Synthesis of a new class of double-hydrophilic block copolymers with calcium binding capacity as builders and for biomimetic structure control of minerals

Small block copolymers consisting of a hydrophilic poly(ethylene glycol) block and a second, also hydrophilic, moiety which strongly interacts with alkaline earth ions were synthesized by diverse reaction sequences based on poly(ethylene glycol) monomethyl ethers (MW = 2000 and 5000 g/mol, respectively). These starting blocks were transferred to the poly(ethylene glycol) monomethyl monoglycidyl ether or to poly(ethylene glycols) with one terminal acid chloride group. Both intermediates were subsequently reacted with poly(ethyleneimine) (MW = 700 g/mol) and bromoacetic acid to yield poly(ethylene glycol)-block-poly[(N-carboxymethyl)ethyleneimine] (PEG-b-PEIPA, average MW = 3800 resp. 6800 g/mol) as a polymeric analog of EDTA. The terminal epoxy group is also convenient for the connection of simple pèptide sequences. For the desired purpose of ion binding, poly(aspartic acid) (PAsp) was applied, resulting in the block copolymer PEO-b-PAsp. A simple testing procedure concerning the inhibition of calcium carbonate precipitation was applied for the prepared structures. A comparison with commercial builders for water treatment such as poly[(acrylic acid)-co-(maleic anhydride)] or poly(aspartic acid) stresses the superb calcium carbonate crystallization inhibition efficiency (up to the 20 fold) of the double hydrophilic block copolymer stabilizers.     

Synthesis and structural study of an ABA block copolymer consisting of poly(γ-benzyl l-glutamate) as the A component and poly(propylene glycol) as the B component

ABA type block copolymers composed of poly(γ-benzyl L-glutamate) (PBLG) as the A component and poly(propylene glycol) as the B component were obtained by polymerization of γ-benzyl L-glutamate N-carboxyanhydride, initiated by amine groups at both ends of poly(propylene glycol). From circular dichroism measurements in ethylene dichloride solution as well as from infrared spectra measurements in the solid state, it was found that the polypeptide block exists in the α-helical conformation, as in PBLG homopolymer. Wide-angle X-ray diffraction patterns for the block copolymers depend on the casting solvent and show basically similar reflections as the PBLG homopolymer.     

Polymerization of lactones, 17. Synthesis of ethylene glycol-L-lactide block copolymers

The anionic polymerization of L -lactide in the presence of the sodium poly(ethylene glycol)ate in tetrahydrofuran at 25°C yields “tailored” ABA triblock copolymers having the expected compositions and molecular weights. During the polymerization, a slight racemization of L-lactide was observed. The water absorption experiments indicate that the introduction of the poly(ethylene glycol) block into the L-lactide polymer chain markedly increases its hydrophilicity. It was revealed that the morphology and mechanical properties of block copolymers depend strongly on their composition and thermal treatment.     

Monomeric and polymeric azoinitiators

The reaction of ethylene glycol, 1,4-butanediol, 1,6-hexanediol, 3,6-dioxaoctane-1,8-diol (triethylene glycol), poly(ethylene oxide)s with M?_n = 300,1000 and 3000, or with poly(propylene oxide)s with M?_n = 425 and 2000 in excess with AIBN leads to the corresponding bis(hydroxyalkyl) 2,2′-azodiisobutyrates ( 1a – i ). These initiators are suited to synthesize telechelics. With equimolar amounts of AIBN and 3-oxapentane-1,5-diol (diethylene glycol), poly(ethylene oxide)s with M?_n = 300, 1000 and 12000, poly(propylene oxide) with M?_n = 425, or with poly(tetrahydrofuran) with M?_n = 1000 and 2000 polymeric azoinitiators of structure 2 are formed. Blockcopolymers may be synthesized by means of these polymeric azocompounds.     

