多重响应纳米凝胶的一步回流沉淀聚合法制备及性能表征

以甲基丙烯酸(MAA)和N-异丙基丙烯酰胺(NIPAM)为单体,通过一步回流沉淀聚合法制得了具有温度、pH和还原多重响应的单分散P(MAA-co-NIPAM)纳米凝胶。利用动态光散射仪(DLS)、透射电子显微镜(TEM)对纳米凝胶的尺寸和形貌进行了表征,进一步研究了纳米凝胶的多重刺激响应性及其药物负载行为和细胞毒性。结果表明,通过调节反应单体、交联剂和引发剂的投料量,可以得到系列不同粒径的单分散纳米凝胶,代表性纳米凝胶具有良好的温度、pH和还原响应性,能够有效负载抗肿瘤药物阿霉素(DOX),且细胞相容性良好,有利于作为智能药物输送载体应用。     

惰性气体带水法合成甲基丙烯酸聚乙二醇单甲醚(1200)酯的研究

采用惰性气体带水法,以对甲苯磺酸为催化剂,对苯二酚为阻聚剂,以甲基丙烯酸(MAA)和聚乙二醇单甲醚(MPEG)为原料直接酯化合成了甲基丙烯酸聚乙二醇单甲醚酯(MPEGMAA).考察了单体摩尔比、阻聚剂用量、催化剂用量以及反应时间等条件对酯化率的影响,并通过红外光谱分析表征了酯化产物的结构.研究结果表明:当n(MAA)∶...     

NVP/HEMA/RMA共聚水凝胶溶胀性能研究

采用本体聚合法,制备了N-乙烯基吡咯烷酮(NVP)/甲基丙烯酸羟乙酯(HEMA)、NVP/HEMA/EMA(甲基丙烯酸乙酯)和NVP/HEMA/BMA(甲基丙烯酸丁酯)3种不同的共聚水凝胶材料,并用重量法和TG法研究了这3种不同组成水凝胶的溶胀性能.研究结果表明:加入疏水性单体甲基丙烯酸酯类,共聚水凝胶溶胀性能下降,由于EMA与HEMA结构相似,相容性好,其对溶胀性能的影响比BMA的影响小.     

聚丙烯酰胺/聚甲基丙烯酸(2-甲基氨基)乙酯高强度双网络水凝胶的制备及pH响应性

利用两步法合成了聚丙烯酰胺(PAM)/聚甲基丙烯酸(2-甲基氨基)乙酯(PDMAEMA)双网络水凝胶,第一网络为锂藻土(Laponite)物理交联的PAM纳米复合水凝胶,第二网络为化学交联剂N,N-亚甲基双丙烯酰胺(BIS)交联PDMAEMA。研究了2种网络相对含量、纳米黏土Laponite用量、化学交联剂BIS用量对水凝胶强度和pH响应性的影响。研究结果表明,PAM/PDMAEMA双网络水凝胶具有高强度,改变单体AM和DMAEMA的配比、交联剂的用量,其拉伸强度在36～91.9 kPa范围内可调。PAM/PDMAEMA双网络水凝胶还具有灵敏的pH刺激响应性,在pH=4时双网络水凝胶溶胀度急剧下降。     

pH调节法制备自愈合明胶/聚甲基丙烯酸甲酯-甲基丙烯酸复合水凝胶

以甲基丙烯酸甲酯(MAA)与甲基丙烯酸(MAA)为单体,纳米SiO_2为稳定剂,通过Pickering乳液聚合合成了粒径约300nm的表面负载SiO_2的聚甲基丙烯酸甲酯-甲基丙烯酸乳胶粒(PMMS胶粒)。pH升高,流动性PMMS的水分散体系形成固态凝胶。PMMS与明胶的混合物在pH调节下形成具有自愈合能力的复合水凝胶。采用扫描电子显微镜观察了凝胶的微观结构,动态流变仪表征凝胶的黏弹性质及自愈合性质。结果表明:明胶/PMMS复合凝胶具有很好的自愈合性质。     

