Effect of alkyl chain lengths on the assemblies of magnetic nanoparticles coated with multi-functional thiolactone-containing copolymer

This work presents the synthesis of magnetite nanoparticle (MNP) coated with poly(N,N-diethylaminoethyl methacrylate)-b-poly(N-isopropyl acrylamide-st-thiolactone acrylamide) (PDEAEMA-b-P(NIPAAm-st-TlaAm) copolymer and its use in controlled drug release and bio-conjugation. TlaAm units in the copolymer were ring-opened with various alkyl amines to form thiol groups (-SH), followed by thiol-ene coupling reactions with acrylamide-coated MNP and then quaternized to obtain cationic copolymer-MNP assemblies (the size <?200 nm/cluster). The use of alkyl amines having various chain lengths (e.g., 1-propylamine, 1-octylamine, or 1-dodecylamine) in the nucleophilic ring-opening reactions of the thiolactone rings affected their magnetic separation ability, water dispersibility, and release rate of doxorubicin model drug. In all cases, when increasing the temperature, they showed a thermo-responsive behavior as indicated by the decrease in hydrodynamic size and the accelerated drug release rate. These copolymer-MNP assemblies could be used as a novel platform with thermal-triggering controlled drug release and capability for adsorption with any negatively charged biomolecules.

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Graphical abstract MNP coated with multi-functional PDEAEMA-b-P(NIPAAm-st-TlaAm) copolymer and its proposed drug release

     

Surface modification of poly(styrene-b-(ethylene-co-butylene)-b-styrene) elastomer via photo-initiated graft polymerization of poly(ethylene glycol)

Poly(styrene-b-(ethylene-co-butylene)-b-styrene) (SEBS) copolymer biomedical elastomer was covalently grafted with poly(ethylene glycol) methyl ether methacrylate (PEGMA) via a photo-initiated graft polymerization technique. The surface graft polymerization of SEBS with PEGMA was verified by ATR-FTIR and XPS. Effect of graft polymerization parameters, i.e., monomer concentration, UV irradiation time and initiator concentration on the grafting density was investigated. Comparing with the virgin SEBS film, the PEGMA-modified SEBS film presented an enhanced wettability and a larger surface energy. Besides, the surface grafting of PEGMA imparted excellent anti-platelet adhesion and anti-protein adsorption to the SEBS surface.     

Modification of polysulfone membranes via surface-initiated atom transfer radical polymerization

Hydrophilic poly((poly(ethylene glycol) methyl ether methacrylate) (P(PEGMA)) and poly(glycidylmethacrylate) (PGMA) brushes were grafted from chloromethylated polysulfone (CMPSF) membrane surfaces via surface-initiated atom transfer radical polymerization (ATRP). Prior to ATRP, chloromethylation of PSF was performed beforehand and the obtained CMPSF was prepared into porous membranes by phase inversion process. It was demonstrated that the benzyl chloride groups on the CMPSF membrane surface afforded effective macroinitiators to graft the well-defined polymer brushes. ¹H NMR was employed to confirm the structure of CMPSF. The grafting yield of P(PEGMA) and PGMA was determined by weight gain measurement. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS) confirmed the grafting of P(PEGMA) and PGMA chains. Water contact angle measurements indicated that the introduction of P(PEGMA) and PGMA graft chains promoted remarkably the surface hydrophilicity of PSF membranes. The effects of P(PEGMA) and PGMA immobilization on membrane morphology, permeability and fouling resistance were investigated. It was found that P(PEGMA) and PGMA grafts brought higher pure water flux, improved hydrophilic surface and better anti-protein absorption ability to PSF membranes after modification. And evidently, macromonomer P(PEGMA) brought much better properties to the PSF membranes than PGMA macromonomer.     

