Methotrexate-loaded biodegradable polymeric micelles: preparation, physicochemical properties and in vitro drug release

Polymeric micelles based on amphiphilic diblock copolymers methoxy poly(ethylene glycol)-polylactide with various hydrophobic lengths were designed as carriers of poorly water-soluble anticancer drug methotrexate (MTX). Relationship between physicochemical characteristics of micelles and release behavior was explored. The critical micelle concentration was determined by fluorescence spectroscopy using 9-chloromethyl anthracene as fluorescence probe. Core-shell type polymeric micelles were prepared by free-surfactant dialysis technique. The mean size of micelles loaded with MTX was 50-200 nm with narrow polydispersity. Physicochemical properties of drug-loaded micelles were evaluated. In vitro release behavior of MTX was also investigated. MTX was continuously released from micelles and less than 50% MTX was released in 5 days. Release rate was dependent on chemical structures of micelles and enhanced by decreasing polylactide lengths.     

Self-aggregated nanoparticles of cholesterol-modified glycol chitosan conjugate: Preparation, characterization, and preliminary assessment as a new drug delivery carrier

Cholesterol-modified glycol chitosan (CHGC) conjugate was synthesized and characterized by FTIR and ¹H NMR. The degree of substitution (DS) was 6.7 cholesterol groups per 100 sugar residues of glycol chitosan. CHGC formed self-aggregated nanoparticles with a roughly spherical shape and a mean diameter of 228 nm by probe sonication in aqueous medium. The physicochemical properties of the self-aggregated nanoparticles were studied using dynamic light scattering (DLS), transmission electron microscopy (TEM) and fluorescence spectroscopy. The critical aggregation concentration (CAC) of self-aggregated nanoparticles in aqueous solution was 0.1223 mg/mL. Indomethacin (IND), as a model drug, was physically entrapped into the CHGC nanoparticles by dialysis method. The characteristics of IND-loaded CHGC (IND-CHGC) nanoparticles was analyzed using DLS, TEM and high performance liquid chromatography (HPLC). The IND-CHGC nanoparticles were almost spherical in shape and their size increased from 275 to 384 nm with the IND-loading content increasing from 7.14% to 16.2%. The in vitro release behavior of IND from CHGC nanoparticles was studied by a dialysis method in phosphate buffered saline (PBS, pH 7.4). IND was released in a biphasic way. The initial rapid release in 2 h and slower release for up to 12 h were observed. The results indicated that CHGC nanoparticles had a potential as a drug delivery carrier.     

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.     

共同装载吴茱萸碱和Fe3O4纳米粒子的磁性药物载体的制备

以单甲醚-聚乙二醇-聚（丙交酯-乙交酯）（mPEG-PLGA）作为载体,采用溶液透析的方法共同装载抗癌药物吴茱萸碱和Fe₃O₄ 磁性纳米粒子. 通过透射电子显微镜、红外光谱、紫外-可见光谱及体外释放实验、普鲁士蓝染色、体外毒性实验和磁靶向研究,综合评价了磁性纳米药物载体的性能. 结果表明,磁性药物载体胶束分散性良好,粒径均一,有较高的载药量和包封率,能够实现药物缓释,具有磁靶向特性.     

Synthesis of amphiphilic poly(ether-amide) dendrimer endcapped with poly(ethylene glycol) grafts and its solubilization to salicylic acid

An amphiphilic dendrimer (DPEA-PEG) grafting polyethylene glycol at the terminals was prepared by endcapping of dendritic poly(ether-amide) (DPEA) with isocyanate terminated linear polyethylene glycol (PEG-NCO). The molecular structure was verified by gel permeation chromatography (GPC), ¹H NMR and FT-IR. The micelle characteristic of DPEA-PEG in water was investigated. The critical micelle concentration (CMC) was determined by a fluorescence technique to be 55.5 mg/L. The hydrodynamic radius of micelles was measured by dynamic light scattering (DLS) to be 76.2 nm. The UV–vis spectrum showed that the solubility of salicylic acid increased from 1.91 to 2.78 mg/L when the concentration of DPEA-PEG attained 5 mg/mL in an aqueous solution.     