Synthesis and aqueous phase behavior of thermoresponsive biodegradable poly(D,L‐3‐methylglycolide)‐block‐poly(ethylene glycol)‐block‐poly(D,L‐3‐methylglycolide) triblock copolymers

Novel biodegradable thermosensitive triblock copolymers of poly(D ,L ‐3‐methylglycolide)‐block‐poly(ethylene glycol)‐block‐poly(D ,L ‐3‐methylglycolide) (PMG‐PEG‐PMG) have been synthesized. Ring‐opening polymerization of D ,L ‐3‐methyl‐glycolide (MG) initiated with poly(ethylene glycol) (PEG) and Ca[N(SiMe₃)₂]₂(THF)₂ provided triblock copolymers with alternating lactyl/glycolyl sequences of controlled molecular weight, low polydispersity index and uniform chain structure. At relatively low temperatures (≈ 10 °C) these copolymers formed clear solutions in water up to high concentrations (50 wt.‐%). Depending on molecular mass ratios of PMG and PEG blocks, a sol‐gel transition or an increase in viscosity without gel formation was observed upon increasing the temperature of the aqueous solutions. The temperature‐induced gelation was ascertained by rheology and dynamic differential scanning calorimetry (DDSC).

Phase diagram of PMG‐PEG‐PMG 1 400‐1 450‐1 400 in an aqueous solution.     

Preparation of poly(ethylene glycol) grafted poly(3-hydroxyalkanoate) networks

Poly(3-hydroxyalkanoate)-g-poly(ethylene glycol) crosslinked graft copolymers are described. Poly(3-hydroxyalkanoate)s containing double bonds in the side chain (PHA-DB) were obtained by co-feeding Pseudomonas oleovorans with a mixture of nonanoic acid and anchovy (hamci) oily acid (in weight ratios of 50/50 and 70/30). PHA-DB was thermally grafted with a polyazoester synthesized by the reaction of poly(ethylene glycol) with MW of 400 (PEG-400) and 4,4′-azobis(4-cyanopentanoyl chloride). Sol-gel analysis and spectrometric and thermal characterization of the networks are reported.     

Grafting of N-vinylpyrrolidone onto segmented polyurethane initiated by 2,2′-azoisobutyronitrile

An unsaturated segmented polyurethane was prepared from cis-2-butene-1,4-diol, poly(ethylene glycol), butane-1,4-diol, and methylene bis(4-phenyl isocyanate). Graft copolymerization of N-vinylpyrrolidone onto the segmented polyurethane was studied using 2,2′-azoisobutyronitrile (AIBN) as initiator in DMF as solvent. The graft copolymers were isolated from the homopolymer and the ungrafted polyurethane by selective solvent extraction. The effect of reaction time, temperature, and of monomer and initiator concentrations on the degree of grafting was also investigated. The percent grafting was enhanced with increasing [AIBN] up to 40 mmol.dm^-3, but then decreased at higher concentrations. An explanation based on complex formation between the monomer and the urethane linkages in polyurethane is suggested.     

Complex formation of polyampholyte with proton-accepting polymers through hydrogen bonding

Polyampholytes, copolymers of methacrylic acid and 2-dimethylaminoethyl methacrylate [C(MA-AM)x] of various composition, were synthesized. Their isoelectric points (pI) are in the range 5 < pH < 7. Undissociated methacrylic acid residues in the copolymers can interact with ether oxygens of poly(ethylene glycol) (PEG) and ketone groups of poly(N-vinyl-2-pyrrolidone) (PVPo) in the acidic pH region through hydrogen bonding. However, only copolymers having more than about 60 mol-% of methacrylic acid residues form complexes with PVPo and high molecular weight PEG. The composition of the obtained complexes is 1:1 (mole ratio of methacrylic acid residues of the copolymer to repeating units of PVPo and PEG).     

Synthesis of amphiphilic star-shaped and graft copolymers based on polystyrene and poly(ethylene oxide)

Amphiphilic block macromonomers possessing a central unsaturation were synthesized by condensation of polystyrene half-ester of maleic acid {α-[2-(3-carboxyacryloyloxy)ethyl]-ω-sec-butylpoly[1-phenylethylene]} with poly(ethylene glycol) monoether or polystyrene-block-poly(ethylene oxide). In the radical monomer cis-trans-isomerization homopolymerization of the diblock macromonomers, four-to eight-armed amphiphilic star-shaped copolymers were obtained. Radical copolymerization of the diblock macromonomers with styrene led to graft copolymers with low degree of grafting. The triblock macromonomers proved to be unable to polymerize.     