One-step copolymerization modified magnetic nanoparticles via surface chain transfer free radical polymerization

Copolymer brushes growing onto magnetic nanoparticles were prepared by surface chain transfer free radical polymerization. Block copolymer brushes (P(PEGMA)-co-PNIPAAm) consist of poly(ethylene glycol) monomethacrylate (PEGMA) and N-isopropylacrylamide monomer. X-ray photoelectron spectroscopy (XPS) characterized the chemical composition of copolymer. Thermogravimetric analysis (TGA) suggested that the amount of copolymer on magnetic nanoparticles decreased with increasing azodiisobutyronitrile (AIBN). The saturation magnetization decreased significantly with increasing P(PEGMA)-co-PNIPAAm. The thermosensitive point is about 43 °C for magnetic nanoparticles with 33.8% P(PEGMA)-co-PNIPAAm.     

Surface-initiated atom transfer radical polymerization of poly(4-vinylpyridine) from magnetite nanoparticle

Surface modification of magnetite nanoparticles (MNP) with a covalently bonded poly(4-vinylpyridine) (P4VP) by surface-initiated atom transfer radical polymerization (ATRP) is reported in this article. MNP was first prepared via thermal decomposition of Fe(acac)₃ and grafted with an ATRP initiator on its surface. ATRP of 4-vinylpyridine was then initiated from the MNP surface in the presence of CuBr/PMDETA (1,1,4,7,7-pentamethyldiethylenetriamine) catalytic complex in dioxane. FTIR in combination with photocorrelation spectroscopy (PCS), thermogravimetric analysis (TGA), and vibrating sample magnetometry (VSM) techniques indicated the growth of P4VP on the particle surface with increasing ATRP reaction time. Transmission electron microscopy (TEM) disclosed that the average particle size was 8 nm in diameter with some nanoaggregation observed. The PCS results revealed that decreasing the solution pH enhanced the particle dispersibility because of the positive charge repulsion of the protonated P4VP on the particle surface. TGA was also performed to elucidate the composition of P4VP shell and magnetite core in the hybrid material.     

Enantiomeric PLA–PEG block copolymers and their stereocomplex micelles used as rifampin delivery

A novelty approach to self-assembling stereocomplex micelles by enantiomeric PLA–PEG block copolymers as a drug delivery carrier was described. The particles were encapsulated by enantiomeric PLA–PEG stereocomplex to form nanoscale micelles different from the microspheres or the single micelles by PLLA or PDLA in the reported literatures. First, the block copolymers of enantiomeric poly(l-lactide)–poly(ethylene–glycol) (PLLA–PEG) and poly(D-lactide)–poly(ethylene–glycol) (PDLA–PEG) were synthesized by the ring-opening polymerization of l-lactide and d-lactide in the presence of monomethoxy PEG, respectively. Second, the stereocomplex block copolymer micelles were obtained by the self-assembly of the equimolar mixtures of enantiomeric PLA–PEG copolymers in water. These micelles possessed partially the crystallized hydrophobic cores with the critical micelle concentrations (cmc) in the range of 0.8–4.8 mg/l and the mean hydrodynamic diameters ranging from 40 to 120 nm. The micelle sizes and cmc values obviously depended on the hydrophobic block PLA content in the copolymer. Compared with the single PLLA–PEG or PDLA–PEG micelles, the cmc values of the stereocomplex micelles became lower and the sizes of the stereocomplex micelles formed smaller. And lastly, the stereocomplex micelles encapsulated with rifampin were tested for the controlled release application. The rifampin loading capacity and encapsulation efficiency by the stereocomplex micelles were higher than those by the single polymer micelles, respectively. The drug release time in vitro was depending on the composites of the block copolymers and also could be controlled by the polymer molecular weight and the morphology of the polymer micelles.     

两亲性壳聚糖基聚合物碳点的合成及其在载药方面的应用

通过水热法合成了系列具有高荧光量子产率（42.9%）辛基化壳聚糖基两亲性聚合物碳点荧光材料。利用红外光谱、紫外吸收光谱、光电子能谱、透射电镜、X射线衍射及荧光光谱对聚合物碳点进行了表征。以阿霉素为模型药物,研究了聚合物碳点对阿霉素的载药性能。当辛基取代度为76.42%时,其最大载药量和包封率分别为49.6%与47.4%。在磷酸盐缓冲液中,载药纳米胶束呈前期快速释放,后期缓慢释放的双相特征。将载药纳米胶束与鼻咽癌细胞作用,发现其存活率随着载药纳米胶束加入量的增加而降低,说明该纳米胶束对鼻咽癌细胞有一定的抑制作用。总之,该聚合物碳点材料在药物载体与荧光示踪方面有潜在的应用价值。     

