Micelle-like structures of poly(ethylene oxide)-block-poly(2-hydroxyethyl aspartamide)-methotrexate conjugates

The objective of this research was to prepare and characterize a micelle-like structure composed of a diblock copolymer-methotrexate (MTX) conjugate. MTX was attached on poly(ethylene oxide)-block-poly(2-hydroxyethyl aspartamide) (PEO-b-PHAA), obtained by aminolysis of PEO-b-poly(β-benzyl- -aspartate) (PBLA) with ethanolamine. It was hypothesized that after attachment of MTX onto PEO-b-PHAA through an ester bond, the amphiphilic conjugate would self-assemble into a micelle-like structure that would gradually release MTX, owing to unfavorable hydrolysis in a nonpolar core. An active ester of MTX was reacted with PEO-b-PHAA, providing a substitution ratio of 20–45% (molar ratio of drug to aspartamide units). At these levels, PEO-b-PHAA-MTX conjugate may self-assemble in an aqueous medium. Transmission electron microscopy revealed small spherical particles that had a mean diameter of 14 nm. There was no evidence of secondary aggregation. An absence of ¹H-NMR peaks of MTX in D₂O indicated that PEO-b-PHAA-MTX conjugates self-assembled into supramolecular structure where MTX resides in a site with highly restricted mobility, likely a core of a micelle-like structure. Accordingly, the loss of MTX by hydrolysis from PEO-b-PHAA-MTX conjugates was slow at neutral pH, with less than 20% released after 10 days. The stabilization of ester bonds in a nonpolar core of a micelle-like structure is novel in the design of soluble polymer-drug conjugates. PEO-b-PHAA-MTX conjugate micelles may help improve the biodistribution of MTX and help overcome drug resistance.     

Fluorocarbon- containing hydrophobically modified poly(N-isopropylacrylamide)

A fluorocarbon-modified poly(N-isopropylacrylamide) has been synthesized by copolymerization of N-isopropyl acrylamide with a small amount of acrylate or methacrylate containing a perfluoroalkyl group. It was found that the hydrophilicity of macromolecular backbone is an important factor to the solution properties of the copolymers and that hydrophobic association between fluorocarbon groups is stronger than that between the corresponding hydrocarbon analogies. The viscosity of some of the copolymer solutions was very sensitive to temperature. It was dilatant at higher fluorocarbon comonomer content ( > 0.20-1.0 mol%) and was Newtonian at very low fluorocarbon comonomer content (0.03-0.2 mol% ) . Evidence for hydrophobic association of the fluorocarbon groups was obtained from the effects of adding Nad and surfactants on the solution viscosity. The LC-ST properties of these copolymers were studied by DSC method and this was also found to be consistent with hydrophobic association between the fluorocarbo     

疏水改性聚丙烯酸溶液的流变特性研究

本文通过沉淀聚合制备了具有不同主链结构的疏水改性聚丙烯酸(HMPA),由Huggins方程确定了HMPA在溶液(水,盐/水,醇/水)中的特性粘数[η]和Huggins常数KH,采用流变学法研究了HMPA溶液的疏水缔合行为和流变特性.研究表明,HMPA溶液具有典型的剪切变稀行为,主链结构对HMPA溶液的缔合行为和流变特性有显著影响.主链含有疏水链段的HMPA在乙二醇/水溶液中形成类似弹性体的凝胶网络结构,具有较大的活化能,其表观粘度具有明显的温度敏感性.     

Dilute solution properties of tactic poly(2-hydroxyethyl methacrylate)

Isotactic and syndiotactic poly(2-hydroxyethyl methacrylate) (PHEMA) have been prepared. Intrinsic viscosity–molecular weight relationships were established for the isotactic and syndiotactic PHEMA in N,N-dimethylformamide (DMF) at 25°C by solution viscometry and light scattering. The unperturbed dimensions and interaction parameters were examined in DMF, water, methanol, ethanol, and water–methanol (1:7 by volume) mixture for isotactic PHEMA and in DMF, methanol, and water–methanol (1:7 by volume) mixture for syndiotactic PHEMA using the Stockmayer–Fixman representation. The results suggest that the compact random coil structure for isotactic PHEMA occurs in water solvent and the isotactic PHEMA is more highly extended in polar solvents.     

