Synthesis of hydroxyl-capped comb-like poly(ethylene glycol) to develop shell cross-linkable micelles

A novel hydroxyl-capped comb-like poly[poly(ethylene glycol) methacrylate] (PPEGMA) was prepared via atom transfer radical polymerization (ATRP) of α-methylacryloyl-ω-hydroxyl-poly(ethylene glycol) at ambient temperature. The polymerization kinetics of the block copolymer was studied by gel permeation chromatography (GPC) and ¹H NMR. It is of interest to find the well-defined comb-like PEG can associate into micelles, which have hydrophilic PEG shell end-capped by hydroxyl groups. The hydroxyl in the shell were further cross-linked by divinyl sulfone (DVS), which could couple with two capped-end hydroxyl groups. The XPS, TEM, AFM and laser scattering particle size distribution analyzer results revealed that reactive micelles could be cross-linked by DVS. The reactive, cross-linkable micelles with PEG shell may have great potential as new drug carrier and nanoreactor, etc.     

Fabrication of core or shell reversibly photo cross-linked micelles and nanogels from double responsive water-soluble block copolymers

Poly(butanedioic acid, 1-[3-[(2-methyl-1-oxo-2-propen-1-yl)oxy]propyl] ester)-b-poly(methoxydi(ethylene glycol) methacrylate-co-4-methyl-[7-(methacryloyl)oxyethyloxy] coumarin) (PSPMA-b-P(DEGMMA-co-CMA)) block copolymer was synthesized via atom transfer radical polymerization (ATRP). The temperature and pH responsive micellization behaviors of PSPMA-b-P(DEGMMA-co-CMA) were investigated to obtain P(DEGMMA-co-CMA)-core and PSPMA-core micelles. After the two types of micelles were exposed to 365 nm UV light, core cross-linked (CCL) micelles and shell cross-linked (SCL) micelles were facilely prepared. The photo cross-linking was proved to be reversibly controlled under alternative irradiation of 365 nm and 254 nm UV light. More interestingly, block copolymer nanogels were fabricated by translating the hydrophobic core of the CCL and SCL micelles into hydrophilic via adjusting the temperature and pH. The sizes of the block copolymer nanogels can be facilely controlled by UV light irradiation. The introduction of reversibly photo cross-linkable groups into the double responsive block copolymers provides a novel approach to develop more sophisticated, controllable, and smarter nanocarriers that might have great potentials in biomedical applications.     

Preparation of core cross-linked micelles using a photo-cross-linking agent

A new method for preparing polymeric, core cross-linked (CCL) micelles has been developed using a bifunctional photo-cross-linking agent of di(4-hydroxyl benzophenone) dodecanedioate (BPD). An amphiphilic diblock copolymer of poly(ethylene glycol)-b-poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (PEG-b-P(HEMA-co-MMA)) was synthesized via atom-transfer radical polymerization (ATRP) using a PEG macroinitiator at 85 °C. The core domains of the PEG-b-P(HEMA-co-MMA) micelles containing BPD in aqueous solution were successfully photo-cross-linked by UV irradiation for only 30 min. The HEMA units incorporated in the hydrophobic block of PEG-b-P(HEMA-co-MMA) donated labile hydrogens to excited-state BP groups in BPD, and they were subsequently cross-linked by BPD through radical-radical combination. A sufficient degree of cross-linking was obtained at an equivalent ratio of the BP groups to the HEMA units.     

Synthesis of phenylphosphinic acid-containing amphiphilic homopolymers by reversible addition-fragmentation transfer (RAFT) polymerization and its aggregation in water

A novel amphiphilic phosphorus-containing polymer was prepared by RAFT polymerization of 3-[2-(acryloyloxy)ethoxy]-3-oxopropyl(phenyl) phosphinic acid (AOPA). The monomer was first synthesized by esterification of 3-[hydroxy(phenyl)phosphoryl]propanoic acid and 2-hydroxyethyl acrylate, and then the polymerizations were performed at 60 °C. The polymerization was well controlled, and the polymers with “well-defined” structures were successfully synthesized. The polymers can self-assemble to form the micelles in distilled water due to the special amphiphilic structure, and the shell of the micelles could be cross-linked by the coordination of phosphinic acid with cations. The property may promote the polymers to be used in the ionic exchange for the environment protection.     

