Methoxy poly(ethylene glycol)‐b‐poly(octadecanoic anhydride)‐b‐methoxy poly(ethylene glycol) amphiphilic triblock copolymer nanoparticles as delivery vehicles for paclitaxel

A series of amphiphilic triblock copolymers, methoxy poly(ethylene glycol)‐b‐poly(octadecanoic anhydride)‐b‐methoxy poly(ethylene glycol) (mPEG‐b‐POA‐b‐mPEG), were prepared via melt polycondensation of methoxy poly(ethylene glycol) (mPEG) and poly(octadecanoic anhydride) (POA). mPEG‐b‐POA‐b‐mPEG were characterized by FTIR, ¹H‐NMR, GPC, DSC, and XRD. Drug‐loaded mPEG‐b‐POA‐b‐mPEG nanoparticles (NPs) with spherical morphology and narrow size polydispersity index were prepared by nanoprecipitation technique with paclitaxel as the model drug. In vitro release behaviors of drug‐loaded NPs present that the biphasic process and the release mechanism of each phase are zero order drug releases. According to this study, mPEG‐b‐POA‐b‐mPEG NPs could serve as suitable delivery agents for paclitaxel and other hydrophobic drugs. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and micelle formation of triblock copolymers of poly(methyl methacrylate)-b-poly(ethylene oxide)-b-poly(methyl methacrylate) in aqueous solution

Amphiphilic triblock copolymers of poly(methyl methacrylate)-b-poly(ethylene oxide)-b-poly(methyl methacrylate) (PMMA-b-PEO-b-PMMA) with well-defined structure were synthesized via atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA) initiated by the PEO macroinitiator. The macroinitiator and triblock copolymer with different PMMA and/or PEO block lengths were characterized with ¹H and ¹³C NMR and gel permeation chromatography (GPC). The micelle formed by these triblock copolymers in aqueous solutions was detected by fluorescence excitation and emission spectra of pyrene probe. The critical micelle concentration (CMC) ranged from 0.0019 to 0.016 mg/mL and increased with increasing PMMA block length, while the PEO block length had less effect on the CMC. The partition constant K_v for pyrene in the micelle and in aqueous solution was about 10⁵. The triblock copolymer appeared to form the micelles with hydrophobic PMMA core and hydrophilic PEO loop chain corona. The hydrodynamic radius R_h,app of the micelle measured with dynamic light scattering (DLS) ranged from 17.3 to 24.0 nm and increased with increasing PEO block length to form thicker corona. The spherical shape of the micelle of the triblock copolymers was observed with an atomic force microscope (AFM). Increasing hydrophobic PMMA block length effectively promoted the micelle formation in aqueous solutions, but the micelles were stable even only with short PMMA blocks.     

Characterization of amphiphilic hydrocarbon modified Poly(ethylene glycol) synthesized through ring-opening reaction of 2-(1-octadecenyl)succinic anhydride

Poly(ethylene glycol) (PEG) triblock and diblock amphiphilic block copolymers were synthesized from poly(ethylene glycol) and poly(ethylene glycol) monomethyl ether, respectively. The hydroxyl groups of PEG readily react with 2-(1-octadecenyl) succinic anhydride (OSA) at 140 °C through ring-opening reaction of the succinic anhydride. Both the PEG-OSA diblock and triblock copolymers are produced without use of any solvent or catalyst. The molecular structure of the copolymers was characterized by ¹H NMR and FTIR spectroscopy, and the thermal properties by DSC. The behavior of the copolymers in selective and nonselective solvents was studied by ¹H NMR spectroscopy in deuterium oxide and d-chloroform. The aggregation of the polymers in water was studied with a particle size analyzer and a transmission electron microscope (TEM) in bright field mode. The results show that the hydrophobic C₁₈ chain with intramolecular succinic anhydride linker can be attached to the hydrophilic PEG chain, an ester bond forming between the blocks. The copolymers exhibit flexible, liquid-like hydrophobic blocks even in water, which is a nonsolvent for OSA. PEG-OSA block copolymers self-organize in water, forming micellar polymer aggregates in nanoscale.     