Interpolymer complexes of poly(acrylic acid) with poly(2-hydroxyethyl acrylate) in aqueous solutions

Complexes formed from poly(acrylic acid) and poly(2-hydroxyethyl acrylate) were studied in aqueous solutions by viscometric, turbidimetric, FTIR spectroscopic, and thermogravimetric analysis methods. The formation of interpolymer complexes stabilized by hydrogen bonds was observed. It was found that the compositions of these interpolymer complexes are strongly dependent on the concentration of polymers, the order of mixing the solutions, and the pH. It was demonstrated that the complexation ability of poly(2-hydroxyethyl acrylate) is relatively low compared to other known nonionic water-soluble polymers. However, it can be significantly increased via hydrophobic modification of the poly(acrylic acid) using cetyl pyridinium bromide.     

Synthesis of hydrophobically modified poly(acrylamides) in water-in-oil emulsions

High-molecular-mass hydrophobically modified poly(acrylamides) have been prepared via water-in-oil miniemulsion copolymerization of acrylamide and lauryl methacrylate initiated by 2,2′-azoisobutyronitrile. The incorporation of the hydrophobic comonomer into the polymer backbone is indirectly confirmed by the rheological and associative properties of polymer solutions. The copolymers prepared from the reaction mixtures containing less than 5 mol % lauryl methacry late demonstrate the associative behavior in aqueous solutions, as evidenced by fluorescence spectroscopy (a decrease in the polarity parameter of pyrene), static and dynamic light scattering (overestimated effective molecular masses and appearance of a peak due to aggregates), and rheological measurements (a rise of viscosity relative to that of the acrylamide homopolymer). A further increase in the content of lauryl methacrylate leads to formation of polymers possessing limited solubility in water. At the acrylamide-to-hydrophobic monomer equimolar ratio, homopolymers arise along with the insoluble copolymer.     

Aggregation behaviour of hydrophobically modified poly(allylammonium) chloride

 The behaviour of hydrophobically modified poly(allylammonium) chloride having octyl, decyl, dodecyl and hexadecyl side chains has been studied in aqueous solution using fluorescence emission techniques. Micropolarity studies using the I ₁/I ₃ ratio of the vibronic bands of pyrene show that the formation of hydrophobic microdomains depends on both the length of the side chain and the polymer concentration. The I ₁/I ₃ ratio of the polymers with low hydrophobe content (less than 5% mol) changes substantially when reaching a certain concentration. These changes are assigned to aggregation originating from interchain interactions. This behaviour is also confirmed by the behaviour of the monomer/excimer emission intensities of pyrenedodecanoic acid used as a probe. For polymers having dodecyl side chains and hydrophobe contents higher than 10%, aggregates are formed independently of the polymer concentration. Anisotropy measurements show that microdomains resulting from the inter- and/or intramolecular interactions are similar to those observed for cationic surfactants. Viscosity measurements show that the coil dimensions are substantially decreased for the polymers having high hydrophobe contents, indicating intramolecular associations. Received: 10 November 1999/Accepted: 7 April 2000     

Effects of temperature on neutron scattering from aqueous solutions of hydrophobically modified poly(ethylene oxide)

The effect of temperature on the structure of aqueous dispersions of hydrophobically end-capped poly(ethylene oxide) (PEOM) was investigated by small angle neutron scattering (SANS). Polymers with hydrogenated or deuterated n-octadecyl end-groups were studied in heavy water or in a mixture heavy water / water, respectively. In the latter case the PEO chains were selectively matched. In all the cases, the scattering curves were characterised by a main peak which revealed organisation of polymers into micelles consisting of hydrophobic cores surrounded by repulsive PEO coronae. Measurements were performed in the semi-dilute regime where micelles coronae overlap. At constant polymer concentration, an increase in temperature leads to decreasing solvent strength of water for the PEO chains and decreasing repulsion between the PEO coronae. As a result, the intensity of the peak in a mixture of water /heavy water decreases with temperature On the contrary, in heavy water, the peak of the scattered intensity increases with increasing temperature. This scattering behaviour is interpreted on the basis of a scaling theory of the semi-dilute solutions of star-like polymer micelles.     