两亲性类树枝状聚合物的合成与药物控释

结合阴离子开环聚合方法合成了内壳为聚(乙氧基乙基缩水甘油醚),外层为聚环氧乙烷的两亲性类树枝状嵌段共聚物PEEGE-G2-b-PEO(OH)₁₂. 使用核磁共振氢谱以及凝胶渗透色谱等表征了中间产物和目标产物. 选择阿霉素作为实验药物,研究了该聚合物的载药和控释行为. 聚合物的载药率和包覆效率分别为13.07%和45.75%,体外释放试验表现为持续性的释放,并受到释放介质pH影响.     

Multifunctional antitumor magnetite/chitosan-<Emphasis Type="SmallCaps">l</Emphasis>-glutamic acid (core/shell) nanocomposites

The development of anticancer drug delivery systems based on biodegradable nanoparticles has been intended to maximize the localization of chemotherapy agents within tumor interstitium, along with negligible drug distribution into healthy tissues. Interestingly, passive and active drug targeting strategies to cancer have led to improved nanomedicines with great tumor specificity and efficient chemotherapy effect. One of the most promising areas in the formulation of such nanoplatforms is the engineering of magnetically responsive nanoparticles. In this way, we have followed a chemical modification method for the synthesis of magnetite/chitosan-l-glutamic acid (core/shell) nanostructures. These magnetic nanocomposites (average size ≈340 nm) exhibited multifunctional properties based on its capability to load the antitumor drug doxorubicin (along with an adequate sustained release) and its potential for hyperthermia applications. Compared to drug surface adsorption, doxorubicin entrapment into the nanocomposites matrix yielded a higher drug loading and a slower drug release profile. Heating characteristics of the magnetic nanocomposites were investigated in a high-frequency alternating magnetic gradient: a stable maximum temperature of 46 °C was successfully achieved within 40 min. To our knowledge, this is the first time that such kind of stimuli-sensitive nanoformulation with very important properties (i.e., magnetic targeting capabilities, hyperthermia, high drug loading, and little burst drug release) has been formulated for combined antitumor therapy against cancer.     

Biodegradable thermoresponsive polymeric magnetic nanoparticles: a new drug delivery platform for doxorubicin

The use of nanoparticles as drug delivery systems for anticancer therapeutics has great potential to revolutionize the future of cancer therapy. The aim of this study is to construct a novel drug delivery platform comprising a magnetic core and biodegradable thermoresponsive shell of tri-block-copolymer. Oleic acid-coated Fe₃O₄ nanoparticles and hydrophilic anticancer drug “doxorubicin” are encapsulated with PEO–PLGA–PEO (polyethylene oxide–poly d, l lactide-co-glycolide–polyethylene oxide) tri-block-copolymer. Structural, magnetic, and physical properties of Fe₃O₄ core are determined by X-ray diffraction, vibrating sample magnetometer, and transmission electron microscopy techniques, respectively. The hydrodynamic size of composite nanoparticles is determined by dynamic light scattering and is found to be ~36.4 nm at 25 °C. The functionalization of magnetic core with various polymeric chain molecules and their weight proportions are determined by Fourier transform infrared spectroscopy and thermogravimetric analysis, respectively. Encapsulation of doxorubicin into the polymeric magnetic nanoparticles, its loading efficiency, and kinetics of drug release are investigated by UV–vis spectroscopy. The loading efficiency of drug is 89% with a rapid release for the initial 7 h followed by the sustained release over a period of 36 h. The release of drug is envisaged to occur in response to the physiological temperature by deswelling of thermoresponsive PEO–PLGA–PEO block-copolymer. This study demonstrates that temperature can be exploited successfully as an external parameter to control the release of drug.     