The different behaviors of skeletal muscle cells and chondrocytes on PEGT/PBT block copolymers are related to the surface properties of the substrate

The attachment, proliferation, morphology, and differentiation of two cell types-skeletal muscle cells and chondrocytes-were investigated on different compositions of poly(ethylene glycol) and poly(butylene terephthalate) segmented block copolymers. Four weight percentages (40, 55, 60, and 70%) and two different molecular weights (300 and 1000 Da) of poly(ethylene glycol) were tested. Varying the weight percentage and molecular weight of poly(ethylene glycol) resulted in different behaviors for skeletal muscle cells and chondrocytes. The attachment of skeletal muscle was the highest (similar to tissue culture polystyrene) when copolymers containing 55 wt % of poly(ethylene glycol) were used, regardless of the poly(ethylene glycol) molecular weight. Maximum proliferation and differentiation of skeletal muscle cells was achieved when copolymers containing 55 wt % and 300 Da molecular weight of poly(ethylene glycol) were used. In contrast, the weight percentage and molecular weight of poly(ethylene glycol) had no significant effect on chondrocyte attachment and proliferation; the attached chondrocytes retained a differentiated phenotype only when a 70 wt % of poly(ethylene glycol) was used. Cell behavior was correlated with the surface properties of the copolymer films, as indicated by contact-angle measurements. These results suggest that an optimized wt % and molecular weight of poly(ethylene glycol) will be useful depending on the specific cell type.     

Synthesis and characterization of multiblock copolymers poly[poly(L-lactide)-block-polydimethylsiloxane]

The preparation of multiblock copolymers poly[poly(L -lactide)-block-polydimethylsiloxane] by polycondensation of bifunctional oligomers via hydrosilylation is described. The procedure consists first to synthesize the two bifunctional oligomers α,ω-disilyl-polydimethylsiloxane and α,ω-diallyl-poly(L -lactide). The former is prepared in one step by cationic polymerization of octamethylcyclotetrasiloxane in the presence of 1,1,3,3-tetramethyldisiloxane as end-blocker. Two steps are necessary to prepare α,ω-diallyl-poly(L -lactide). The first one is the polymerization of L-lactide initiated by the system ethylene glycol/tin 2-ethylhexanoate. In a second step, the hydroxyl end-groups of the resulting α,ω-dihydroxy-poly(L -lactide) are transformed, by reaction with allyl isocyanate, into terminal allylic functions. Different multiblock copolymers were prepared by hydrosilylation (catalyzed by hexachloroplatinic acid) using the same α,ω-diallyl-poly(L -lactide) (M?_n = 2000 g · mol ^?1) and various α,ω-disilyl-polydimethylsiloxanes (M?_n from 1 750 to 9 000 g · mol ^?1). The influence of parameters such as temperature, stoichiometry of reactive end-groups and catalyst concentration on the molecular weight of the copolymers was studied. High molecular weight copolymers were obtained (DP_n > 12 by SEC). In addition to the biodegradability of the lactic acid units, the immiscibility of the polydimethylsiloxane and poly(L -lactide) blocks imparts thermoplastic elastomer properties to these copolymers. The crystallinity of the poly(L -lactide) phase is dependent on the molecular weight of the polydimethylsiloxane blocks.     

Initiators based on poly(ethylene glycol) for starting heterophase polymerizations: generation of block copolymers and new particle morphologies

Radical heterophase polymerizations with poly(ethylene glycol) radicals lead to the formation of block copolymer particles where the block copolymer architecture and the particle morphology depend on the number of radical per poly(ethylene glycol) chain, the radical termination mode, and the polarity of the monomer, respectively. The thermal decomposition of symmetrical poly(ethylene glycol) azo-initiators following the classical recipes of Heitz results in one radical per poly(ethylene glycol) chain whereas the number of radicals can be adjusted between one or two in the redox system poly(ethylene glycol)/cerium ions. The polymerization of styrene results in latex particles with an almost spherical morphology, consisting of block copolymers, only. In case of a methyl methacrylate polymerization the latex morphology depends on the architecture of the block copolymers formed. Heterophase polymerization with poly(ethylene glycol) azoinitiators in oligo(ethylene glycol) (average molecular weight 200 g · mol⁻¹) instead of in water results in particles with random shape and a strongly indented interface which is explained by the surface tension between polymers and solvent being close to zero.     

