophilic factor (factor-VIII) concentrates developed by the American National Red Cross (ANRC) have undergone extensive clinical investigation. When administered to severely affected haemophiliacs, the recovery in vivo and the metabolic half-disappearance time were similar to those achieved with plasma.
Antibodies to polyethylene glycol (PEG) were raised in rabbits by immunization with monomethoxy polyethylene glycol modified ovalbumin (OA), bovine superoxide dismutase (SOD), and ragweed pollen extract (Rag), given in Freund's complete adjuvant (FCA). Immunogenicity depended on the nature of the protein and the degree of modification. With modified OA, in the presence of FCA, the majority of animals showed an anti-PEG response. With modified SOD and Rag only a small proportion of animals responded. In the absence of FCA, modified OA, given s.c., did not elicit any anti-PEG antibody response in rabbits and only a weak response in mice. PEG of MW 10,000 and 100,000 given in FCA was found nonimmunogenic in rabbits, and PEG of MW 5.9 X 10(6), given s.c. to mice, showed no or very poor immunogenic properties. Gel diffusion, heterologous passive anaphylaxis and passive hemagglutination were used to demonstrate anti-PEG antibodies raised to PEG-modified proteins. Specificity was confirmed by hapten inhibition of precipitation, inhibition of passive hemagglutination and cross-reactivity tests. PEG of MW greater than or equal to 4,000 produced specific precipitates, smaller molecules acted as monovalent haptens. From hapten inhibition of precipitation by PEG of MW 300 it appears that the antigenic determinant of PEG may be a sequence of 6-7 -CH2CH2O-units. Anti-PEG antibodies can be used analytically. By gel diffusion, Peg was detected in minimal concentrations of 0.1-1 microgram/ml. The clinical relevance of these findings with regard to therapy with PEG-modified enzymes and allergens in humans remains to be established.
The covalent attachment of monomethoxypolyethylene glycol (PEG) to asparaginases from Escherichia coli and Vibrio succinogenes by new coupling methodology produced conjugates that are active, stable, without significant immune response, and with greatly extended plasma half-lives in mice. Therapeutic efficacies were greater for the PEG-asparaginases than for the unmodified asparaginases in mice infected with the L5178Y lymphosarcoma or the 6C3HED tumor. Large single doses of native or modified enzymes were more effective against tumors than the same amount of enzyme given in smaller doses over several days.
Various aspects of the interaction between the fusogen, poly(ethylene glycol) and phospholipids were examined. The aggregation and fusion of small unilamellar vesicles of egg phosphatidylcholine (PC), bovine brain phosphatidylserine (PS) and dimyristoylphosphatidylcholine (DMPC) were studied by dynamic light scattering, electron microscopy and NMR. The fusion efficiency of Dextran, glycerol, sucrose and poly(ethylene glycol) of different molecular weights were compared. Lower molecular weight poly(ethylene glycol) are less efficient with respect to both aggregation and fusion. The purity of poly(ethylene glycol) does not affect its fusion efficiency. Dehydrating agents, such as Dextran, glycerol and sucrose, do not induce fusion. 31P-NMR results revealed a restriction in the phospholipid motion by poly(ethylene glycol) greater than that by glycerol and Dextran of similar viscosity and dehydrating capacity. This may be associated with the binding of poly(ethylene glycol) to egg PC, with a binding capacity of 1 mol of poly(ethylene glycol) to 12 mol of lipid. Fusion is greatly enhanced below the phase transition for DMPC, with extensive fusion occurring below 6% poly(ethylene glycol). Fusion of PS small unilamellar vesicles depends critically on the presence of cations. Large unilamellar vesicles were found to fuse less readily than small unilamellar vesicles. The results suggest that defects in the bilayer plays an important role in membrane fusion, and the 'rigidization' of the phospholipid molecules facilitates fusion possibly through the creation of defects along domain boundaries. Vesicle aggregation caused by dehydration and surface charge neutralization is a necessary but not a sufficient condition for fusion.
The intracarotid infusion of the anti-neoplastic compound, etoposide, has been shown to exert a dose-dependent effect on blood-brain barrier (BBB) permeability. Etoposide, however, is formulated in a complex solvent solution containing alcohol, Tween 80, polyethylene glycol 300, and citric acid. To investigate the contribution of the solvent solution to BBB disruption, the authors studied Sprague-Dawley rats after the internal carotid artery infusion of the solvent solution with and without the addition of etoposide. Experiments were performed at four doses of drug and/or solvent. Disruption of the BBB was evaluated qualitatively by the appearance of the systemically administered dye, Evans blue, in the cerebral hemispheres and quantitatively by the ratio of gamma counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the ipsilateral:contralateral hemisphere. Significant barrier opening was obtained in all four groups of animals infused with solvent plus etoposide. In the corresponding groups of rats infused with the solvent solution alone, BBB disruption was markedly lower. Only in the group infused with the largest dose of solvent was the hemispheric ratio of 99mTc-DTPA significantly different from saline-infused animals. Each of the groups with solvent plus etoposide had 99mTc-DTPA ratios significantly different from the control group. Intracarotid infusion and subsequent BBB disruption were well tolerated by the animals receiving either solvent alone or solvent and etoposide. Disruption of the BBB secondary to the intracarotid infusion of etoposide is primarily caused by the drug itself and not by the solvent solution.
Antibodies to polyethylene glycol (PEG) were analyzed in patients with various allergies and in healthy blood donors employing passive hemagglutination. In untreated allergic patients and in healthy blood donors, naturally occurring anti-PEG antibody titers between 32 and 512 were seen in 3.3 and 0.2%, respectively. During hyposensitization with monomethoxy polyethylene glycol modified ragweed extract and honey bee venom, respectively, the patients showed an anti-PEG antibody response. Titers of 32-512 were found in 50% of the patients directly after the first treatment course. After 2 years of treatment the percentage of patients with such titers declined to 28.5%. Mercaptoethanol treatment of sera indicated that the anti-PEG antibodies predominantly were of the IgM isotype. The weak IgM response found in treated patients is considered to be of no clinical significance.
The rate and extent of penetration of radiolabelled polyethylene glycols (900 and 4000 daltons) from plasma into brain was examined in the Atlantic hagfish (Myxine glutinosa), a primitive vertebrate, and, for comparison, in the rat. Tracer penetration into brain was limited to a similar extent in hagfish and in rats, indicating a basic similarity between the two species in the blood-brain barrier to polar non-electrolytes. The permeability of hagfish brain capillaries to the electron microscopic tracer microperoxidase (2000 Daltons) was also examined. Intravenously injected microperoxidase remained confined to the capillary lumen and was not found in the basal lamina or surrounding brain parenchyma. In contrast to an earlier study, these results indicate that the hagfish has a blood-brain barrier to hydrophilic molecules larger than 900 Daltons. It is concluded that a blood-brain barrier is a general characteristic of all vertebrates.
The protein fractionating properties of the high molecular weight linear polymers, polyethylene glycol, dextran, nonylphenol-ethoxylate, polyvinyl alcohol and polyvinyl pyrrolidone have been investigated.All were protein precipitants, but varied in selectivity.Polyethylene glycol (mol. wt. 6000) appears to be the most suitable protein precipitants in this group because its solutions are less viscous and cause virtually no denaturation at room temperature.The efficiency of protein fractionation increases with the molecular weight, and therefore chain length, of the polymer.Rapid simple methods for the preparation of γ-globulin and fibrinogen with the aid of polyethylene glycol are described. The products were homogeneous on electrophoresis and centrifugation and retained satisfactory biological properties.
- A Abuchowski
- T Van Es
- N C Palczuk
- E E Davis