Thermo-responsive behavior of hybrid core cross-linked polymer micelles with biocompatible shells

Poly(2-(methacryloyloxy)ethyl phosphorylcholine)-b-poly(N-isopropylacrylamide-co-2-(N,N-dimethylamino)ethyl methacrylate) (pMPC-b-p(NIPAM/DMA)) was synthesized via reversible addition-fragmentation chain transfer (RAFT) controlled radical polymerization. Below the critical aggregation temperature (CAT), i.e., about 40 °C, the diblock copolymer dissolved in water as a unimer with a hydrodynamic radius (R_h) of ca. 10 nm. Above CAT the diblock copolymers formed polymer micelles with an R_h of ca. 40 nm, composed of a p(NIPAM/DMA) core and biocompatible pMPC shell due to hydrophobic self-aggregation of the thermo-responsive p(NIPAM/DMA) block. The pendent 2-(N,N-dimethylamino)ethyl group of DMA in pMPC-b-p(NIPAM/DMA) reduced HAuCl₄ to form gold nanoparticles (AuNPs) and could attach to their surfaces. The cores of these polymer micelles could be cross-linked above CAT by HAuCl₄, which upon being reduced generated AuNPs as cross-linking points to form core cross-linked (CCL) polymer micelles, as confirmed by UV-vis absorption and dynamic light scattering measurements. The CCL polymer micelles absorbed visible light at 532 nm because of surface plasmon resonances of the AuNPs. The R_h of the CCL polymer micelles remained at ca. 40 nm regardless of temperature.     

双丙酮丙烯酰胺与海藻酸钠接枝聚合制备双亲性药物载体

双丙酮丙烯酰胺(DAAM)与海藻酸钠(SA)进行接枝聚合反应,过硫酸钾作为引发剂,制备了海藻酸钠-双丙酮丙烯酰胺两亲性共聚物,接枝率可以达到43%,该产物在水相中发生自聚集,形成直径300～500 nm的胶束。用红外光谱(FTIR)、热重分析(TGA)、荧光光谱(FS)、元素分析(EA)、扫描电镜(SEM)和Zeta电位对产物进行了表征。结果表明,胶体粒子表面带负电荷,在水中分散,结构稳定。将其用钙离子交联后形成凝胶,对于模型药物布洛芬(ibuprofen)有较好的负载率和缓释行为,载药率可以达到12%。     

Nanostructures from photo-cross-linked amphiphilic poly(ethylene oxide)-b-alkyl diblock copolymers

Poly(ethylene oxide) monomethylether was functionalized by alkyl chains of various lengths (l=10-19 methylene groups) bearing a polymerizable methacrylate moiety. Each synthesis step on the polymer gives quantitative functionalization rates. The self-assembly of the amphiphilic polymers in water was studied by light scattering for various end-groups. Sterical and polar effects were shown to influence the micellization step. The cores of the micelles formed by PEO-C_l-methacrylate were irreversibly cross-linked by UV irradiation. Star polymers that are stable under dilution in good solvent are obtained after 1-min irradiation. The hydrodynamic radius and the molar mass of the nanoparticles depend on the amount of photoinitiator introduced in the cores.     