Excess molar enthalpies of binary mixtures containing ethylene glycols or poly(ethylene glycols) + ethyl alcohol at 308.15 K and atmospheric pressure

Excess molar enthalpies, , of binary mixtures containing ethylene glycols and poly(glycols) + ethyl alcohol were measured by a flow microcalorimeter at 308.15 K and at atmospheric pressure over the whole composition range. Binary mixtures contain ethyl alcohol + ethylene glycol, + di(ethylene glycol), + tri(ethylene glycol), + tetra(ethylene glycol), + poly(ethylene glycol)-200, + poly(ethylene glycol)-300, + poly(ethylene glycol)-400, + poly(ethylene glycol)-600. Effects of the molecular weight distribution (MWD), of the polymer were investigated too, by preparing three additional samples of poly(ethylene glycol) with the same number average molecular weight (M_n ≈ 300), but different MWD. For all mixtures, results were fitted to the Redlich–Kister polynomial. curves are asymmetrical, showing positive values which vary from 280 J mol⁻¹ (diethylene glycol + ethyl alcohol) to 1034 J mol⁻¹ (mixture containing PEGs (200 + 400) + ethyl alcohol). Effects of changes in the glycols chain length and in MWD on the molecular interactions among the mixture components are discussed.     

Self-aggregated nanoparticles of cholesterol-modified chitosan conjugate as a novel carrier of epirubicin

Cholesterol-modified chitosan conjugate with succinyl linkages (CHCS) was synthesized and characterized by fourier transform infrared (FTIR) and proton nuclear magnetic resonance (¹H NMR). The degree of substitution (DS) of cholesterol moiety determined by elemental analysis was 7.3%. The self-aggregation behavior of CHCS was evaluated by the fluorescence probe technique and the critical aggregation concentration (CAC) was 1.16 × 10⁻² mg mL⁻¹ in 0.1 M acetic acid solution. CHCS formed monodisperse self-aggregated nanoparticles with a roughly spherical shape and a mean diameter of 417.2 nm by probe sonication in aqueous media. Epirubicin (EPB), as a model anticancer drug, was physically entrapped inside CHCS self-aggregated nanoparticles by the remote loading method and the characteristics of EPB-loaded CHCS self-aggregated nanoparticles were analyzed using dynamic laser light scattering (DLLS), transmission electron microscopy (TEM) and fluorescence spectroscopy. EPB-loaded CHCS self-aggregated nanoparticles were almost spherical in shape and their size increased from 338.2 to 472.9 nm with the EPB-loading content increasing from 7.97% to 14.0%. The release behavior of EPB from CHCS self-aggregated nanoparticles was studied in vitro by dialysis method. The results showed that EPB release rate decreased with the pH increase of the release media. In phosphate buffered saline (PBS, pH 7.4), the EPB release was very slow and the total release amount was about 24.9% in 48 h.     

Amphiphilic poly(ethylene glycol)-b-poly(ethylene brassylate) copolymers: One-pot synthesis,self-assembly,and controlled drug release

A set of amphiphilic poly(ethylene glycol)-b-poly(ethylene brassylate) (PEG-b-PEB) copolymers based on the PEB hydrophobic block was first synthesized by ring-opening polymerization of ethylene brassylate with an organic catalyst. The EB/PEGmolar ratios and reaction times were adjusted to achieve different chain lengths of PEB. Block copolymers that were characterized by ¹H NMR and GPC could selfassemble into multimorphological aggregates in aqueous solution, which were characterized by DLS and TEM. The hydrophobic doxorubicin (DOX) was chosen as a drug model and successfully encapsulated into the nanoparticles. The release kinetics of DOX were investigated.     

Depolymerisation of poly(ethylene terephthalate) fibre wastes using ethylene glycol

Poly(ethylene terephthalate) [PET] fibre wastes from an industrial manufacturer was depolymerised using excess ethylene glycol [EG] in the presence of metal acetate as a transesterification catalyst. The glycolysis reactions were carried out at the boiling point of ethylene glycol under nitrogen atmosphere up to 10 h. Influences of the reaction time, volume of EG, catalysts and their concentrations on the yield of the glycolysis products were investigated. The glycolysis products were analysed for hydroxyl and acid values and identified by different techniques, such as HPLC, ¹H NMR and ¹³C NMR, mass spectra, and DSC. It was found that the glycolysis products consist mainly of bis(hydroxyethyl)terephthalate [BHET] monomer (>75%) which was effectively separated from dimer in quite pure crystalline form.     

Amphiphilic hydrogel nanoparticles. Preparation, characterization, and preliminary assessment as new colloidal drug carriers

Inverse emulsion photopolymerization of acrylated poly(ethylene glycol)-bl-poly(propylene glycol)-bl-poly(ethylene glycol) and poly(ethylene glycol) was successfully employed to prepare stable, cross-linked, amphiphilic nanoparticles. Even at low emulsifier concentrations (2%) and high water-to-hexane weight ratios (35/65), the stability of the inverse emulsion allowed for the formation of well-defined colloidal material. Inverse emulsion characteristics and polymerization conditions could be controlled to vary the size of the nanoparticles between 50 and 500 nm. The presence of hydrophobic nanodomains within these otherwise hydrophilic nanoparticles was verified by using pyrene as a microenvironmentally sensitive probe. The hydrophobic poly(propylene glycol)-rich domains appear to be suitable for incorporation of hydrophobic drugs, encapsulating Doxorubicin up to 9.8% (w/w). We believe that the complex nano-architecture of these materials makes them a potentially interesting colloidal drug delivery carrier system and that the method should be useful for a number of amphiphilic macromolecular precursors.     

Methotrexate-incorporated polymeric nanoparticles of methoxy poly(ethylene glycol)-grafted chitosan

We prepared methotrexate (MTX)-encapsulated polymeric nanoparticles using methoxy poly(ethylene glycol) (MPEG)-grafted chitosan (ChitoPEG) copolymer. MTX-encapsulated polymeric nanoparticles of ChitoPEG copolymer has around 50–300 nm in particle size and showed spherical shape when observed by transmission electron microscope (TEM). In ¹H nuclear magnetic resonance (NMR) study, the specific peaks of MTX and chitosan as a drug carrying inner-core disappeared at D₂O and only the specific peak of MPEG was observed, while specific peaks of MPEG, MTX, and chitosan appeared in DCl/D₂O mixtures. These results indicated that MTX was complexed with chitosan and then core–shell type nanoparticles had formed in aqueous environment, i.e., MTX/chitosan complexes composed of inner-core and MPEG composed of outer-shell of the nanoparticles. Loading efficiency of MTX in the polymeric nanoparticles was 94% (w/w) of ChitoPEG-1, 91.1% (w/w) of ChitoPEG-2, 90.1% (w/w) of ChitoPEG-3 and 65.2% (w/w) of ChitoPEG-4, expectively. The higher the drug feeding ratio, the higher the drug content and the lower the loading efficiency. The higher the MPEG graft ratio in the copolymer, the lower the drug content and loading efficiency. Drug contents evaluated by ¹H NMR were the same as found by UV spectrophotometer.     