Novel Route to Control Interfacial Properties of Glass Fiber-Reinforced Polystyrene Composites via a Photo-Cross-Linkable Block Copolymer Coupling Agent

A diblock copolymer of polystyrene–block–poly(2-hydroxyethyl acrylate) (PS-b-PHEA) was synthesized via atom transfer radical polymerization (ATRP) and reacted with cinnamoyl chloride in triethylamine to yield PS-b-(PCEA-co-PHEA) copolymer with photo-cross-linkable poly(2-cinnamoylethyl acrylate) (PCEA) moieties. Then the triblock copolymer of polystyrene–block–poly(2-cinnamoylethyl acrylate-co-2-hydroxyethyl acrylate)–block–poly(γ-methacryloxypropyltrimethoxysilane) (PS-b-(PCEA-co-PHEA)-b-PMPS) was synthesized viaATRP from PS-b-(PCEA-co-PHEA) copolymer. Using as-prepared triblock copolymer as a macromolecular coupling agent to modify glass fibers, via microbond tests, the interfacial bond strength between pretreated glass fiber and polystyrene was compared before and after copolymer photo-crosslinking. The partially crosslinked block copolymer coupling agent greatly improved the interfacial adhesion of glass fiber-reinforced polystyrene.     

A photosensitive copolymer for the gate insulator of organic thin-film transistors

A novel cross-linkable copolymer for the gate insulators of organic thin-film transistors (OTFTs) was synthesized by free radical copolymerization with methyl methacrylate and ethylene methylacrylate cinnamoylate. Copolymers of molecular weights (Mn: 109200–160000 g mol⁻¹) and polydispersities (1.59–2.24) were characterized by FTIR and NMR. Spin-coated thin films had smooth surfaces with the root-mean-square (RMS) surface roughness of 0.23 nm, 0.41 nm, respectively, before and after UV irradiation. Exposure of the copolymers to UV light produced cross-linking of the polymeric chains that could be confirmed by comparing the FTIR and UV spectra recorded prior and after irradiation. Moreover, the vanadyl-phthalocyanine (VOPc) OTFTs with the photosensitive copolymer as gate insulator were fabricated and found to exhibit a carrier mobility of 0.25 cm²/V s, an on/off ratio of 10⁴.     

Tungsten content and grain boundary misorientation angle effect on crack blunting in nanocrystalline Ni-W alloy

To improve the stability of polymeric micelles, here we describe interlayer-crosslinked micelles prepared from star-shaped copolymer via click chemistry. The formation of interlayer-crosslinked micelles was investigated and confirmed by proton nuclear magnetic resonance, Fourier-transform infrared spectroscopy, and fluorescence spectroscopy. The morphology of un-crosslinked micelles and crosslinked micelles observed by transmission electron microscope is both uniform nano-sized spheres (approximately 20 nm). The crosslinking enhances the stability of polymeric micelles and improves the drug loading capacity of polymeric micelles. The interlayer-crosslinked micelles prepared from star-shaped copolymer and a crosslinker containing a disulfide bond are reduction-responsive and can release the drug quickly in the presence of the reducing agents such as glutathione (GSH).

     

In vitro study of magnetic nanoparticles as the implant for implant assisted magnetic drug targeting

Magnetic nanoparticle (MNP) seeds were studied in vitro for use as an implant in implant assisted-magnetic drug targeting (IA-MDT). The magnetite seeds were captured in a porous polymer, mimicking capillary tissue, with an external magnetic field (70 mT) and then used subsequently to capture magnetic drug carrier particles (MDCPs) (0.87 μm diameter) with the same magnetic field. The effects of the MNP seed diameter (10, 50 and 100 nm), MNP seed concentration (0.25-2.0 mg/mL), and fluid velocity (0.03-0.15 cm/s) on the capture efficiency (CE) of both the MNP seeds and the MDCPs were studied. The CE of the 10 nm MNP seeds was never more than 30%, while those of the 50 and 100 nm MNP seeds was always greater than 80% and in many cases exceeded 90%. Only the MNP seed concentration affected its CE. The 10 nm MNP seeds did not increase the MDCP CE over that obtained in the absence of the MNP seeds, while the 50 and 100 nm MNP seeds increased significantly, typically by more than a factor of two. The 50 and 100 nm MNP seeds also exhibited similar abilities to capture the MDCPs, with the MDCP CE always increasing with decreasing fluid velocity and generally increasing with increasing MNP seed concentration. The MNP seed size, magnetic properties, and capacity to self-agglomerate and form clusters were key properties that make them a viable implant in IA-MDT.     