In vitro ageing and degradation of PEG-PLA diblock copolymer-based nanoparticles

Diblock copolymers composed of poly(oxy-ethylene) (POE) and poly(dl-lactic acid) segments were synthesized by anionic polymerization of d,l-lactide using the oxyanion formed by reaction of the monohydroxyl monomethoxy-poly(ethylene glycol) on sodium hydride. For comparison, a similar copolymer was prepared by using tin octoate to catalyze the lactide polymerization. The copolymers were used to make nanoparticles, which were stored at 4 °C. After a few months under these storage conditions, a dramatic decrease of the poly(ethylene glycol) content was observed, however, the mean diameter of the nanoparticles was not affected. The degradation of the nanoparticles was investigated in vitro under conditions selected to mimic physiological conditions. Changes of characteristics were monitored by ¹H NMR, SEC, DLLS and CZE on nanoparticles and/or on the degradation by-products dissolved in the ageing medium. According to their nanometric dimensions, the microparticles degraded very slowly and there was no difference in behaviour between the sodium hydride and the stannous octoate-derived copolymers.     

Calorimetric investigation of temperature effect on the interaction between poly(ethylene oxide) and sodium dodecylsulfate in water

The interaction of four poly(ethylene oxides), with molar masses of 1500, 3350, 10 000 and 100 000 g mol⁻¹ with sodium dodecylsulfate, at 15, 25, 35 and 65 °C was investigated by isothermal titration calorimetry. No significant change of the critical aggregation concentration values or of the amount of surfactant bound was observed within this temperature range. The profiles for the variation of the observed enthalpies with surfactant concentration, however, are quite different for the four studied temperatures, what has been interpreted as a consequence of a change in the mode of poly(ethylene oxide) (PEO) interaction with sodium dodecylsulfate (SDS) micelles within this temperature range.     

Thermal degradation mechanism of poly(ethylene succinate) and poly(butylene succinate): Comparative study

Two aliphatic polyesters that consisted from succinic acid, ethylene glycol and butylene glycol, —poly(ethylene succinate) (PESu) and poly(butylene succinate) (PBSu)—, were prepared by melt polycondensation process in a glass batch reactor. These polyesters were characterized by DSC, ¹H NMR and molecular weight distribution. Their number average molecular weight is almost identical in both polyesters, close to 7000 g/mol, as well as their carboxyl end groups (80 eq/10⁶ g). From TG and Differential TG (DTG) thermograms it was found that the decomposition step appears at a temperature 399 °C for PBSu and 413 °C for PESu. This is an indication that PESu is more stable than PBSu and that chemical structure plays an important role in the thermal decomposition process. In both polyesters degradation takes place in two stages, the first that corresponds to a very small mass loss, and the second at elevated temperatures being the main degradation stage. The two stages are attributed to different decomposition mechanisms as is verified from the values of activation energy determined with iso-conversional methods of Ozawa, Flyn, Wall and Friedman. The first mechanism that takes place at low temperatures, is auto-catalysis with activation energy E = 128 and E = 182 kJ/mol and reaction order n = 0.75 and 1.84 for PBSu and PESu, respectively. The second mechanism is nth-order reaction with E = 189 and 256 kJ/mol and reaction order n = 0.68 and 0.96 for PBSu and PESu, respectively, as they were calculated from the fitting of experimental results.     

Chitosan-N-poly(ethylene glycol) brush copolymers: Synthesis and adsorption on silica surface

Chitosan-N-poly(ethylene glycol) brush copolymers with different degree of substitution (DS) were synthesized via reductive amination of chitosan by methoxy poly(ethylene glycol) (MPEG) aldehyde. Chitosan-N-MPEG copolymers were high-molecular-weight products with desirable DS; solubility and solution viscosity of those copolymers depended on the method of the synthesis of MPEG aldehyde and on DS. Synthesis of MPEG aldehyde by the use of TEMPO radical/BAIB was not suitable because of partial oxidation of methoxy groups of MPEG resulting in bifunctional PEG derivatives leading to cross-linking. Adsorption studies of chitosan-N-MPEG graft copolymers on silica surface show that these polymers adsorb in highly hydrated layers.     

PEO coated magnetic nanoparticles for biomedical application

This paper reports on the preparation, characterization and stealthiness of superparamagnetic nanoparticles (magnetite Fe₃O₄) with a 5 nm diameter and stabilized in water (pH ? 6.5) by a shell of water-soluble poly(ethylene oxide) (PEO) chains. Two types of diblock copolymers, i.e., poly(acrylic acid)-b-poly(ethylene oxide), PAA-PEO, and poly(acrylic acid)-b-poly(acrylate methoxy poly(ethyleneoxide)), PAA-PAMPEO, were prepared as stabilizers with different compositions and molecular weights. At pH ? 6.5, the negatively ionized PAA block interacts strongly with the positively-charged nanoparticles, thus playing the role of an anchoring block. Aggregates of coated nanoparticles were actually observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The hydrodynamic diameter was in the 50-100 nm range and the aggregation number (number of nanoparticles per aggregate) was lying between several tens and hundred. Moreover, the stealthiness of these aggregates was assessed “in vitro” by the hemolytic CH50 test. No response of the complement system was observed, such that biomedical applications can be envisioned for these magnetic nanoparticles. Preliminary experiments of magnetic heating (10 kA/m; 108 kHz) were performed and specific absorption rate varied from 2 to 13 W/g_(Fe).     