P(MAA-co-DMA)两性电解质微凝胶的制备与性能

以甲基丙烯酸(MAA)和甲基丙烯酸二甲氨基乙酯(DMA)为单体,N,N’-亚甲基双丙烯酰胺(MBA)为交联剂,采用反相微乳液聚合法制备了一系列不同单体物质的量比的聚两性电解质微凝胶P(MAA-co-DMA)。通过傅里叶红外光谱(FT-IR)、电位与电导滴定、动态光散射(DLS)及紫外可见分光光度法等测试手段对其进行表征与分析。研究结果表明,P(MAA-co-DMA)为两性聚合物,其实际组成与投料比一致;在低和高pH值范围,微凝胶粒子处于溶胀状态,在等电点(IEP)附近,粒子收缩,微观结构变得紧密,IEP值与理论预测值相比有所偏移;随着pH值的变化,微凝胶分散液透光率变化不明显。     

温敏性三元共聚水凝胶溶胀及消溶胀行为

采用自由基溶液聚合法,室温下制备了聚(N-异丙基丙烯酰胺-co-壳聚糖-co-甲基丙烯酸)[P(NIPAM-co-CS-co-MAA)]三元共聚水凝胶,以红外光谱及质量法对凝胶结构和溶胀性进行了表征。结果表明,高交联凝胶溶胀符合non-Fickian扩散;温度高于35℃时溶胀的共聚凝胶均发生明显收缩;相同甲基丙烯酸(MAA)和壳聚糖(CS)单体用量,MAA对凝胶溶胀和消溶胀影响大于CS。不同pH溶液中的溶胀碱性时比酸性条件下更大,pH=5.0左右较差,显示与传统甲基丙烯酸系水凝胶不同的pH敏感性,其消溶胀动力学满足一级动力学方程。     

微凝胶基复合水凝胶的合成与流变性能研究

阳离子共聚物poly(HEMA-co-DMA+)(HEMA—甲基丙烯酸-β-羟乙酯,DMA—甲基丙烯酸-N,N-二甲氨基乙酯)经原子转移自由基聚合和季铵化反应得到。采用乳液聚合法制备甲基丙烯酸甲酯(MMA)和甲基丙烯酸(MAA)的交联微凝胶poly(MMA/MAA)。微凝胶和阳离子共聚物混合后调节pH,形成离子键交联的复合水凝胶。SEM结果显示复合水凝胶具有珊瑚状疏松网络结构,形成了更好的介质输送通道。流变学研究结果表明,微凝胶和阳离子共聚物的质量比为12/7时,复合凝胶具有更高的临界屈服应变(γ*≈10),而同浓度微凝胶形成的凝胶γ*≈1.75。     

甲基丙烯酸树脂的合成及在负性光致抗蚀剂中的应用

以甲基丙烯酸(MAA)、甲基丙烯酸甲酯(MMA)、甲基丙烯酸羟乙酯(HEMA)和2-甲基-2-金刚烷基甲基丙烯酸酯(MAd MA)为单体,通过自由基聚合制备了不同MAd MA含量的共聚物PMMHM,再与甲基丙烯酸缩水甘油酯(GMA)反应制得光敏共聚物PMMHM-G。用傅里叶变换红外光谱、核磁共振氢谱、凝胶渗透色谱、差示扫描量热等表征了聚合物的结构与性能;以PMMHM-G为基体树脂配制了光致抗蚀剂,测试了抗蚀剂膜的硬度与附着力,并用扫描电子显微镜观测了光致抗蚀剂的分辨率。结果表明,随着MAd MA含量升高,共聚物的相对分子质量下降,玻璃化转变温度升高,树脂的耐碱性增强,光致抗蚀剂的硬度和附着力良好,分辨率达50μm。     

pH敏感P(MAA-co-AM)水凝胶的制备及溶胀行为研究

以甲基丙烯酸(MAA)、丙烯酰胺(AM)为单体,N,N-亚甲基双丙烯酰胺作交联剂(BIS),过硫酸铵为引发剂(APS),用溶液聚合的方法合成水凝胶P(MAA-co-AM),研究了单体配比及干燥方式对水凝胶表面形貌以及对水、不同pH溶液及盐溶液的溶胀行为的影响。结果表明,P(MAA-co-AM)16凝胶(MAA/AM摩尔比为16∶100)冻干处理后具有均匀的大孔;与PAM和PMAA凝胶相比,P(MAA-co-AM)16凝胶的吸水溶胀速率快(1h溶胀平衡)、平衡溶胀比大(ESR=250)、pH体积响应变化大(pH为4.01、6.86、9.18时的ESR分别为20、60、141),吸盐率比PMAA有所提高。     

Polyethyleneimine modified biocompatible poly(N-isopropylacrylamide)-based nanogels for drug delivery