Complex nanostructured materials from segmented copolymers prepared by ATRP

The development of new controlled/living radical polymerization processes, such as Atom Transfer Radical Polymerization (ATRP) and other techniques such as nitroxide mediated polymerization and degenerative transfer processes, including RAFT, opened the way to the use of radical polymerization for the synthesis of well-defined, complex functional nanostructures. The development of such nanostructures is primarily dependent on self-assembly of well-defined segmented copolymers. This article describes the fundamentals of ATRP, relevant to the synthesis of such systems. The self-assembly of block copolymers prepared by ATRP is illustrated by three examples. In the first, block copolymers of poly(butyl acrylate) with polyacrylonitrile phase separate, leading to spherical, cylindrical or lamellar morphologies, depending on the block copolymer composition. At a higher temperature, polyacrylonitrile block converts to nanostructured carbon clusters, whereas poly(butyl acrylate) block serves as a sacrificial block, aiding the development of designed nanostructures. In the second example, conductive nanoribbons of poly(n-hexylthiophene) surrounded by a matrix of organic polymers are formed from block copolymers prepared by ATRP. The third example describes an inorganic-organic hybrid system consisting of hard nanocolloidal silica particles (20 nm) grafted by ATRP with well-defined polystyrene-poly(benzyl acrylate) block copolymer chains (1000 chains per particle). Silica cores in this system are surrounded by a rigid polystyrene inner shell and softer polyacrylate outer shell. Received 9 July 2002 Published online: 11 March 2003     

纳米金刚石的分散、修饰及载药应用研究

纳米金刚石(nanodiamond,ND)作为一种重要的碳纳米材料,具有表面易修饰、比表面积大、生物毒性低以及物理化学稳定性好等特点,使其在生物医学领域具有独特的优势.本文通过对ND进行分散和化学修饰得到了分散性良好的羧基化纳米金刚石(ND-COOH),并通过透射电子显微镜、X-射线衍射、傅里叶变换红外谱仪等手段对其形貌和结构进行了表征分析.ND-COOH在水溶液中水解后呈现出较高的负电位,致使其可以通过静电相互作用吸附带正电的抗癌药物盐酸阿霉素(dox),且对阿霉素的负载量可达325μg/mg.由于ND-COOH与dox之间通过带负电的羧酸根与带正电的质子化氨基结合,因此在H~+浓度较高的酸性溶液中,药物复合体ND-dox呈现出显著的p H值依赖药物释放特性,在p H值为5.0的磷酸盐缓冲液中药物释放率达到85%,而在p H值为7.4的PBS中药物释放率低于40%.此外,ND-COOH和ND-dox的细胞毒性和体外细胞杀伤能力结果表明,ND-COOH在0—150μg/m L范围内对细胞活性没有明显抑制,而ND装载药物dox后的ND-dox对SGC-7901胃癌细胞活性则表现出显著的抑制作用,表明ND-COOH作为药物载体具有较低的生物毒性,而负载药物后则对肿瘤细胞具有较强的杀伤能力.通过对ND进行简单的分散和表面改性,使ND具备良好的药物装载和独特的p H值依赖药物释放特性,这对于促进纳米金刚石在药物载体方面的应用具有重要的借鉴意义.     

Preparation of well-defined polymer-silicon wafer hybrids via surface-initiated RAFT-mediated process

A simple method was developed for the immobilization of reversible addition-fragmentation chain-transfer (RAFT) initiators on the silicon surface. Well-defined polymer-silicon hybrids, including the tethered brushes of glycidyl methacrylate (GMA) polymer, poly(ethylene glycol) monomethacrylate (PEGMA) polymer and block copolymer on a silicon wafer, were prepared via surface-initiated RAFT living radical polymerization. The “living” chain ends were used as the macroinitiator for the subsequent synthesis of diblock copolymers.     