Interaction between PAMAM 4.5 dendrimer, cadmium and bovine serum albumin: a study using equilibrium dialysis, isothermal titration calorimetry, zeta-potential and fluorescence

Binding of Cd²⁺ by PAMAM 4.5 dendrimer was studied by equilibrium dialysis, isothermal titration calorimetry and zeta-potential measurement. The following binding parameters were obtained: n = 23.8 ± 9.5, K_b = 4.7 ± 0.9 × 10³ in water; and n = 41.3 ± 13.4, K_b = 2.1 ± 0.8 × 10³ in 0.15 mol/l phosphate-buffered saline. The location of the bound Cd²⁺ is discussed. The interactions between bovine serum albumin, PAMAM 4.5 dendrimer and cadmium were analyzed using fluorescence and equilibrium dialysis. The competition between Cd²⁺ binding to BSA and PAMAM 4.5 dendrimer was investigated. It is proposed that PAMAM 4.5 dendrimer could be successfully used for extracting Cd²⁺ from aqueous solutions (environmental protection).     

Y-shaped block copolymers of poly(ethylene glycol) and poly(N-isopropylacrylamide) synthesized by ATRP

Novel Y-shaped block copolymers of poly(ethylene glycol) and poly(N-isopropylacrylamide),PEG-b-(PNIPAM)_2,were successfully synthesized through atom transfer radical polymerization(ATRP).A difunctional macroinitiator was prepared by esterification of 2,2-dichloroacetyl chloride with poly(ethylene glycol) monomethyl ether(PEG).The copolymers were obtained via the ATRP of N-isopropylacrylamide(NIPAM) at 30℃with CuCl/Me_6TREN as a catalyst system and DMF/H_2O(v/v = 3:1) mixture as solvent.The resulting copo...     

pH-Responsive Self-assembled Nanoparticles of Simulated P(AA-co-SA)-g-PEG for Drug Release

Simulated graft copolymer of poly(acrylic acid-co-stearyl acylate) [P(AA-co-SA)] and poly(ethylene glycol) (PEG) was synthesized, where acrylic acid, stearyl acylate and PEG was employed as the pH-sensitive, hydrophobic and hydrophilic segment, respectively. Polymeric nanoparticles prepared by the dialysis of simulated graft copolymer solution in dimethylformamide against citrate buffer solution with different pH values were characterized by transmission electron microscopy (TEM), fluorescence technique and laser light scattering (LLS). TEM image revealed the spherical shape of the self-aggregates, which was further confirmed by LLS measurements. The critical aggregation concentration increased markedly (10 to 150 mg/L) with increasing pH (4.6 to 7.0), consistent with the de-protonation of carboxylic groups at higher pH. The hydrodynamic radius of polymeric nanoparticles decreased from 118 nm at pH 3.4 to 90 nm at pH 7.0. The controlled release of indomethacin from those nanoparticles was investigated, and the self-assembled nanoparticles exhibited improved performance in controlled drug release.     

Polymeric complex micelle loaded with axially substituted silicon（IV） phthalocyanine

A novel axially substituted silicon(IV) phthalocyanine, namely di-pyridyloxy axially substituted silicon(IV) phthalocyanine 2 was synthesized and characterized by UV/vis, IR, elemental analysis, MS as well as ¹H NMR spectroscopy. Hydrophobic 2 was encapsulated by amphiphilic triblock copolymer poly[N^ε-(benzyloxycarbonyl-lysine]-poly(ethylene glycol)-poly[N^ε-(benzyl oxycarbonyl) (PLL(Z)-b-PEG-b-PLL(Z)) to form hydrophobic 2-loaded polymeric complex micelle (PIC) (2-loaded PIC). Atom force microscopy (AFM) image showed that 2-loaded PIC formed a spherical nanocarrier with approximately 35-50 nm in diameter. The fluorescence intensity and lifetime of 2-loaded PIC was significantly enhanced by the incorporation 2 into PIC nanocarrier.     

Application of the ISM EoS for polymer solutions and blends

A method for predicting an analytical equation of state for polymer mixtures and blends from surface tension and liquid state density at normal (ordinary) temperature (γ_n, ρ_n), as scaling constants, is presented. B₂(T) follows a promising corresponding-states principle. Calculation of (T) and b(T), the two other temperature-dependent constants of the equation of state, are made possible by scaling. As a result, γ_n and ρ_n are sufficient for determination of thermophysical properties of polymer mixtures and blends.