A series of biocompatible and stimuli-sensitive poly(N-isopropylacrylamide-co-propyl acrylic acid) (P(NIPAAm-co-PAAc)) nanogels were synthesized by emulsion polymerization. In addition, polyethyleneimine (PEI) was further grafted to modify the PNIPAAm-based nanogels. The P(NIPAAm-co-PAAc)-g-PEI nanogels exhibited good thermosensitivity as well as pH sensitivity. Transmission electron microscopy (TEM) showed that the P(NIPAAm-co-PAAc)-g-PEI and P(NIPAAm-co-PAAc) nanogels displayed well dispersed spherical morphology. The mean sizes of the nanogels measured by dynamic light scattering (DLS) were from 100 nm to 500 nm at different temperatures. The cytotoxicity study indicated P(NIPAAm-co-PAAc) nanogels exhibited a better biocompatibility than both PNIPAAm nanogel and P(NIPAAm-co-PAAc)-g-PEI nanogel although all the three kinds of nanogels did not exhibit apparent cytotoxicity. The drug-loaded nanogels, especially the PEI-grafted nanogels, showed temperature-trigged controlled release behaviors, indicating the potential applications as an intelligent drug delivery system.     

Poly(N-isopropylacrylamide) copolymer nanogels with thermogelling ability prepared by a single step of dispersion polymerization

The copolymer nanogels composed of two N-substituted acrylamides with different water solubility, N-isopropylacrylamide (NIPAM, water-soluble) and N-t-butylacrylamide (TBAM, water-insoluble), were prepared by free-radical polymerization in the presence of sodium dodecyl sulfate (SDS) as a dispersant and found to exhibit thermogelling ability at very low concentrations. To investigate the structure of the P(NIPAM-TBAM) nanogel and its formation mechanism in dispersion polymerization, we prepared the nanogels by changing the conditioning time, which is the time between the addition of SDS to the monomer solution and the start of polymerization, and compared the thermogelling properties of the resultant nanogels. As the conditioning time increased, (i) the hydrodynamic diameter of the nanogel decreased, (ii) the sol–gel and gel-syneresis transition temperatures of the nanogel dispersion decreased, and (iii) the storage moduli of the nanogel dispersion in a gel state increased. These results indicate that the P(NIPAM-TBAM) nanogel has a block-like structure composed of the TBAM-rich brushes and the NIPAM-rich core with three-dimensional polymer network, and that the TBAM ratio in the brushes increases with an increase in the conditioning time. It should be noted that the critical gelation concentration of the P(NIPAM-TBAM) nanogel dispersion was very low (～1.3 wt%), compared with other thermogelling polymers reported in literatures. This low gelation concentration can be attributed to the gel structure of the nanogel core because the NIPAM-rich core can retain water inside even when the TBAM-rich brushes are dehydrated and crosslink with each other to induce gelation of the system.     

Sparsely cross-linked "nanogel" matrixes as fluid, mechanically stabilized polymer networks for high-throughput microchannel DNA sequencing

We have developed sparsely cross-linked "nanogels", subcolloidal polymer structures composed of covalently linked, linear polyacrylamide chains, as novel replaceable DNA sequencing matrixes for capillary and microchip electrophoresis. Nanogels were synthesized via inverse emulsion (water-in-oil) copolymerization of acrylamide and a low percentage (approximately 10(-4) mol %) of N,N-methylene bisacrylamide (Bis). Nanogels and nanogel networks were characterized by multiangle laser light scattering and rheometry, respectively, and tested for DNA sequencing in both capillaries and chips with four-color LIF detection. Typical nanogels have an average radius of approximately 230 nm, with approximately 75% of chains incorporating a Bis cross-linker. The properties and performance of nanogel matrixes are compared here to those of a linear polyacrylamide (LPA) network, matched for both polymer weight-average molar mass (M(w)) and the extent of interchain entanglements (c/c). At sequencing concentrations, the two matrixes have similar flow characteristics, important for capillary and microchip loading. However, because of the physical network stability provided by the internally cross-linked structure of the nanogels, substantially longer average read lengths are obtained under standard conditions with the nanogel matrix at a 98.5% accuracy of base-calling (for CE: 680 bases, an 18.7% improvement over LPA, with the best reads as long as 726 bases, compared to 568 bases for the LPA matrix). We further investigated the use of the nanogel matrixes in a high-throughput microfabricated DNA sequencing device consists of 96 separation channels densely fabricated on a 6-in. glass wafer. Again, preliminary DNA sequencing results show that the nanogel matrixes are capable of delivering significantly longer average read length, compared to an LPA matrix of comparable properties. Moreover, nanogel matrixes require 30% less polymer per unit volume than LPA. The addition of a small amount of low molar mass LPA or ultrahigh molar mass LPA to the optimized nanogel sequencing matrix further improves read length as well as the reproducibility of read length (RSD < 1.6%). This is the first report of a replaceable DNA sequencing matrix that provides better performance than LPA, in a side-by-side comparison of polymer matrixes appropriately matched for molar mass and the extent of interchain entanglements. These results could have significant implications for the improvement of microchip-based DNA sequencing technology.     

