Biodegradable nanosize particles of poly(L,L-lactide)-b-poly(ethylene glycol)-b-poly(L,L-lactide)

Two series of poly(L,L-lactide-b-ethylene glycol-b-L,L-lactide) copolymers, PLA-PEO-PLA, were synthesized by polymerization Of L,L-lactide using a dihydroxy-terminated poly(ethylene glycol) (PEG) (M-n = 4000 or 600 g/mol) as coinitiator and stannous 2-ethylhexanoate, Sn(Oct)(2), as initiator. The synthesized copolymers have shown high stereoregularity as observed by C-13 NMR analyses. The nanoparticles were prepared by using a solvent diffusion method and the self-assemblage process and were characterized by NMR and SEM. It was possible to conclude that the self-assembled particles presented a core-shell structure characterized by a hydrophobic PLA core and a hydrophilic PEG shell, thus the NMR of the aqueous solutions indicated a quasi-solid behavior for the particles` interior. The diameters of the spherical particles as observed by SEM were in the 50-250 nm range, depending on the copolymer composition and the preparation procedure.

Degradation of Poly(ethylene glycol) in Aqueous Solution by Photo-Fenton and H(2)O(2)/UV Processes

This article reports experimental results obtained in a laboratory-scale photochemical reactor on the photodegradation of poly(ethylene glycol) (PEG) in aqueous solutions by means of the photo-Fenton and H(2)O(2)/UV processes. Dilute water solutions of PEG were fed to a batch reactor, mixed with pertinent reactants, and allowed to react under different conditions. Reaction progress was evaluated by sampling and analyzing the concentration of the total organic carbon (TOC) in solution as a function of the reaction time. Organic acids formed during oxidation were determined by HPLC analyses. The main acids detected in both processes were acetic and formic. Glycolic acid was detected only in the photo-Fenton process, and malonic acid was detected only in the H(2)O(2)/UV treatment, indicating that different reaction paths occur in these processes. The characteristics of both processes are discussed, based on the evolution of the TOC-time curves and the concentration profiles of the monitored organic acids. The experimental results constitute a contribution to the design of industrial processes for the treatment of wastewaters containing soluble polymers with similar properties.

Protein partitioning in poly(ethylene glycol)/sodium polyacrylate aqueous two-phase systems

The partition of hemoglobin, lysozyme and glucose-6-phospate dehydrogenase (G6PDH) in a novel inexpensive aqueous two-phase system (ATPS) composed by poly(ethylene glycol) (PEG) and sodium polyacrylate (NaPA) has been studied. The effect of NaCl and Na2SO4, pH and PEG molecular size on the partitioning has been studied. At high pH (above 9), hemoglobin partitions strongly to the PEG-phase. Although some precipitation of hemoglobin occurs, high recovery values are obtained particularly for lysozyme and G6PDH. The partitioning forces are dominated by the hydrophobic and electrochemical (salt) effects, since the positively charged lysozyme and negatively charged G6PDH partitions to the non-charged PEG and the strongly negatively charged polyacrylate enriched phase, respectively. (c) 2007 Elsevier B.V. All rights reserved.

Convenient synthesis of heterobifunctional poly(ethylene glycol) suitable for the functionalization of iron oxide nanoparticles for biomedical applications.

A straightforward route is proposed for the multi-gram scale synthesis of heterobifunctional poly(ethylene glycol) (PEG) oligomers containing combination of triethyloxysilane extremity for surface modification of metal oxides and amino or azido active end groups for further functionalization. The suitability of these PEG derivatives to be conjugated to nanomaterials was shown by pegylation of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles (NPs), followed by functionalization with small peptide ligands for biomedical applications.

Poly(ethylene glycol)-supported nitroxyls: branched catalysts for the selective oxidation of alcohols

Nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) are highly selective oxidation catalysts for the conversion of primary alcohols into the corresponding aldehydes. In this study, direct tethering of TEMPO units onto linear poly(ethylene glycol) (PEG) has afforded macromolecular catalysts that exhibit solubility in both aqueous and organic solvents. Recovery of the dissolved polymer-supported catalyst has been carried out by precipitation with a suitable solvent such as diethyl ether. The high catalyst activities and selectivities associated traditionally with nitroxyl-mediated oxidations of alcohols are retained by the series of "linker-less" linear PEG-TEMPO catalysts in which the TEMPO moiety is coupled directly to the PEG support. Although the selectivity remains unaltered, upon recycling of the linker-less polymer-supported catalysts, extended reaction times are required to maintain high yields of the desired carbonyl compounds. Alternatively, attachment of two nitroxyl radicals onto each functionalized PEG chain terminus via a 5-hydroxyisophthalic acid linker affords branched polymer-supported catalysts. In stark contrast to the linker-less catalysts, these branched nitroxyls exhibit catalytic activities up to five times greater than 4-methoxy-TEMPO alone under similar conditions. In addition, minimal decrease in catalytic activity is observed upon recycling of these branched macromolecular catalysts via solvent-induced precipitation. The high catalytic activities and preservation of activity upon recycling of these branched systems is attributed to enhanced regeneration of the nitroxyl species as a result of intramolecular syn-proportionation.

