Synthesis of biocompatible amino acid-modified poly(acrylic acid) derivatives for intracellular gene delivery

Cationic polymers provide versatile traits that fit for nonviral gene delivery applications. However, cationic polymers could exhibit significant cytotoxicity. Poly(acrylic acid) by conjugating side chains with either primary amine or with different number of alpha mine of alanine (denoted as PAla polymers) was chemically modified and the impact of amine groups of poly(acrylic acid) regarding biocompatibility and intracellular gene delivery efficiency was investigated. Design of PAla polymers proved that the incorporation of alanine in cationic polymers may significantly decrease cytotoxicity of the resulting polymers while maintaining the efficiency of cellular uptake and the intracellular gene delivery of the DNA/cationic polymer complex.     

Photopolymerization of N,N-Didodecyl- N-methyl-N-ethylmethacrylate ammonium chloride,a reverse micelle forming surfactant

A detailed study of the photopolymerization of N,N-didodecylmethylethylmethacrylate ammonium chloride, a reverse micelle forming surfactant, is presented. The polymerization was photochemically initiated at 350 nm using AIBN and p-AIBN as initiators. However, the polymerization could also be initiated through direct excitation of the methacrylate group. High rates of polymerization resulted because of the organization of the monomer in reverse micellar assemblies. The molecular weights of the polymer decrease with increasing initiator concentration and are always larger than the molecular weight of the reverse micelle. The properties of the monomeric reverse micellar system are compared with those of the polymeric system and show that the dynamic character of the reverse micellar system can be lowered upon polymerization. The properties of the polymeric aggregates, however, differ if a given amount of water is solubilized before or after polymerization. The mean aggregation number of the monomeric and polymeric aggregates as well as the aggregation behaviour of both systems are compared. This comparison suggests that a polymeric aggregate consists of more than one polymer chain.     

Access to new carbohydrate-functionalized polylactides via organocatalyzed ring-opening polymerization

The 4-dimethylaminopyridine (DMAP) catalyzed ring-opening polymerization of lactide using various carbohydrate initiators has been assessed for the functionalization of polylactide. Selectively protected glucose derivatives bearing a free primary alcohol (Glc-1r) and a free secondary alcohol (Glc-2r), glucose and cyclodextrin diol derivatives (Glc-diol and CD-diol), methyl-α-d-glucopyranoside (Glc-Me) and native β-cyclodextrin (CD) were used as initiators. According to the solubility of the carbohydrate derivative, the polymerizations were conducted in chlorinated solvents and in the bulk. Relatively narrow distributions are obtained in high yields in the absence of side reactions, affording a 100% functionalization efficiency. The catalytic synthesis of new carbohydrate link-functionalized polylactides and carbohydrate core star polylactides is reported.     

Efficient Delivery of Plasmid DNA Using Cholesterol-Based Cationic Lipids Containing Polyamines and Ether Linkages

Cationic liposomes are broadly used as non-viral vectors to deliver genetic materials that can be used to treat various diseases including cancer. To circumvent problems associated with cationic liposome-mediated delivery systems such as low transfection efficiency and serum-induced inhibition, cholesterol-based cationic lipids have been synthesized that resist the effects of serum. The introduction of an ether-type linkage and extension of the aminopropyl head group on the cholesterol backbone increased the transfection efficiency and DNA binding affinity compared to a carbamoyl-type linkage and a mono aminopropyl head group, respectively. Under optimal conditions, each liposome formulation showed higher transfection efficiency in AGS and Huh-7 cells than commercially available cationic liposomes, particularly in the presence of serum. The following molecular structures were found to have a positive effect on transfection properties: (i) extended aminopropyl head groups for a strong binding affinity to plasmid DNA; (ii) an ether linkage that favors electrostatic binding to plasmid DNA; and (iii) a cholesterol backbone for serum resistance.     

阳离子聚合物的研究

对于阳离子聚合物的制备，分成两部分进行了简单综述。第一部分主要介绍了合成法制备阳离子聚合物，第二部分主要介绍了通过大分子改性的途径制备阳离子聚合物。并简要论述了阳离子聚合物的特性及应用。     

Synthesis and characterization of an amphiphilic graft polymer and its potential as a pH-sensitive drug carrier

The synthesis and properties of a new pH-sensitive polymer Poly(?-caprolactone) Grafted Poly(ethylene glycol) Based Poly(ß-amino ester) (PEGAE-g-PCL) are described here. The successful synthesis of the graft copolymer was confirmed by ¹H NMR. The self-assemble behavior of the amphiphilic polymer was investigated using pyrene as a probe. Dynamic light scattering (DLS) showed that the polymeric micelles had a size of 60 nm at physiological pH and were responsive to pH. A spherical morphology was observed for the micelles using transmission electron microscopy (TEM). Zeta-potential measurement at different pH showed that the micelles were neutral at pH 7.4 and positively charged at lower pH. Doxorubicin (DOX) was used as a model drug and loaded in the micelles. The drug loaded micelles showed a slow and pH-dependant drug release behavior. The remaining hydroxyl groups on the main chain made it possible the further conjugation of imaging agents or targeting groups.     