Lysine-block-tyrosine block copolypeptides: Self-assembly,cross-linking,and conjugation of targeted ligand for drug encapsulation

This report describes the synthesis and self-assembly of poly(l-lysine)-block-poly(l-tyrosine) (PLL-b-PLT) block copolypeptides. These block copolypeptides self-assembled to form vesicles or micelles with sizes between 100 and 350 nm as confirmed by light scattering and electron microscopy. The spectral properties and chain conformation of these block copolypeptides were studied by UV/vis, fluorescence, and circular dichroism. UV cross-linked micelles and vesicles can be prepared by dimerization of tyrosine residues, evidenced by the presence of fluorescence emission at 410–430 nm. The block copolypeptides can be functionalized by a variety of cell-targeted ligands as demonstrated by conjugation of a saccharide group, lactobionolactone, onto the copolymers. A preliminary evaluation of the glycopeptides for in vitro drug release was studied. Due to the unique features exhibited by both PLL and PLT segments, it can be expected that these amphiphilic block copolypeptides to be useful as targeted drug carriers, functional nanobioreactors, and biomimetic encapsulants in the biomedical fields.     

Substrate Protection in Controlled Enzymatic Transformation of Peptides and Proteins

Proteins are involved in practically every single biological process. The many enzymes involved in their synthesis, cleavage, and posttranslational modification (PTM) carry out highly specific tasks with no usage of protecting groups. Yet, the chemists’ strategy of protection/deprotection potentially can be highly useful, for example, when a specific biochemical reaction catalyzed by a broad-specificity enzyme needs to be inhibited, during infection of cells by enveloped viruses, in the invasion and spread of cancer cells, and upon mechanistic investigation of signal-transduction pathways. Doing so requires highly specific binding of peptide substrates in aqueous solution with biologically competitive affinities. Recent development of peptide-imprinted cross-linked micelles allows such protection and affords previously impossible ways of manipulating peptides and proteins in enzymatic transformations.     

Neutron spin echo study of the dynamics of micellar solutions of randomly sulphonated polystyrene

The dynamics of phase separated micellar solutions of randomly sulphonated polystyrene ionomers in toluene were examined with neutron spin echo spectroscopy (NSE). The correlation functions demonstrated single exponential decays with a constant background offset. The relaxation rate (Γ) of the ionomer micelles at small length scales in the q range 0.075-0.16 Å⁻¹ was diffusive (Γ ∼ q²) as expected for the collective breathing mode of a cross-linked gel. At intermediate length scales in the q-range 0.025-0.075 Å⁻¹ the relaxation rates were non-diffusive (Γ ∼ q^0.36, q^0.72), which is attributed to the hopping dynamics of the individual stickers inside the ionomer micelles (τ_sticker ∼ 10 ns). At large length scales the scattering due to the phase separated inhomogeneities of the micellar network did not relax on the time scales of the measurements (<20 ns), giving rise to a constant background on the correlation functions. This slow relaxation process may be due to the hopping dynamics of whole micelles previously observed in rheology experiments (τ_micelle ∼ 0.05 s). The NSE results are in agreement with a model developed in previous small-angle neutron scattering and rheology experiments for concentrated solution of ionomeric micelles. The NSE results for the associating ionomers are markedly different from the Zimm dynamics (Γ ∼ q³) previously observed for semi-dilute and cross-linked polystyrene polymers in a good solvent. The ionomeric cross-links thus have a large impact on the polymer chain dynamics at the nanosecond time scale.     

Preparation and Characterization of Copolymer Micelles Formed by Poly(ethylene glycol)-Polylactide Block Copolymers as Novel Drug Carriers

Diblock copolymer poly(ethylene glycol) methyl ether-polylactide (MePEG-PLA) micelles were prepared by dialysis against water. Indomethacin (IMC) as a model drug was entrapped into the micelles by dialysis method. The critical micelle concentration (CMC) of the prepared micelles in distilled water investigated by fluorescence spectroscopy was 0.0051 mg/mL which is lower than that of common low molecular weight surfactants. The diameters of MePEG-PLA micelles and IMC loaded MePEG-PLA micelles in number-averaged scale measured by dynamic light scattering were 52.4 and 53.7 nm respectively. Transmission electron microscope and scanning electron microscope observation showed that the appearance of MePEG-PLA micelles was in a spherical shape. The content of IMC incorporated in the core portion of the micelles was 18 wt.%. The effects of the synthesis method of the copolymer on the polydispersity of the micelles and the yield of the micelles formation were discussed.     