Nanostructure formation in poly(gamma-benzyl-L-glutamate)-poly(ethylene glycol)-poly(gamma-benzyl-L-glutamate) triblock copolymers in the solid state

The morphology in the solid state of a series of triblock copolymers comprising a poly(ethylene glycol) (PEG) midblock and symmetric poly(gamma-benzyl-L-glutamate) (PBLG) end blocks has been studied using X-ray scattering and microscopy techniques. Transmission electron microscopy (TEM) on samples selectively stained with uranyl acetate provided clear assignment of morphologies for as-cast and annealed samples. The thickness of both PEG and PBLG domains was in good agreement with calculations based on the conformations of the respective chains, allowing for the crystal or amorphous state of PEG and the a-helical or P-sheet structure of the PBLG. Atomic force microscopy provided complementary information on surface morphology for several samples that was in good agreement with the structure observed by TEM. A morphology diagram was constructed. Cylindrical structures were observed for ordered samples with low f(PBLG), whereas at higher f(PLBG) there was evidence for broken lamellar and "hockey puck" nanostructures. Regular lamellae were observed for intermediate compositions.

Protein partitioning in poly(ethylene glycol)/sodium polyacrylate aqueous two-phase systems

The partition of hemoglobin, lysozyme and glucose-6-phospate dehydrogenase (G6PDH) in a novel inexpensive aqueous two-phase system (ATPS) composed by poly(ethylene glycol) (PEG) and sodium polyacrylate (NaPA) has been studied. The effect of NaCl and Na2SO4, pH and PEG molecular size on the partitioning has been studied. At high pH (above 9), hemoglobin partitions strongly to the PEG-phase. Although some precipitation of hemoglobin occurs, high recovery values are obtained particularly for lysozyme and G6PDH. The partitioning forces are dominated by the hydrophobic and electrochemical (salt) effects, since the positively charged lysozyme and negatively charged G6PDH partitions to the non-charged PEG and the strongly negatively charged polyacrylate enriched phase, respectively. (c) 2007 Elsevier B.V. All rights reserved.

Synthesis, characterization and solution properties of amphiphilic N-isopropylacrylamide-poly(ethylene glycol)-dodecyl methacrylate thermosensitive polymers

Terpolymers of N-isopropylacrylamide, dodecyl methacrylate (DOMA) and poly(ethylene glycol) (PEG) methacrylate, were synthesized by random copolymerization, and the composition was controlled to achieve systems having different thermosensitivities. H-1 NMR spectra and gel permeation chromatography (GPC) were employed to characterize the different samples obtained. The solution properties were studied by employing spectrophotometry, fluorescence, and dynamic light scattering techniques. The chemical compositions in the final terpolymers are close to those in the feed. The polymers exhibited cloud point temperatures (T-es) varying from 17 to 52 degrees C. Micropolarity studies using I-1/I-3 ratio of the vibronic bands of pyrene show the formation of amphiphilic aggregates capable of incorporating hydrophobic drugs as the polymer concentration is increased. The critical aggregation concentration (CAC) increases from 3.6 x 10(-3) to 1 x 10(-2) g/l with the PEG content varying from 5 to 35 mol%. Anisotropy measurements confirm the results obtained by pyrene fluorescence and show that the aggregates resulting from intermolecular interactions present different organizations. The hydrodynamic diameters (Dh) of the aggregates determined by dynamic light scattering (DLS) vary from 40 to 150 nm depending on the terpolymer composition. The T-cs and Dh values decreased with the ionic strength, and this behavior was attributed to the dehydration of the polymeric micelles. The capacity of solubilization of the aggregates was evaluated by employing pyrene, and the obtained results confirm the ability to incorporate hydrophobic molecules. (c) 2005 Elsevier B.V All rights reserved.