Temperature-responsive Pickering foams stabilized by poly(N-isopropylacrylamide) nanogels

Poly(N-isopropylacrylamide) (PNIPAM) nanogels were synthesized by emulsion polymerization using sodium dodecyl sulfate (SDS). After removal of SDS by dialysis, the surface tensions of the PNIPAM nanogel aqueous dispersions were measured at various temperatures by the pendant-drop method, and it was found that the surface tensions of the nanogel dispersion below the lower critical solution temperature (LCST) of PNIPAM were much smaller than those of water and comparable to those of the SDS aqueous solution. The stability of the aqueous foams generated by nitrogen bubbling thorough the PNIPAM nanogel dispersion was investigated below and above the LCST of PNIPAM. The foam prepared below the LCST was stable in some degree, whereas almost no foam was formed above the LCST. Moreover, the foam prepared below the LCST was quickly collapsed by changing the temperature above the LCST. This rapid defoaming represents that the surface activity of the PNIPAM nanogel can be switched off by the temperature increase across the LCST.     

Hollow core-porous shell structure poly(acrylic acid) nanogels with a superhigh capacity of drug loading

Poly(acrylic acid) (PAA) nanogels with a hollow core-porous shell structure were prepared by the direct polymerization of an acrylic acid monomer in the presence of hydroxypropylcellulose (HPC) and a cross-linking agent, N,N-methylenebisacrylamide, followed by removal of HPC from the generated HPC-PAA nanoparticles in a basic environment. The properties of PAA nanogel were characterized by dynamic light scattering, FT-IR, transmission electron microscopy, and atomic force microscopy. It is found that the nanogels have a hollow core-porous shell structure. Protein, bovine serum albumin (BSA), and an antitumor agent, doxorubicin hydrochloride, were used as model drugs to investigate their loading abilities as versatile drug-delivery vehicles. The nanogel exhibits surprisingly high loading ability to both protein and small molecular drugs. For example, the maximum BSA loading capacity of PAA nanogel can reach as high as 800% (i.e., 1 mg of nanogel can load about 8.0 mg of BSA). This high loading capacity may be related with the hollow core-porous shell structure of PAA nanogels. PAA nanogels have also shown sustained drug release properties and can cross biological barriers to deliver loaded cargo inside cells. Considering the high stability of the materials, simple and mild preparation procedure, high loading capacity, sustained-release property, and ability to protect biological agents from denaturation, PAA nanogels should be promising drug-delivery carriers for drug-delivery systems.     

Combination of nanogel polyethylene glycol-polyethylenimine and 6(hydroxymethyl)-1,4-anthracenedione as an anticancer nanomedicine

Polyethylene glycol-polyethylenimine (PEG-PEI) nanogels have been used to deliver nucleic acids and oligonucleotides into cells. First, we synthesized PEG-PEI nanogels with methylene proton ratios (CH2O:CH2N) in PEG-PEI ranging from approximately 6.8:1 to 4:1 and less, as shown by 1H NMR spectra. We first synthesized various nanogels with varying ratios of CH2O:CH2N (methylene proton) in PEG-PEI as shown by 1H NMR spectra and tested their cytotoxicity using a rodent pancreatic adenocarcinoma cell line (Pan 02). We showed that the nanogel PEG-PEI with methylene proton ratio of 4:1 was strongly cytotoxic to Pan 02 cells in vitro, while the nanogel with the methylene proton ratio of 6.8:1 was not toxic. We incorporated a novel anti-cancer drug, 6-(hydroxymethyl)-1,4-anthracenedione (AQ) analogue (AQ10) into nontoxic nanogel PEG-PEI and tested the effect of AQ10 loaded nanogel PEG-PEI (AQ10-nanogel PEG-PEI) and AQ10 dissolved in DMSO on Pan 02 cell growth. The size of this AQ10-nanogel PEG-PEI was characterized using atomic force microscopy (AFM). Our studies showed that the AQ10-nanogel PEG-PEI is readily taken up by Pan 02 cells. Growth attenuation of Pan 02 cells treated with AQ10-nanogel PEG-PEI was three to four times that of cells treated with AQ10 dissolved in DMSO. These results suggest that PEG-PEI, usually used to deliver nucleic acids into cells, can also be used to deliver an insoluble small molecule anticancer drug, AQ10.     