New multiblock poly(ether-ester)s based on poly(trimethylene terephthalate) as rigid segments

A series of novel poly(trimethylene terephthalate)-block-poly(tetramethylene oxide) (PTT--PTMO) segmented block copolymers were synthesised by transesterification in the melt of dimethyl terephthalate, 1,3-propanediol and poly(tetramethylene oxide) glycol (PTMO, 1000 g/mol). A range of multiblock copolymers were synthesized, with flexible PTMO segments contents varying from 20 to 80 wt%. The novel poly(ether-block-ester)s were characterized by using viscometry, hardness measurements, differential scanning calorimetry (DSC), dynamic mechanical thermal analysis (DMTA), and tensile properties.     

Transformations of poly(methoxy hexa(ethylene glycol) methacrylate)-b-(2-(diethylamino)ethyl methacrylate) block copolymer micelles upon metalation

Micelle transformations upon metalation (i.e., incorporation of metal compounds and metal nanoparticle formation) in poly(methoxy hexa(ethylene glycol) methacrylate)-block-poly((2-(diethylamino)ethyl methacrylate)), PHEGMA-b-PDEAEMA, solutions have been studied using transmission electron microscopy (TEM) and photon correlation spectroscopy (PCS). Three different methods for the formation of metalated micelles are compared: (A) dissolution of the block copolymers in pure water followed by incorporation of platinic acid (H(2)PtCl(6).6H(2)O), (B) micellization in acidic molecular solutions of block copolymers induced by interaction of the protonated amino groups with the PtCl(6)(2)(-) ions, and (C) incorporation of metal species in pH-induced micelles. The latter method leads to well-defined metalated micelles of 22-25 nm diameter containing nanoparticles with diameters of 1.3-1.5 nm. No nanoparticle aggregation is observed. Good agreement is obtained for the sizes of the platinic acid-containing micelles assessed by TEM and PCS.     

Thermal characterization of biodegradable methoxy poly(ethylene glycol)-b-poly(d,l-lactide)/methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) blend nanoparticles

Biodegradable methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (MPEG-b-PDLL) and methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (MPEG-b-PCL) diblock copolymers were synthesized by ring-opening polymerization of DLL and CL monomers in bulk using stannous octoate, and MPEG as the initiating system. Surfactant-free MPEG-b-PDLL/MPEG-b-PCL blend nanoparticles were prepared by the nanoprecipitation method. The influences of block length and blend ratio on morphology, average size, and thermal properties of the blend nanoparticles were determined. The blend nanoparticles were spherical in shape. The average particle sizes slightly decreased as the MPEG-b-PCL blend ratio increased. ¹H-NMR and thermogravimetry revealed the different MPEG-b-PDLL/MPEG-b-PCL blend ratios of the nanoparticles. Differential scanning calorimetry showed that the MPEG-b-PCL crystallinity steadily decreased as the MPEG-b-PDLL blend ratio increased, suggesting miscible blending between the MPEG-b-PDLL and MPEG-b-PCL in the amorphous phase of the nanoparticle matrix.     

A novel strategy for synthesis of amphiphilic π-shaped copolymers by RAFT polymerization

The amphiphilic π-shaped copolymers with narrow molecular weight distribution (M_w/M_n = 1.04-1.09) based on polystyrene (PSt) and poly(ethylene glycol) have been synthesized successfully. The reversible addition-fragmentation transfer (RAFT) polymerization of St in the presence of dibenzyl trithiocarbonate and N,N′-azobis(isobutyronitrile) (AIBN) yielded macro RAFT agent PSt-SC(S)S-PSt, subsequent reaction with excess maleic anhydride (MAh) at 80 °C in tetrahydrofuran afforded the PSt-MAh-SC(S)S-MAh-PSt. It was used as RAFT agent in the RAFT polymerization of St, and finally the amphiphilic π-shaped copolymers were obtained by the reaction of MAh with hydroxyl-terminated poly(ethylene glycol methyl ether) at 90 °C for 48 h. Their structures were confirmed by FT-IR and ¹H NMR spectra, and their molecular weight and molecular weight distribution were measured by gel permeation chromatography.     