Synthesis and aqueous solution properties of hydrophobically modified anionic acrylamide copolymers

In this investigation, hydrophobically modified polyacrylamide with low amounts of anionic long‐chain alkyl was synthesized by the free radical polymerization in deionized water. This water‐soluble copolymerization method is more convenient compared with the traditional micellar copolymerization methods. The copolymers were characterized using Fourier transform infrared, ¹H NMR, and the molecular weight and polydispersity were determined using gel permeation chromatography. The solution behavior of the copolymers was studied as a function of composition, pH, and added electrolytes. As NaCl was added to solutions of AM/C₁₁AM copolymers or pH was lowered, the shielding or elimination of electrostatic repulsions between carboxylate groups of the C₁₁AM unit lead to coil shrinkage. The steady shear viscosity and dynamic shear viscoelastic properties in semidilute, salt‐free aqueous solutions were conducted to examine the concentration effects on copolymers. In addition, the shear superimposed oscillation technique was used to probe the structural changes of the network under various stresses or shear conditions. We prepared hydrophobically modified polyacrylamide with N‐alkyl groups in the aqueous medium. The advantage of this method is that the production is pure without surfactants. These results suggest that the unique aqueous solution behavior of the copolymers is different from conventional hydrophobically associating acrylamide. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 2465–2474, 2008     

Thin films of hydrophobically modified poly(N,N-dimethylacrylamide)

The behavior of a poly(N,N-dimethylacrylamide) hydrophobically modified by incorporating 0.33 mol % of a pyrenyl derivative, [4-(1-pyrenyl)butyl]amine hydrochloride (PY) and 3.56 mol % of dodecylamine (DO) has been studied at the air/water interface. Surface pressure-area isotherm measurements show that the film is initially anchored by the hydrophobic groups at the air-water interface with a pancake-like structure and, with increasing surface pressure, evolves to a quasi mushroom structure, finally reaching a brush configuration at high pressures. Monolayers of this polymer were transferred to silica substrates using the Langmuir-Blodgett (LB) technique at 5, 15, and 25 mN.m(-1). The properties of the LB films were studied by steady-state and time-resolved fluorescence as well as by atomic force microscopy. The results show that the aggregates formed at low pressures are disrupted by pressure increase, while the water-soluble poly(N,N-dimethylacrylamide) becomes dissolved in the water subphase.     

Composition dependence of ordered structures in mixed micellar aqueous solutions of hydrophobically modified poly(ethylene glycol)s

Ordered structures of micellar aqueous solutions of poly(ethylene glycol) (PEG) monododecylether mixtures [octaethylene glycol monododecylether (C12E8) and poly(ethylene glycol) monododecylether (C12E25)] have been investigated as a function of the C12E8/C12E25 composition by means of X‐ray scattering. C12E8 and C12E25 have different chain lengths of corona PEG, that is, 8 and 25 repeating units, respectively. The following results have been obtained. First, in the C12E8‐rich and C12E25‐rich regions, the mixtures take hexagonal and cubic phases, respectively. The hexagonal phase remains over a wider range of compositions and is more stable for the mixing of the other component than the cubic phase. Second, in the C12E8‐rich region of the cylindrical hexagonal packing, the nearest‐neighbor micellar distance increases, whereas the association number density remains constant, with an increasing amount of mixed C12E25 possessing longer corona chains. Third, in contrast to this, the nearest‐neighbor micellar distance of the body‐centered cubic packing exhibits almost no change, whereas the association number increases as C12E8 of shorter corona chains is increasingly incorporated. Fourth, self‐consistent field calculations reasonably reproduce the experimental findings of the second and third observations. We discuss the phase stability and the structural changes with the composition in terms of differences in the PEG corona‐chain length. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 2474–2483, 2005     

The conformational stability of tactic poly(2-hydroxyethyl methacrylate) in aqueous salt solutions

The conformational stability of tactic poly(2-hydroxyethyl methacrylate) (PHEMA) in aqueous salt solutions was investigated by measurements of swelling, surface-free energy, and differential scanning calorimetry, as this polymer in water is sensitive in various electrolytes. In the case of inorganic salts, the major role for the salt effect is played by the anions, and the exposure of hydrophobic components at the PHEMA surface can be correlated with the increase of the degree of swelling. The influence of cations is considerably weaker. In the case of organic salts, tetraalkylammonium halides cause the chain extension more effectively with the increase of alkyl chain length in the cations. This result indicates that the breakdown of the hydrophobic parts in PHEMA provides an important clue on conformational stability. The amount of water molecules bound with the hydrophilic sites of tactic-PHEMA mainly depends on the chain extension and the hydration of cations. Since the sites in tactic-PHEMA influenced by the cation and the anion are different, their effects cause the conformational transition at a specific range of salt concentration. © 1993 John Wiley & Sons, Inc.     