Fractal character of the SAXS correlation volume in poly(ethylene glycol)/silica hybrid wet gels

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structure and luminescence of Eu3+-doped class I siloxane-poly(ethylene glycol) hybrids

Transparent, flexible, and luminescent EU3+-doped siloxane-poly(ethylene glycol) (PEG) nanocomposites have been obtained by the sol-gel process. The inorganic (siloxane) and organic PEG phases are usually linked by weak bonds (hydrogen bonds or van der Waals forces), and small-angle X-ray scattering (SAXS) measurements suggest that the structure of these materials consists of fractal siloxane aggregates embedded in the PEG matrix. For low Eu3+ contents, n = 300 and n = 80, the aggregates are small and isolated and their fractal dimensions are 2.1 and 1.7, respectively. These values are close to those expected for gelation mechanisms consisting of reaction-limited cluster-cluster aggregation (RLCCA) and diffusion-limited cluster-cluster aggregation (DLCCA). For high Eu3+ content, SAYS results are consistent with a two-level structure: a primary level of siloxane aggregates and a second level, much larger, formed by the coalescence of the primary ones. The observed increase in the glass transition temperature for increasing Eu3+ content is consistent with the structural model derived from SAXS measurements. Extended X-ray absorption fine structure (EXAFS) and luminescence spectroscopy measurements indicate that under the experimental conditions utilized here Eu3+ ions do not strongly interact with the polymeric phase.

Interaction between poly(ethylene glycol) and C12E8 investigated by dynamic light scattering, time-resolved fluorescence quenching, and calorimetry

Dynamic light scattering (DLS), time-resolved fluorescence quenching (TRFQ), and isothermal titration microcalorimetry have been used to show that, in dilute solution, low molecular weight poly(ethylene glycol) (PEG, M-w = 12 kDa) interacts with the nonionic surfactant octaethylene glycol n-dodecyl monoether, C12E8, to form a complex. Whereas the relaxation time distributions for the binary C12E8/water and PEG/water systems are unimodal, in the ternary mixtures they may be either uni- or bimodal depending on the relative concentrations of the components. At low concentrations of PEG or surfactant, the components of the relaxation time distribution are unresolvable, but the distribution becomes bimodal at higher concentrations of either polymer or surfactant. For the ternary system in excess surfactant, we ascribe, on the basis of the changes in apparent hydrodynamic radii and the scattered intensities, the fast mode to a single micelle, the surface of which is associated with the polymer and the slow mode to a similar complex but containing two or three micelles per PEG chain. Titration microcalorimetry results show that the interaction between C12E8, and PEG is exothermic and about 1 kJ mol(-1) at concentrations higher than the CMC of C12E8. The aggregation number, obtained by TRFQ, is roughly constant when either the PEG or the C12E8 concentration is increased at a given concentration of the second component, owing to the increasing amount of surfactant micelles inside the complex.

Molecular dynamics of poly(Ethylene Glycol) intercalated in clay, studied using 13C solid-state NMR

In this study, Cross-Polarization Magic-angle Spinning CP/MAS, 2D Exchange, Centerband-Only Detection of Exchange (CODEX), and Separated-Local-Field (SLF) NMR experiments were used to study the molecular dynamics of poly(ethylene glycol) (PEG) inside Hectorite/PEG intercalation compounds in both single- and double-layer configurations. The results revealed that the overall amplitude of the motions of the PEG chain in the single-layer configuration is considerably smaller than that observed for the double-layer intercalation compound. This result indicates that the effect of having the polymer chain interacting with both clay platelets is to produce a substantial decrease in the motional amplitudes of those chains. The presence of these dynamically restricted segments might be explained by the presence of anchoring points between the clay platelets and the PEG oxygen atoms, which was induced by the Na+ cations. By comparing the PEG motional amplitudes of the double-layered nanocomposites composed of polymers with different molecular weights, a decrease in the motional amplitude for the smaller PEG chain was observed, which might also be understood using the presence of anchoring points.

Expanding the scope of poly(ethylene glycol)s for bioconjugation to squaric acid-mediated PEGylation and pH-sensitivity

Poly(ethylene glycol) (PEG) is used in a broad range of applications due to its unique combination of properties and is approved use in formulations for body-care products, edibles and medicine. This thesis aims at the synthesis and characterization of novel heterofunctional PEG structures and the establishment of diethyl squarate as a suitable linker for the covalent attachment to proteins. Chapter 1 is an introduction on the properties and applications of PEG as well as the fascinating chemistry of squaric acid derivatives. In Chapter 1.1, the synthesis and properties of PEG are described, and the versatile applications of PEG derivatives in everyday products are emphasized with a focus on PEG-based pharmaceuticals and nonionic surfactants. This chapter is written in German, as it was published in the German Journal Chemie in unserer Zeit. Chapter 1.2 deals with PEGs major drawbacks, its non-biodegradability, which impedes parenteral administration of PEG conjugates with polyethers exceeding the renal excretion limit, although these would improve blood circulation times and passive tumor targeting. This section gives a comprehensive overview of the cleavable groups that have been implemented in the polyether backbone to tackle this issue as well as the synthetic strategies employed to accomplish this task. Chapter 1.3 briefly summarizes the chemical properties of alkyl squarates and the advantages in protein conjugation chemistry that can be taken from its use as a coupling agent. In Chapter 2, the application of diethyl squarate as a coupling agent in the PEGylation of proteins is illustrated. Chapter 2.1 describes the straightforward synthesis and characterization of squaric acid ethyl ester amido PEGs with terminal hydroxyl functions or methoxy groups. The reactivity and selectivity of theses activated PEGs are explored in kinetic studies on the reactions with different lysine and other amino acid derivatives, followed by 1H NMR spectroscopy. Further, the efficient attachment of the novel PEGs to a model protein, i.e., bovine serum albumin (BSA), demonstrates the usefulness of the new linker for the PEGylation with heterofunctional PEGs. In Chapter 2.3 initial studies on the biocompatibility of polyether/BSA conjugates synthesized by the squaric acid mediated PEGylation are presented. No cytotoxic effects on human umbilical vein endothelial cells exposed to various concentrations of the conjugates were observed in a WST-1 assay. A cell adhesion molecule - enzyme immunosorbent assay did not reveal the expression of E-selectin or ICAM-1, cell adhesion molecules involved in inflammation processes. The focus of Chapter 3 lies on the syntheses of novel heterofunctional PEG structures which are suitable candidates for the squaric acid mediated PEGylation and exhibit superior features compared to established PEGs applied in bioconjugation. Chapter 3.1 describes the synthetic route to well-defined, linear heterobifunctional PEGs carrying a single acid-sensitive moiety either at the initiation site or at a tunable position in the polyether backbone. A universal concept for the implementation of acetal moieties into initiators for the anionic ring-opening polymerization (AROP) of epoxides is presented and proven to grant access to the degradable PEG structures aimed at. The hydrolysis of the heterofunctional PEG with the acetal moiety at the initiating site is followed by 1H NMR spectroscopy in deuterium oxide at different pH. In an exploratory study, the same polymer is attached to BSA via the squarate acid coupling and subsequently cleaved from the conjugate under acidic conditions. Furthermore, the concept for the generation of acetal-modified AROP initiators is demonstrated to be suitable for cholesterol, and the respective amphiphilic cholesteryl-PEG is cleaved at lowered pH. In Chapter 3.2, the straightforward synthesis of α-amino ω2-dihydroxyl star-shaped three-arm PEGs is described. To assure a symmetric length of the hydroxyl-terminated PEG arms, a novel AROP initiator is presented, who’s primary and secondary hydroxyl groups are separated by an acetal moiety. Upon polymerization of ethylene oxide for these functionalities and subsequent cleavage of the acid-labile unit no difference in the degree of polymerization is seen for both polyether fragments.

Comparative stability studies of poly(2-methyl-2-oxazoline) and poly(ethylene glycol) brush coatings

Non-fouling surfaces that resist non-specific adsorption of proteins, bacteria, and higher organisms are of particular interest in diverse applications ranging from marine coatings to diagnostic devices and biomedical implants. Poly(ethylene glycol) (PEG) is the most frequently used polymer to impart surfaces with such non-fouling properties. Nevertheless, limitations in PEG stability have stimulated research on alternative polymers that are potentially more stable than PEG. Among them, we previously investigated poly(2-methyl-2-oxazoline) (PMOXA), a peptidomimetic polymer, and found that PMOXA shows excellent anti-fouling properties. Here, we compare the stability of films self-assembled from graft copolymers exposing a dense brush layer of PEG and PMOXA side chains, respectively, in physiological and oxidative media. Before media exposure both film types prevented the adsorption of full serum proteins to below the detection limit of optical waveguide in situ measurements. Before and after media exposure for up to 2 weeks, the total film thickness, chemical composition, and total adsorbed mass of the films were quantified using variable angle spectroscopic ellipsometry (VASE), X-ray photoelectron spectroscopy (XPS), and optical waveguide lightmode spectroscopy (OWLS), respectively. We found (i) that PMOXA graft copolymer films were significantly more stable than PEG graft copolymer films and kept their protein-repellent properties under all investigated conditions and (ii) that film degradation was due to side chain degradation rather than due to copolymer desorption.