Syntheses of amphiphilic biodegradable copolymers of poly(ethyl ethylene phosphate) and poly(3-hydroxybutyrate) for drug delivery

Biodegradable and amphiphilic triblock copolymers poly(ethyl ethylene phosphate)-poly(3-hydroxy-butyrate)-poly(ethyl ethylene phosphate) (PEEP-b-PHB-b-PEEP) have been successfully synthesized through ring-opening polymerization. The structures are confirmed by gel permeation chromatography and NMR analyses. Crystallization investigated by X-ray diffraction reveals that the block copolymer with higher content of poly(ethyl ethylene phosphate) (PEEP) is more amorphous, showing decreased crystallizability. The obtained copolymers self-assemble into biodegradable nanoparticles with a core-shell micellar structure in aqueous solution, verified by the probe-based fluorescence measurements and transmission electronic microscopy (TEM) observation. The hydrophobic poly(3-hydroxybutyrate) (PHB) block serves as the core of the micelles and the micelles are stabilized by the hydrophilic PEEP block. The size and size distribution are related to the compositions of the copolymers. Paclitaxel (PTX) has been encapsulated into the micelles as a model drug and a sustained drug release from the micelles is observed. MTT assay also demonstrates that the block copolymers are biocompatible, rendering these copolymers attractive for drug delivery. Supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No.20060358036)     

Crystallization of photo-chain extended poly(ethylene glycol)

Coumarin-functionalized poly(ethylene glycol) (PEG) monols and diols were isothermally crystallized at temperatures between 20 and 35 °C before and after exposure to approximately 110 J cm⁻² of ultra-violet A (λ > 300 nm, UVA) irradiation. Irradiation dimerized the coumarin groups and chain-extended the coumarin-functionalized PEG oligomers. The higher molecular weights reduced the crystal growth rate by as much as 50% compared to the non-irradiated coumarin-functionalized PEG oligomers under ambient crystallization conditions. Hoffman’s kinetic nucleation theory was utilized to evaluate the types of nucleation that occurred for the coumarin-functionalized PEG diols (COU-PEG-COU). Crystallization regimes II and III were observed for the coumarin-modified PEG oligomers before and after exposure to UVA light.     

Aggregation and solubilization of organic solvents and petrol/gasoline in water mediated by block copolymers

A series of AB and ABA block copolymers of pDEGMEMA-b-pCHMA and pCHMA-b-pDEGMEMA-b-pCHMA cyclohexyl methacrylate (CHMA) and di(ethylene glycol) methyl ether methacrylate (DEGMEMA) with M_n ranging between 18,000 and 50,000 g mol⁻¹ and PDI = 1.09-1.32 were prepared via copper(I) mediated living radical polymerization with pyridylmethanimine ligands. Aggregation properties were investigated using a combination of ¹H NMR, dynamic and static light scattering. For comparative purposes poly(CHMA) and poly(DEGMEMA) homopolymers were prepared. The CAC values estimated for the di- and triblock copolymers soluble in cyclohexane are lower than 0.005 g L⁻¹ whereas the values found for block copolymers in methanol solutions are less than 0.070 g L⁻¹. DLS analysis showed the presence of micellar aggregates with diameters ranging from 25 to 40 nm with particle polydispersity indexes between 0.003 and 0.183. The pCHMA-b-pDEGMEMA-b-pCHMA micelles solubilized the aqueous phase in petrol/gasoline. The block copolymer-based micelles incorporate water within their hydrophilic domains, potentially overcoming a number of practical problems such as the formation of biphasic mixtures in solvent blends due to undesired water accumulation.     

Nanosized Micelles Self-Assembled from amphiphilic dextran-graft-methoxypolyethylene glycol/poly(ε-caprolactone) copolymers

A series of amphiphilic copolymers, dextran-graft-methoxypolyethylene glycol/poly(ε-caprolactone) (Dex-g-mPEG/PCL) were synthesized by grafting both PCL and mPEG chains to dextran, and subsequently the micellar self-assembly behavior of resultant copolymers was investigated. PCL was designed by using Fmoc-protected valine other than organometallic catalyst as the initiator to ring-opening polymerize ε-caprolactone (CL) in view of the safety demand as well as the extra application potential resulting from -NH₂ group introduced after Fmoc deprotection. All the copolymers were characterized by ¹H NMR, FT-IR and GPC measurements. The prepared copolymers are capable of self-assembling into nanosized spherical micelles in aqueous solution with the diameter of around 100-200 nm determined by TEM image and DLS measurement. The critical micellar concentration (CMC) of the graft copolymers is in the range of 10-100 mg/L determined by the fluorescence robe technique using pyrene. The result also indicated that the CMC of self-assembled micelles could be adjusted by controlling the degree of substitution of mPEG and PCL, and these micelles may find great potential as drug carriers in biomedical fields.     