Docetaxel‐Loaded Nanoparticles of Dendritic Amphiphilic Block Copolymer H40‐PLA‐b‐TPGS for Cancer Treatment

A dendritic amphiphilic block copolymer H40‐poly(d,l ‐lactide)‐block‐d‐α‐tocopheryl polyethylene glycol 1000 succinate (H40‐PLA‐b‐TPGS) is synthesized, which is then employed to develop a system of nanoparticles (NPs) loaded with docetaxel (DTX) as a model drug for cancer treatment due to its higher drug‐loading content and drug encapsulation efficiency, smaller particle size, faster drug release, and higher cellular uptake in comparison to the linear PLA polymer NPs and PLA‐b‐TPGS copolymer NPs. The drug‐loaded NPs are prepared by a modified nanoprecipitation method and characterized in terms of size and size distribution, surface morphology, drug release profile, and physical state of DTX. Cellular uptake of coumarin 6‐loaded NPs by MCF‐7 cancer cells is determined by flow cytometry and confocal laser scanning microscopy. The antitumor efficacy of the drug‐loaded NPs is investigated in vitro by MTT assay and in vivo by xenograft tumor model. The 72 h IC50 of the drug formulated in the PLA, PLA‐b‐TPGS, and H40‐PLA‐b‐TPGS NPs is found to be, 1.5 ± 0.3, 0.9 ± 0.1, and 0.15 ± 0.06 μg mL^?1, which are 7.3, 12.2, and 73.3‐fold effective than 11.0 ± 1.2 μg mL^?1 for Taxotere, respectively. Such advantages are further confirmed by the measurement of the tumor size and weight.     

Synthesis, characterization, and controllable drug release of pH-sensitive hybrid magnetic nanoparticles

The synthesis of magnetite nanoparticles coated with pH-sensitive poly((2-dimethylamino) ethyl methacrylate) (PDMAEMA) via atom transfer radical polymerization (ATRP) for use as novel potential carriers for targeted drug delivery and controllable release is reported. The organic/inorganic hybrid nanoparticles were obtained with a narrow molecular weight distribution. The pH-sensitivity of the nanoparticles was investigated by the measurement of the pH dependence of hydrodynamic radius and the superparamagnetism was illustrated by vibrating sample magnetometer (VSM). The behavior of model drug phenolphthalein released from the nanoparticles indicated that the rate of drug release could be effectively controlled by altering the pH values of the environment.     

Enhanced gastrointestinal absorption of N3-O-toluyl-fluorouracil by cationic solid lipid nanoparticles

This study was aimed to prepare N₃-O-toluyl-fluorouracil (TFu) loaded cationic solid lipid nanoparticles (TFu-SLNs) and evaluate the potential of a novel lipid-based drug delivery system to enhance the oral absorption of TFu. TFu-SLNs were prepared by the film dispersion-ultrasonication method, using hexadecyltrimethylammonium bromide as cationic tenside. The formulation and manufacture parameters were optimized concerning the drug encapsulation efficiency and the particle size. The in vitro release characteristics, in vivo pharmacokinetic properties and bioavailability, and in situ intestinal absorption features were investigated. The morphology of TFu-SLNs was approximately spherical and the mean particle size was 178.8 ± 9.99 nm; the zeta potential was +19.54 ± 0.32 mV. The mean entrapment efficiency and drug loading were 71.03 ± 1.19% and 3.57 ± 0.08%, respectively. The release behaviors of TFu from TFu-SLNs in PBS were fitted to the bioexponential model, while in artificial gastric juice, artificial intestinal juice and artificial gastric juice (2 h) followed by artificial intestinal juice (2–48 h) were fitted to the Weibull equation. The results of the pharmacokinetic studies in mice showed that the bioavailability of TFu-SLNs was significantly increased compared with that of the TFu suspensions after oral administration. The absorption of TFu-SLNs in intestine of rat was fitted to first-order kinetics with passive diffusion mechanism and the main segments of TFu-SLNs absorbed in intestine were duodenum and jejunum for the bioadhesion mediated by electrostatic interaction between the positively charged colloidal particles and the negatively charged mucosal surface. These results indicated that cationic SLNs would offer a promising delivery system for the facilitation of the bioavailability of poorly oral absorption drugs by enhancing the bioadhesion between the absorption mucosal surface and the drug carriers.