Interaction between a nonionic surfactant and a hydrophobically modified 2-hydroxyethyl cellulose

Interaction between the nonionic surfactant Tergitol 15-S-7 and hydrophobically modified 2-hydroxyethyl cellulose (HMHEC) was studied rheologically in a semidilute regime of HMHEC. The low-shear viscosity of HMHEC was increased with addition of surfactant from 25 to 250 ppm, in which the critical micelle concentration of surfactant was near 39 ppm, and then decreased to a value smaller than that of pure HMHEC with further addition of surfactant to 1000 ppm. An interesting shear-induced phenomenon was observed. The steady-state shear measurements show that there exist crossovers between viscosity-shear rate curves of HMHEC solutions with and without surfactant added, whereas it was not observed in the HEC-surfactant systems. Moreover, added Tergitol 15-S-7 reversed the temperature effect on the viscosity of the HMHEC solution. That is, increasing temperature to or near the cloud point raises the viscosity of the HMHEC-surfactant aggregates, in contrast to the viscosity decrease in the pure HMHEC solutions. A possible mechanism based on the necklace model and the clouding phenomenon is conjecturally introduced to explain such phenomena.     

Effects of poly(N‐isopropylacrylamide) on the solution properties of hydrophobically modified acrylamide copolymer

The hydrophobic interaction between hydrophobically modified acrylamide copolymer (HMPAM) and poly(N‐isopropylacrylamide) (PNIPAM) in aqueous solutions was investigated. The results show that the solution properties of HMPAM are significantly influenced by the addition of PNIPAM. In dilute regime, the intrinsic viscosity of HMPAM in 0.025 wt % PNIPAM/0.1 M NaCl mixed solution is 17.52 dL g^?1, about 2 times 8.66 dL g^?1, that in 0.1 M NaCl solution, which is due to the attractive interaction between the hydrophobic parts of PNIPAM and HMPAM molecules. In semidilute regime, below the saturation concentration, the addition of PNIPAM can lead to both the apparent viscosity and the modulus of HMPAM solutions increasing, which is attributed to the number of aggregation junctions increasing, responsible for the increase of the contribution of the reversible network to the viscosity increase, the β value. In addition, a thermothickening behavior for the HMPAM/PNIPAM mixed solution is observed with increasing temperature over 15–30 °C, which is consistent with the large increase of the Huggins coefficient of HMPAM in the presence of PNIPAM from 1.95 to 7.59 as temperature increases from 25 to 30 °C. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 709–715, 2005     

Interactions of hydrophobically modified poly(sodium acrylate) with globular proteins

The association of a series of hydrophobically modified poly(sodium acrylate) (HMPA) with lysozyme, a cationic globular protein, or with bovine serum albumin (BSA), an anionic globular protein, was investigated at pH=9 by rheology and to a lesser extent by steady-state fluorescence spectroscopy. Under suitable concentration conditions, this association leads to a drastic viscosity enhancement which is improved when the polymer hydrophobicity is increased. A mechanism is proposed: the hydrophobic regions of the globular proteins interact strongly with the alkyl groups of one or more polymer chains. In the later case, the macromolecules are crosslinked via the proteins, which leads to viscosity enhancement and even gelation. Analogies and differences between these systems and surfactant/HMPA systems previously studied in our laboratory are emphasized and discussed.     