We applied the procedure to predict liquid density of poly(ethylene glycol) (PEG-200) + 1-octanol solutions and poly(propylene glycol) (PPG) + poly(ethylene glycol) (PEG-200) blends at compressed state with temperature range from 298.15 to 338.15 K and pressures up to 40 MPa. In this work, the ISM EoS is extended to polymer mixtures and blends as well as pure case without proposing any mixing rule.     

1H-NMR评价不同重油缓和热转化过程中的相对供氢能力

以蒽为化学夺氢探针,采用 ¹H-NMR为检测手段测定了三种典型重质渣油及其亚组分在380℃、临氮初压4MPa、反应8 min条件下的可供氢含量,并分析了产物的甲苯不溶物、液体馏程分布以及气体组成。结果表明,本实验条件下的热反应较为缓和,渣油及组分反应前后结构变化不明显,样品体系内部主要发生渣油及组分向夺氢体(蒽)的氢转移反应。¹H-NMR中化学位移在1.4~2.0的H_cβ和2.5~4.7的H_cα含量的变化值与化学探针法测定的实际可供氢量有较好的线性关联,可利用此两段化学位移内的氢含量评价不同重质油品在缓和热改质过程中的相对供氢能力。     

Synthesis and characterization of an acrylate polymer containing chlorine-1,3-dioxalane groups in side chains

Poly[2-（4-chlorophenyl）-1,3-dioxolan-4-yl]methyl acrylate,poly（CPhDMA）,was synthesized with radical polymerization process using 2,2′-azobisisobutyronitrile as radical initiator in 1,4-dioxane at 60℃.The structure of poly（CPhDMA） was confirmed by means of UV-Vis,FT-IR,¹H-NMR,and ¹³C-NMR spectral techniques.The molecular weight distribution values of the polymer were determined with gel permeation chromatography（GPC）.The number-average molecular weight（M_n）,weight-average molecular weight（M_W） and polydispersity index（PDI） values of poly（CPhDMA） were determined to be 10300,21600 and 2.097,respectively.The thermal degradation kinetics of the polymer was investigated by using TG/DTG-DTA and DSC analyses at different heating rates in dynamic nitrogen atmosphere.The apparent activation energy values obtained by Flynn-Wall-Ozawa and Friedman methods were found to be 91.68 and 85.23 kJ mol^-1,respectively,for thermal decomposition of poly（CPhDMA）.Also,the thermal degradation activation energy value of poly（CPhDMA） was calculated by using the Kissinger method based on the DTG,DTA and DSC data.Then the mechanism function of it was determined by master plots method.Finally,electrical and optical properties of poly（CPhDMA） were determined by four-point probe and UV-Vis techniques,respectively.     

Copolymer of tetraethylenepentamine and ethylene glycol diacrylate: Synthesis and degradation

A degradable polycation with high density of discrete charge was synthesized from tetraethylenepentamine (TEPA) and ethylene glycol diacrylate (EGDA) based on Michael addition and amidation. The cationic polymer synthesized here was denoted as PTE. Polymerization was monitored by ¹H NMR spectroscopy. According to ¹H NMR spectra, Michael addition proceeded more rapidly than amidation. After 6 h, there were no double bonds left, while amidation existed throughout the polymerization. In addition, when PTE was synthesized in chloroform and dichloromethane, respectively, there were some structural differences as shown by ¹H NMR spectroscopy. The degradation laws of PTE in aqueous solution were studied by ¹H NMR and viscosity measurements. When PTE was dissolved in deionized water, degradation proceeded in high velocity. However, in NaH₂PO₄ aqueous solution, degradation was slowered. Degradation at 37 °C proceeded obviously more rapidly than that at 25 °C. A certain degree of amidation facilitated the reduction of degradation velocity. The effect of concentration on degradation was not obvious. Interestingly, PTE synthesized in CHCl₃ was degraded more rapidly than that in CH₂Cl₂.