环糊精聚合物的合成及应用研究

环糊精聚合物(CDPs)兼具了环糊精\"内疏水?外亲水\"的空腔结构特征和聚合物高分子稳定性的特点,是一类有巨大发展潜力的功能高分子材料。该文根据环糊精聚合物的结构特点对其进行分类并详细介绍了其合成方法,阐述了环糊精聚合物在食品、催化剂、化妆品、环境、医学、分离分析技术等多方面的应用研究。对环糊精聚合物的发展作了展望,为今后新型环糊精聚合物的制备及应用提供了参考依据。     

N-十二烷基-N-羟乙基氯化铵的性能研究

用滴体积法对合成纯化所得N－烷基－N－羟乙基氯化铵（AEAC）水溶液测定表面张力发现,随着N原子上羟乙基数的增加,AEAC的临界胶束浓度降低,但此时的表面张力上升。AEAC胶束化的主要驱动力是熵变。AEAC的表达过剩浓度随N原子上羟乙基数的增加而增加,但表面分子面积减小。AEAC降低表面张力的效率随羟乙基数的增加而增大。     

Preparation and Application of Fluorinated Cationic Surfactants

Four fluorinated cationic surfactants were prepared by condensing 2,2,3,3, tetrafluoro-1-propyl chloroacetate with stoichiometric amounts of pyridine, 2-hydroxypyridine, 8-hydroxyquinoline and 8-hydroxyquinaldine to produce four quaternary ammonium salts. The surface and biocidal properties of these surfactants were investigated. Surface properties of their solutions including surface tension, critical micelle concentration (CMC), effectiveness (Π_cmc), maximum surface excess (Γ_max) and minimum surface area (A _min) were investigated with respect to different concentrations at 25 °C. Standard free energies of micellization and adsorption of the prepared surfactants in the aqueous solution were studied. The biocidal activity was determined via the inhibition zone diameter of prepared compounds which tested against six strains as a representative group of microorganisms.

Dendritic polyamines: simple access to new materials with defined treelike structures for application in nonviral gene delivery

Polycationic dendrimers are interesting nonviral vectors for in vitro DNA delivery. We describe a simple approach to the synthesis of dendritic polyamines with different molecular weights and adjustable flexibility (degrees of branching; DB). Both parameters influence the transfection efficiency and the cell toxicity of the polymer. Functionalization of hyperbranched polyethylenimine (PEI) by a two-step procedure generated fully branched pseudodendrimers (analogues of polypropylenimine (PPI) and polyamidoamine (PAMAM) dendrimers). The DNA transfection efficiencies observed for these polymers depended on the cell line investigated. The highest efficiencies were observed for polymers whose unfunctionalized PEI cores had molecular weights in the range M(w)=6000-25 000 g mol(-1). The cytotoxicity of the dendrimers generally rises with increasing core size. The data collected for NIH/3T3 and COS-7 cells indicate a maximum transfection efficiency at around 60 % branching for the PPI analogues, and at a PEI-core molecular weight of M(w)=25 000 g mol(-1). PAMAM functionalization of PEI (M(w)=5000 and 21 000 g mol(-1)) leads to polymers with little or no cytotoxity in the cell lines investigated.     

pH-responsive Multi-PEGylated dual cationic nanoparticles enable charge modulations for safe gene delivery

In gene therapy, the cytotoxicity of many polycations is undesirable and has been attributed to nonspecific membrane destabilizing effects and intracellular polyplex-mediated toxicity. To help prolong the pharmacokinetic profile of nonviral vehicles for gene delivery, the cationic surface charge of current systems is typically shielded through the conjugation of polyethylene glycol (PEG) chains to the particle surface. However, the design of an intelligent polycation with environment-sensing charge modulations is essential to minimize cytotoxicity and enhance gene expression. We have designed a novel di-cationic block copolymer, poly(aspartate-hydrazide)-block-poly(L-lysine), capable of pH-mediated endosomal membrane disruption based on charge interactions, which has negligible toxicity elsewhere to the cell. The poly(L-lysine) segment, with a high pK(a) value of approximately 9.4, preferentially forms a poly-ion complex with the negative phosphate groups of pDNA, whereas the pH-responsive poly(aspartate-hydrazide) segment, with the comparatively lower pK(a) approximately 5.0, is characterized by a substantial fraction of unprotonated amino groups at physiological pH. As a consequence, complexation between such a polymer and pDNA leads to the formation of a two-layered nanoparticle. In particular, the nanoparticle possesses an unprotonated pH-responsive segment to serve as both a scaffold for acid-labile linkages of various moieties such as aldehyde-PEG and to transition from neutral to charged for disrupting endosomal membranes, and safely enhancing gene expression. Our system supports an endosomal escape mechanism based on charge interactions rather than the proton-sponge effect, and may be an important step towards engineering new classes of intelligent nonviral vectors.