Swelling properties of pH‐responsive hydrophobically modified hydrogels of poly(methacrylic acid‐co‐diallylammonium salt) in aqueous solution

Using diallylmethyl alkyl ammonium salts (CCX) (X is alkyl's chain length, represents 12, 14, 16, and 18, respectively) as a comonomer of methacrylic (MAA), hydrophobically modified hydrogels of poly diallylmethyl alkyl ammonium salts‐methacrylic acid (PCCX‐MAA) were prepared by free radical copolymerization in aqueous solution. The synthetic conditions, such as dosage of cross‐linking agent, reaction concentration and length of alkyl chain were studied in detail. Results indicated that the swelling degree of hydrogels was decreased with dosage of cross‐linking agent, or monomer concentration increased at different pH. Incorporation of the different length of alkyl chain hydrophobic CCX units on PMAA chains by random distribution can change reswelling kinetics. The required time for reaching equilibrium swelling state was longest for PCC16‐MAA. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and phase behavior of aqueous poly(N-isopropylacrylamide-co-acrylamide), poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) and poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate)

Poly(N-isopropylacrylamide) (PNIPAM) and random copolymers of Poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate) (PNIPAM-HEMA), poly(N-isopropylacrylamide-co-acrylamide) (PNIPAM-AAm), and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PNIPAM-DMAA) with various volume fractions γ of NIPAM were synthesized by radical polymerization. The phase behavior of the polymers in water was investigated by means of optical transmittance and dynamic light scattering. With decreasing γ, the cloud point temperature T _cp for PNIPAM-HEMA decreased whereas the T _cp for both PNIPAM-AAm and PNIPAM-DMAA increased. Increase of hydrodynamic radius around T _cp, which resulted from the aggregation of the globules of each polymer, was observed from dynamic light scattering. The relationships between the reciprocal of T _cp of the polymer solutions and 1-γ were linear for the three copolymers in the experimental range of 0.65<γ<1. The results are discussed from the aspect of the interaction parameters of copolymer solutions.     

Tripolyphosphate-sensitive egg phosphatidylcholine liposomes incorporating hydrophobically modified poly(ethylene imine)

Liposomes, which release their contents in answer to tripolyphosphate (TPP, a penta-anion), were prepared by immobilizing hydrophobically modified poly(ethylene imine) (HmPEI) on the surface of egg phosphatidylcholine (egg PC) liposome. HmPEI was prepared by covalently attaching decanoyl chloride to PEI through a condensation reaction. According to the ¹H NMR spectrum, the number of decanoyl chloride per one molecule of PEI was about 21, and HmPEI was air/water interface-active. HmPEI could readily complex with TPP in HEPES buffer (30 mM, pH 7.0), confirmed by Fourier transformed infrared spectrophotometer spectroscopy. The complexation increased with increasing the concentration of HmPEI and TPP, investigated through the measurement of optical density and light scattering intensity. Liposomes incorporating HmPEI were prepared by a film hydration and sonication method. The liposomes were multi-lamellar vesicles, observed on transmission electron microscope. Liposomes free of HmPEI did not release calcien when they were mixed with TPP. Liposomes whose egg PC/HmPEI was relatively low (e.g., 20:1 and 20:2) released calcein but not extensively (less than 10%) when mixed with TPP. Liposomes whose egg PC/HmPEI was relatively high (e.g., 20:4 and 20:20) released calcein extensively. For example, when the liposomes with lager amount of HmPEI were mixed with TPP so that HmPEI/TPP weight ratio was 8:1, the release degree in 60 sec was more than 70%. HmPEI can complex with TPP through electrostatic interaction and the complexation was thought to cause perturbation in the liposomal membranes and trigger the release.     

Synthesis and characterization of poly(butylene terephthalates) modified by hydroquinone bis(2-hydroxyethyl)ether

A series of thermoplastic poly(butylene-co-hydroquinone bis(2-hydroxyethyl)ether terephthalates) (PBHT), with different molar ratios of hydroquinone bis(2-hydroxyethyl)ether (HQEE)/1,4-butanediol 9/91, 18/82 and 27/73, were synthesized via melt polycondensation. The compositions, thermodynamics and crystallization properties of the obtained copolyesters were characterized in detail by ¹H NMR, differential scanning calorimeters (DSC), thermogravimetric analysis (TGA) and X-ray diffraction (XRD). These results showed that the PBHTs were successfully synthesized, and the incorporation of the HQEE group significantly improved thermal properties of the polymers. However, HQEE did not change the crystal structure of PBT. The T_m values of the copolymers decreased (from 208?°C to 174?°C) with increasing content of HQEE segments, on the contrary, T_g values increased (from 37?°C to 43?°C). The temperatures for 5% weight loss did not decrease and appeared at a range of 373–377?°C.