Crosslinked duplex DNA nanogels that target specified proteins

Specific detection of protein biomarkers plays an important role in diagnostics and therapeutics. We have fabricated polymeric nanogels, which can specifically interact with the cancer biomarker thrombin to serve as a model. Two types of 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers bearing a thrombin-binding oligonucleotide aptamer and its complementary chain were independently synthesized by redox-initiated radical polymerization. These MPC polymers associate in a complimentary fashion due to double strand formation of the oligonucleotides in aqueous media, leading to the spontaneous formation of spherical nanogels. Nanogel formation was confirmed by dynamic light scattering (DLS) and transmittance microscopy. The average size of nanogel particles was 124 ± 2 nm and the nanogels were mono-dispersed (polydispersity index 0.21). Functional intercalators could be stably incorporated into nanogels through the physical interaction between the intercalators and the oligonucleotides. The ethidium bromide (EtBr)-incorporating nanogels were used as detectors for thrombin. The fluorescence intensity of solutions containing the EtBr-incorporating nanogels was decreased with an increase in the concentration of thrombin. The transformation of quadruplex–thrombin structure from complementary double-stranded structures resulted in the decrease in fluorescence intensity. In contrast, the intensity did not change when the nanogels were incubated with albumin. Thrombin is only one such model used to demonstrate this technique; oligonucleotide aptamers can be freely designed to interact with versatile bio-substances. Therefore, aptamer-crosslinked nanogels can be appropriate nanomaterials for disease diagnosis and therapy.     

"Nanohybrids" based on pH-responsive hydrogels and inorganic nanoparticles for drug delivery and sensor applications

Allyl-PEG capped inorganic NPs, including magnetic iron oxide (IONPs), fluorescent CdSe/ZnS quantum dots (QDs), and metallic gold (AuNPs of 5 and 10 nm) both individually and in combination, were covalently attached to pH-responsive poly(2-vinylpyridine-co-divinylbenzene) nanogels via a facile and robust one-step surfactant-free emulsion polymerization procedure. Control of the NPs associated to the nanogels was achieved by the late injection of the NPs to the polymerization solution at a stage when just polymeric radicals were present. Remarkably, by varying the total amount of NPs injected, the swelling behavior could be affected. Furthermore, the magnetic response as well as the optical features of the nanogels containing either IONPs or QDs could be modified. In addition, a radical quenching in case of gold nanoparticles was observed, thus affecting the final nanogel geometry.     

Impact of Glutathione Modulation on Stability and Pharmacokinetic Profile of Redox‐Sensitive Nanogels

Nanoparticles degradable upon external stimuli combine pharmacokinetic features of both small molecules as well as large nanoparticles. However, despite promising preclinical results, several redox responsive disulphide‐linked nanoparticles failed in clinical translation, mainly due to their unexpected in vivo behavior. Glutathione (GSH) is one of the most evaluated antioxidants responsible for disulfide degradation. Herein, the impact of GSH on the in vivo behavior of redox‐sensitive nanogels under physiological and modulated conditions is investigated. Labelling of nanogels with a DNA‐intercalating dye and a radioisotope allows visualization of the redox responsiveness at the cellular and the systemic levels, respectively. In vitro, efficient cleavage of disulphide bonds of nanogels is achieved by manipulation of intracellular GSH concentration. While in vivo, the redox‐sensitive nanogels undergo, to a certain extent, premature degradation in circulation leading to rapid renal elimination. This instability is modulated by transient inhibition of GSH synthesis with buthioninsulfoximin. Altered GSH concentration significantly changes the in vivo pharmacokinetics. Lower GSH results in higher elimination half‐life and altered biodistribution of the nanogels with a different metabolite profile. These data provide strong evidence that decreased nanogel degradation in blood circulation can limit the risk of premature drug release and enhance circulation half‐life of the nanogel.