Fine-Tuning Supramolecular Assemblies by Controlling Micellar Aggregates

Supramolecular assembly can be used to fabricate complex functional materials by organizing simple building blocks. However, it is difficult to control the hierarchical assembly across multiple length scales. The correlation of a supramolecular gel network and a pre-gelling aggregate will help to understand how a molecular-level assembly is translated into a higher order. Here, a functional dipeptide 2NapFF is used that can assemble in different micellar structures at high pH by varying the counterion. Replacing the counterions with a divalent calcium salt results in a cross-linked gel network, or an interesting analog “gel noodles.” The physical properties of the gel noodles can be varied by choosing specific micellar assemblies as the pre-gel. The mechanical rigidity of the gel networks is compared by nanoindentation and tensile testing, and the pattern to the structures of the micelles observed by small-angle X-ray scattering is correlated. The supramolecular assembly can be fine-tuned by using different micelles as the pre-gel without affecting the inherent gel-state properties.     

Adsorption kinetics and stability of poly(ethylene oxide)-block-polystyrene micelles on polystyrene surface

Herein, adsorption kinetics of poly(ethylene oxide)-block-polystyrene (PEO-b-PS) micelles from aqueous solution on PS thin films was investigated by quartz crystal microbalance with dissipation monitoring (QCM-D) and atomic force microscopy (AFM). The stability of adsorbed micelles against water washing was enhanced by the strong physical interaction between the substrate-identical core blocks of micelles and the PS substrate. The adsorption kinetics was investigated and analyzed by a model considering both the effects of diffusion and micelles reorganization on the PS surface. The micelles adsorption process was well captured by this model which demonstrated that the micelles reorganized on the surface after adsorption. The fitting results exhibited that the micelles with longer core blocks had less tendency to reorganize on the surface while reorganization took more part in the adsorption process of the micelles with shorter core blocks. In the stability studies, micelles with shorter PS blocks could partially desorb from the PS substrate while micelles with longer PS blocks were totally hindered from desorption. Desorption process of micelles was evaluated by the hydrodynamics-induced rolling model. The results indicated that hydrodynamic force-induced partial slip of the micelles on the PS surface might be responsible for micelle desorption. Because of the hydrophilicity of adsorbed micelle layer, adsorption amount of BSA on the modified surface was greatly reduced comparing with that of the bare PS surface.     

Synthesis, characterization and self-assembly behavior of six-armed star block copolymers with triphenylene core

Hexa-armed star block copolymers, s-[poly(l-lactide)-b-poly(styrene-co-N-acryloxysuccinimide)]₆ (s-[PLLA-b-poly(St-co-NAS)]₆) with triphenylene core have been successively prepared by the combination of ring-opening polymerization and atom transfer radical copolymerization, and they were used in the self-assembly in tetrahydrofuran, and the micelles with triphenylene core and PLLA as inner layer as well as poly(St-co-NAS) as shell were formed. After shell was cross-linked, PLLA was hydrolyzed in aqueous NaOH solution, the hollow spheres were formed. The structures, molecular weight and polydispersity index of the polymers were characterized by their ¹H NMR and FT-IR spectra, as well as GPC. Their morphologies were studied by TEM. The influence factors on the formation of various morphologies are under investigation.     

Performance properties of self-curing aqueous-based PU system with tri-glycidyl phosphate curing agent