Controlled Synthesis and Characterization of Poly[ethylene‐block‐(L,L‐lactide)]s by Combining Catalytic Ethylene Oligomerization with “Coordination‐Insertion” Ring‐Opening Polymerization

Model poly[ethylene‐block‐(L ,L ‐lactide)] (PE‐block‐PLA) block copolymers were successfully synthesized by combining metallocene catalyzed ethylene oligomerization with ring‐opening polymerization (ROP) of L ,L ‐lactide (LA). Hydroxy‐terminated polyethylene (PE‐OH) macroinitiator was prepared by means of ethylene oligomerization on rac‐dimethyl‐silylen‐bis(2‐methyl‐benz[e]indenyl)‐zirconium(IV)‐dichloride/methylaluminoxane (rac‐MBI/MAO) in presence of diethyl zinc as a chain transfer agent, and subsequent in situ oxidation with synthetic air. Poly[ethylene‐block‐(L ,L ‐lactide)] block copolymers were obtained via ring‐opening polymerization of LA initiated by PE‐OH in toluene at 100 °C mediated by tin octoate. The formation of block copolymers was confirmed by ¹H NMR spectroscopy, fractionation experiments, thermal behavior, and morphological characterization using AFM and light microscopy techniques.

     

Thermotropic liquid-crystalline aromatic-aliphatic polyimides, 2. Effect of aliphatic spacer lengths and polymer compositions on the liquid-crystalline properties of poly(imide-carbonate)s

Novel thermotropic liquid-crystalline (LC) aromatic-aliphatic poly(imide-carbonate)s were prepared by melt polycondensation of N,N′-bis(ω-hydroxyalkyl)pyromellitdiimide and/or 6,6′-(4,4′-biphenylylenedioxy)dihexanol with hexamethylene bis(phenylcarbonate). The monomers, dihydroxyalkyl derivatives of pyromellitdiimide, were obtained by deacetylation of the intermediate diacetylated compounds with p-toluenesulfonic acid. The intermediates were synthesized by condensation of pyromellitic dianhydride (PMDA) with ω-aminoalcohols followed by cyclization with acetic anhydride. Most of the poly(imide-carbonate)s obtained in high yields have high molecular weights and show very good solubilities in organic solvents. The structures of the resulting polymers were confirmed by FT/IR and NMR spectroscopy measurements and elemental analyses. Thermotropic LC properties of the polymers were evaluated by differential scanning calorimetry (DSC), polarizing microscopy and powder X-ray analyses. These measurements suggested that only biphenyl unit-rich copolymers and polymers with shorter spacers next to the imide ring, which favor the orientation of the imide ring and the polymer chains, form nematic LC mesophases. The glass transition temperatures (T_g) and the LC phase transition temperatures tend to decrease with increasing imide-neighboring aliphatic spacer lengths.     

Synthesis and properties of novel block copolymers containing poly(lactic-glycolic acid) and poly(ethyleneglycol) segments

A synthetic process for obtaining high-molecular-weight block copolymers containing poly(lacticglycolic acid) and poly(ethylene glycol) segments has been established. This process involves the reaction of poly(ethylene glycols) with phosgene, followed by polycondensation of the resulting ,ω-bis (chloroformates) with poly(lactic-glycolic acid) oligomers. The copolymers have been characterized for their molecular weight, solubility properties, water absorption and preliminarily thermal behaviour. All evidence points to the conclusion that the process described is a general one, enabling biodegradable polymers to be obtained tailor-made according to specific requirements.     

Polylactones, 22 ABA triblock copolymers of L-lactide and poly(ethylene glycol)

Triblock copolymers were prepared from L-lactide and a poly(ethylene glycol) of M?_n = 1020. With GeO₂ and SnO₂ only low conversions were obtained, regardless of the reaction temperature. Sb₂O₃ caused partial racemization, and only SnO gave satisfactory results. When other samples of poly(ethylene glycol) were used (e.g., with M?_n = 600 or 3250), partial racemization occurred even with SnO. However, with Sn(II) 2-ethylhexanoate, racemization-free triblock copolymers were obtained under the reaction conditions used. The results of the characterization indicate that the triblock copolymers possess unimodal molecular weight distribution. The lactide blocks crystallize in the α-modification and suppress in most, but not all, cases the crystallization of the poly(ethylene glycol) blocks. The crystallization of long poly(ethylene glycol) blocks observed in several cases indicates a triphasic character of these samples.     

Backbone‐Hydrolyzable Poly(oligo(ethylene glycol) bis(glycidyl ether)‐alt‐ketoglutaric acid) with Tunable LCST Behavior

A novel class of backbone‐hydrolyzable LCST‐type polyesters of poly(oligo(ethylene glycol) bis(glycidyl ether)‐alt‐ketoglutaric acid)s (PE_mKs) with numerous reactive sites is presented in this study. The target polyesters are prepared with commercially available hexa(ethylene glycol) bis(glycidyl ether) (E₆BG), ethylene glycol bis(glycidyl ether) (E₁BG), and 2‐ketoglutaric acid (KGA). By varying the initial feed ratio of E₆BG and E₁BG and the polymer concentration, a tunable thermal responsiveness with excellent repeatability is achieved.     

Synthesis and permeation behavior of membranes from segmented multiblock copolymers containing poly(ethylene oxide) and poly(β-benzyl L-aspartate) blocks

Novel segmented multiblock copolymers ( 7 ) were synthesized by linking poly(ethylene oxide) (PEO) blocks with poly(β-benzyl L -aspartate)(PBLA) blocks via urethane and urea bonds, which were formed by the reaction of 4,4′-methylenediphenyl isocyanate ( 5 ) with the terminal hydroxyl groups of α-hydro-ω-hydroxypoly(oxyethylene) ( 4 ) and the terminal amino groups of poly(β-benzyl L -aspartate)-block-iminohexamethyleneimino-block-poly(β-benzyl L -aspartate) ( 3 ) [prepared from 1,6-hexanediamine ( 1 ) and β-benzyl L -aspartate N-carboxy anhydride ( 2 )], respectively. Membranes with various water contents were obtained from these copolymers by changing the lengths of the PEO and PBLA segments. The study of the permeation of 1-phenyl-1,2-ethanediol, vitamin B₁₂ and myoglobin through the membranes showed a high dependency of the permeability on the molecular weight of the solutes.     

Poly(ethylene glycol)s containing enzymatically degradable bonds

The possibility to use poly(ethylene glycol) (PEG) as a synthetic, water-soluble polymeric carrier of biologically active compounds was investigated. The relationship between structure of oligopeptide (amino acid)-PEG conjugates and their hydrolysis catalyzed by chymotrypsin was studied. Two types of derivatives were synthesized: Derivatives of PEG 2000, containing an oligopeptide sequence terminating in p-nitroaniline (drug model) and higher molecular weight derivatives of PEG 2000 containing in the main chain enzymatically and hydrolytically degradable bonds. The rates of chymotrypsin catalyzed release of p-nitroaniline at pH 8,0 and 25°C were determined over a range of substrate concentrations to derive values for k_cat and K_M. The influence of the length and detailed structure of the oligopeptide sequence on the rate of hydrolysis was demonstrated. Comparison with copolymers of N-(2-hydroxypropyl)methacrylamide and poly(maleic anhydride-co-vinylpyrrolidone) showed that the sterical hindrance of the formation of the enzyme-substrate complex is much less pronounced in the PEG-oligopeptide conjugates. The latter conclusion is also valid in the case of cleavage of PEG derivatives which contain enzymatically degradable bonds in the main chain. The incorporation of a single amino acid residue (phenylalanine) into the main PEG chain is sufficient to make the polymer susceptible to chymotrypsin catalyzed hydrolysis.     

Biodegradable poly(D,L-lactic acid)-poly(ethylene glycol)-monomethyl ether diblock copolymers: structures and surface properties relevant to their use as biomaterials

To obtain biodegradable polymers with variable surface properties for tissue culture applications, poly(ethylene glycol) blocks were attached to poly(lactic acid) blocks in a variety of combinations. The resulting poly(D,L-lactic acid)-poly(ethylene glycol)-monomethyl ether (Me.PEG-PLA) diblock copolymers were subject to comprehensive investigations concerning their bulk microstructure and surface properties to evaluate their suitability for drug delivery applications as well as for the manufacture of scaffolds in tissue engineering. Results obtained from 1H-NMR, gel permeation chromatography, wide angle X-ray diffraction and modulated differential scanning calorimetry revealed that the polymer bulk microstructure contains poly(ethylene glycol)-monomethyl ether (Me.PEG) domains segregated from poly(D,L-lactic acid) (PLA) domains varying with the composition of the diblock copolymers. Analysis of the surface of polymer films with atomic force microscopy and X-ray photoelectron spectroscopy indicated that there is a variable amount of Me.PEG chains present on the polymer surface, depending on the polymer composition. It could be shown that the presence of Me.PEG chains in the polymer surface had a suppressive effect on the adsorption of two model peptides (salmon calcitonin and human atrial natriuretic peptide). The possibility to modify polymer bulk microstructure as well as surface properties by variation of the copolymer composition is a prerequisite for their efficient use in the fields of drug delivery and tissue engineering.