Structure and properties of new polyester elastomers composed of poly(trimethylene terephthalate) and poly(ethylene oxide)

Series of PTT-b-PEO copolymers with different composition of rigid PTT and PEO flexible segments were synthesized from dimethyl terephthalate (DMT), 1,3-propanediol (PDO), poly(ethylene glycol) (PEG, M_n = 1000 g/mol) in a two stage process involving transesterification and polycondensation in the melt. The weight fraction of flexible segments was varied between 20 and 70 wt%. The molecular structure of synthesized copolymers was confirmed by ¹H NMR and ¹³C NMR spectroscopy. The superstructure of these polymers was characterized by DSC, DMTA, WAXS and SAXS measurements. It was observed that domains of three types can exist in PTT-b-PEOT copolymers: semi-crystalline PTT, amorphous PEO rich phase (amorphous PEO/PTT blended phase) and semi-crystalline PEO phase. Semi-crystalline PEO phase was observed only at temperature below 0 °C for sample containing the highest concentration of PEO segment. The phase structure, thermal and mechanical properties are effected by copolymer composition. The copolymers containing 30÷70 wt% of PEO segment posses good thermoplastic elastomers properties with high thermal stability. Hardness and tensile strength rise with increase of PTT content in copolymers.     

Synthesis and characterization of pH-responsive diblock copolymers with cadaverine side groups

In this paper, we report the synthesis and characterization of a new pH-responsive diblock copolymer, methoxy poly(ethylene glycol)-b-poly[N¹-(4-vinylbenzyl) pentane-1,5-diamine dihydrochloride] (mPEG-b-PVBPDA). The monomer with cadaverine side group (N¹-(4-vinylbenzyl)pentane-1,5-diamine dihydrochloride, VBPDA) and the macroinitiator (mPEG-ACVA) were synthesized, respectively, and mPEG-b-PVBPDA was then obtained by free radical polymerization. The structure and molecular weight of mPEG-b-PVBPDA was confirmed by FTIR, ¹H NMR, and GPC-MALLS measurements. At low pH, it is hydrophilic due to the protonation of the amine groups. With increasing pH, deprotonation occurs, and the hydrophobicity of PVBPDA block increases. This molecular feature leads to interesting aggregation behavior of mPEG-b-PVBPDA in aqueous solutions at different pH as revealed by DLS measurements, TEM observations, and fluorescence spectrometry. This polymer was further subjected to gene delivery evaluations, and promising DNA transfection capacity has been found.     

Synthesis of poly(styrene-b-dimethylsiloxane) multi-block copolymers via polyhydrosilylation reaction

Poly(styrene-b-siloxane) multi-block copolymers have been prepared by polyhydrosilylation reaction. Four copolymers have been synthesized by the reaction of α,ω-bis silane polydimethylsiloxanes with α,ω-bis allyl polystyrene. The latter has been obtained by the reaction of carboxy-telechelic polystyrene with allyl glycidyl ether. ¹H NMR and FT-IR analyses show that the polyhydrosilylation reaction is quantitative. The copolymer molecular weights were determined by SEC to be about 25,000 g/mol. The properties of these copolymers were characterized by DSC and DMA analyses. The rubbery plateaus of these copolymers are in the range of −115 °C to 85 °C.     

Novel aromatic poly(amide-hydrazide)s based on the bipyridine. Part I: Synthesis, characterization and thermal stability

A series of new poly(amide-hydrazide)s were obtained by the direct polycondensation of 5-amino 5′-carbohydrazido-2,2′-bipyridine with commercially available diacids by means of triphenyl phosphite and pyridine in the N-methyl-2-pyrrolidone (NMP) solutions containing dissolved LiCl. The resulting hydrazide containing polymers exhibited inherent viscosities in the 0.42-0.64 dL/g range. All copolymers were soluble in polar solvents such as NMP and dimethyl sulfoxide (DMSO). Most of the amorphous hydrazide copolymers formed flexible and tough films by solvent casting. The poly(amide-hydrazide)s had glass-transition temperatures (T_g) between 178 and 206 °C. All hydrazide copolymers could be thermally converted into the corresponding poly(amide-oxadiazole) approximately in the region of 300-400 °C, as evidenced by the DSC thermograms. The oxadiazole polymers and copolymers showed a dramatically decreased solubility and higher T_g when compared to their respective hydrazide prepolymers. They exhibited T_gs of 197-248 °C and were stable up to 450 °C in air or nitrogen.