Amino-terminated and carboxylic acid containing aqueous-based polyurethane (PU) dispersion was prepared by a conventional NCO-terminated PU prepolymer process by using isophorone diisocyanate (IPDI), polypropylene glycol-2000 (PPG-2000) and 2,2′-dimethylolpropanoic acid (DMPA) as the key raw materials. A new curing agent, tri-glycidyl phosphate (POG) was prepared from a substitution reaction of phosphorus oxychloride and glycidol. A single-component self-curable aqueous-based PU system is obtained from an addition of POG into aqueous-base PU dispersion and its curing reaction occurred among POG oxiranes and PU amino groups immediately after hydrophobic POG diffused into PU particles (as polymeric micelles). The cross-linked PU resins were resulted on drying at ambient temperature. Original PU dissolved into THF and ethanol. And its gel content increased to 90.1% and sample loss in ethanol decreased to 9.2% of this self-cured PU system with 5.0 phr POG. The limiting oxygen index (LOI) value is 20 of original PU and its LOI reached to 27 of this same self-cured PU system. The improved mechanical and thermal properties of those self-cured PU resins were evaluated, respectively in this report.     

CTAB混合反胶团萃取工业脂肪酶

研究了CTAB与Tween、含氧有机物形成的混合反胶团对工业脂肪酶进行萃取分离的效果. 实验表明,CTAB-Tween85和CTAB-含氧有机物混合反胶团的萃取率高于单一CTAB反胶团;反萃时CTAB-含氧有机物混合反胶团的反萃率与单一CTAB反胶团的反萃率相似,CTAB-Tween60和Tween40混合反胶团的反萃效果优于单一CTAB反胶团. 通过测定反萃水相的酶活,发现CTAB-TRPO混合反胶团的效果最好,酶活回收率最高,可以达到70%.     

载阿奇霉素-鼠李糖脂胶束制备工艺优化及性能表征

采用薄膜水化法制备载阿奇霉素-鼠李糖脂(AZI-RHL)胶束,以包封率、载药量为评价指标,通过单因素试验和正交试验优化制备工艺,并考察其理化性质。制备载药胶束前先测定RHL水溶液的临界胶束浓度(CMC)。结果表明,RHL水溶液的CMC值约为0.25 mg/mL。优化后的最佳制备工艺条件为：RHL投料量100 mg,甲醇用量12 mL,搅拌时长20 min。在此条件下制备的AZI-RHL胶束呈球形,水动力学直径为136.3±68.5 nm,Zeta电位为-23.1±6.8 mV,包封率为80.34%±0.60%,载药量为19.42%±0.48%。红外光谱证明AZI包埋在胶束中。体外释放试验表明AZI-RHL胶束具有一定的缓释作用,其体外累计释放曲线符合Ritger-Peppas方程,释放药物以Fick扩散为主。综上所述,AZI-RHL胶束的制备工艺稳定可靠,胶束粒径小,且包封率、载药量高,是一种有潜力的新型制剂。     

通过表面活性剂分子结构预测胶束特性的定量计算方法

表面活性剂性能的表现要通过表面活性剂分子形成胶束才可以体现。因此揭示表面活性剂胶束的性质是非常重要的，本文对影响表面活性剂胶束性质的因素进行了研究，提出了切实的计算公式。     

反胶团酶反应过程开发研究进展

反胶团酶反应具有水相与有机相酶反应的共同优点 ,因而受到人们的重视。制约其实际应用的重要原因在于如何解决酶的重复利用问题。最初人们采用水溶液萃取法回收酶 ,但由于条件苛刻 ,酶活回收率较低。相变法利用温度的改变使体系分相以实现酶的回收 ,操作简便 ,但仍有较大的酶活损失。连续流两相离心反应器可以实现反胶团酶反应的连续操作且酶的损失很小 ,但该反应器传质速率较低因而转化率不高。膜反应器是反胶团酶反应中研究最多也最有应用前途的一种反应器形式。文中介绍了反胶团酶反应中酶重复利用的方法 ,对其过程开发的最新进展进行了综述。     

Self-Assembled Polymeric Micelles Based on Hyaluronic Acid-g-Poly(d,l-lactide-co-glycolide) Copolymer for Tumor Targeting

Graft copolymer composed hyaluronic acid (HA) and poly(d,l-lactide-co-glycolide) (PLGA) (HAgLG) was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA) to have amine end group in the end of chain (PLGA-amine). PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50–200 nm. Doxorubicin (DOX)-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC)-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting.