共查询到20条相似文献,搜索用时 15 毫秒
1.
2.
3.
LaManna CM Lusic H Camplo M McIntosh TJ Barthélémy P Grinstaff MW 《Accounts of chemical research》2012,45(7):1026-1038
Twenty years after gene therapy was introduced in the clinic, advances in the technique continue to garner headlines as successes pique the interest of clinicians, researchers, and the public. Gene therapy's appeal stems from its potential to revolutionize modern medical therapeutics by offering solutions to myriad diseases through treatments tailored to a specific individual's genetic code. Both viral and non-viral vectors have been used in the clinic, but the low transfection efficiencies when non-viral vectors are used have lead to an increased focus on engineering new gene delivery vectors. To address the challenges facing non-viral or synthetic vectors, specifically lipid-based carriers, we have focused on three main themes throughout our research: (1) The release of the nucleic acid from the carrier will increase gene transfection. (2) The use of biologically inspired designs, such as DNA binding proteins, to create lipids with peptide-based headgroups will improve delivery. (3) Mimicking the natural binding patterns observed within DNA, by using lipids having a nucleoside headgroup, will produce unique supramolecular assembles with high transfection efficiencies. The results presented in this Account demonstrate that engineering the chemical components of the lipid vectors to enhance nucleic acid binding and release kinetics can improve the cellular uptake and transfection efficacy of nucleic acids. Specifically, our research has shown that the incorporation of a charge-reversal moiety to initiate a shift of the lipid from positive to negative net charge improves transfection. In addition, by varying the composition of the spacer (rigid, flexible, short, long, or aromatic) between the cationic headgroup and the hydrophobic chains, we can tailor lipids to interact with different nucleic acids (DNA, RNA, siRNA) and accordingly affect delivery, uptake outcomes, and transfection efficiency. The introduction of a peptide headgroup into the lipid provides a mechanism to affect the binding of the lipid to the nucleic acid, to influence the supramolecular lipoplex structure, and to enhance gene transfection activity. Lastly, we discuss the in vitro successes that we have had when using lipids possessing a nucleoside headgroup to create unique self-assembled structures and to deliver DNA to cells. In this Account, we state our hypotheses and design elements as well as describe the techniques that we have used in our research to provide readers with the tools to characterize and engineer new vectors. 相似文献
4.
5.
Sainlos M Hauchecorne M Oudrhiri N Zertal-Zidani S Aissaoui A Vigneron JP Lehn JM Lehn P 《Chembiochem : a European journal of chemical biology》2005,6(6):1023-1033
Cationic lipids nowadays constitute a promising alternative to recombinant viruses for gene transfer. We have recently explored the transfection potential of a new class of lipids based upon the use of aminoglycosides as cationic polar headgroups. The encouraging results obtained with a first cholesterol derivative of kanamycin A prompted us to investigate this family of vectors further, by modulating the constituent structural units of the cationic lipid. For this study, we have investigated the transfection properties of a series of new derivatives based on a kanamycin A scaffold. The results primarily confirm that aminoglycoside-based lipids are efficient vectors for gene transfection both in vitro and in vivo (mouse airways). Furthermore, a combination of transfection and physicochemical data revealed that some modifications of the constitutive subunits of kanamycin A-based vectors were associated with substantial changes in their transfection properties. 相似文献
6.
Intracellular protein delivery shows great promise in the treatment of various diseases. However, therapeutic applications of this method are limited by its low delivery efficiency and poor targeting ability. As one of most important drug delivery cargoes, Fe3O4 nanoparticles (nFe3O4) have attracted much attention for both therapeutic and diagnostic applications, especially for targeting drug delivery. To use nFe3O4 for protein delivery, a simple but effective modification of nFe3O4 is critical to attach proteins on its surface. In this work, by designing and synthesizing cationic poly(2‐(dimethylamino)ethyl methacrylate) (PDMA)‐grafted nFe3O4 via in situ atom transfer radical polymerization (ATRP), we demonstrate a simple solution to improve interactions between nFe3O4 and proteins. With the grafted PDMA on the surface, nFe3O4 exhibits not only significant enhancement in dispersibility and stability in aqueous phase, but also an excellent capability to attach negative‐charged proteins. Moreover, with the assistance of external magnetic field, PDMA‐grafted nFe3O4 can be used as a targetable vector to deliver proteins into specific cells. This work provides a novel platform based on cationic magnetite nanoparticles that can deliver therapeutic proteins into specific sites for the treatment of various diseases. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40260. 相似文献
7.
通过三步反应,以甲基丙烯酸二甲氨基乙酯(DM)、环氧氯丙烷(ECH)和3种长链烷基叔胺(十二烷基叔胺、十四烷基叔胺、十六烷基叔胺)为主要原料,合成了3种反应型阳离子Gemini 表面活性剂,即C12-3(OH)-DM、C14-3(OH)-DM和C16-3(OH)-DM。利用傅里叶变换红外光谱仪(FTIR)、核磁共振仪(1H NMR)和元素分析仪表征了目标产物结构,通过 DCTA21 表面界面张力仪测定其在水溶液中的表面张力、临界胶束浓度(cmc)以及其热力学常数,并测定了其水溶液的乳化性能和泡沫性能。结果表明:与传统单子季铵盐型表面活性剂相比,Gemini 表面活性剂Cm-3(OH)-DM(m=12,14,16)具有更高的表面活性,其临界胶束浓度(cmc)分别为 0.0265mmol/L、0.0169mmol/L、0.0083mmol/L,对应的表面张力γcmc分别为 32.1mN/m、30.1mN/m、27.7mN/m。 相似文献
8.
9.
10.
阳离子醚化剂3-氯-2-羟丙基三乙基氯化铵(CTA)的合成与表征 总被引:3,自引:1,他引:2
3-氯-2-羟丙基三甲基氯化铵可作为造纸工业中的重要助剂,是有用的活性中间体。以无水乙醇为介质,采用环氧氯丙烷(EPIC)、36%的盐酸、三乙胺替代三甲胺为原料,在乙醇中水法合成了3-氯- 2-羟丙基三乙基氯化铵(CTA),并用FT-IR对产品进行了表征。研究结果表明,CTA的收率达97 6%,产品纯度为96%,熔点为168-170℃;CTA的吸水率在6 h时已基本达到饱和;CTA的最佳合成工艺条件为总反应时间5 h,反应温度为20℃,n(EPIC):n(三乙胺豁酸盐)的比值为0.95∶1,反应体系的pH值为7~8。 相似文献
11.
以脂肪胺聚氧乙烯醚(PAE)替换部分聚己二酸新戊二醇酯(POL7112)为软段,甲苯-2,4-二异氰酸酯(TDI)为硬段,合成了系列侧链含长链烷基与主链嵌入聚醚结构(EO)的阳离子聚氨酯乳液。通过红外(FTIR)、粒径、力学性能、热重分析(TGA)、吸水率及接触角等测试对乳液及胶膜进行分析。研究发现,在PU大分子中引入PAE,热稳定性明显提高;当PAE烷基碳链增长,断裂伸长率显著增大,拉伸强度有所减小;随着PAE用量的增加及其分子中EO加合度的增大,乳液粒径变小,稳定性增强,胶膜的亲水性显著提高。 相似文献
12.
13.
阳离子单体及其聚合物的合成表征 总被引:2,自引:0,他引:2
合成了阳离子单体甲基丙烯酰氧乙基二甲基丁基溴化铵(DMB),将DMB与丙烯酰胺(AM)共聚制备了阳离子聚丙烯酰胺,并用IR,NMR对其结构进行了表征。 相似文献
14.
A new type of pH-labile cationic polymers, poly(ortho ester amidine) (POEAmd) copolymers, has been synthesized and characterized with potential future application as gene delivery carriers. The acid-labile POEAmd copolymer was synthesized by polycondensation of a new ortho ester diamine monomer with dimethylaliphatimidates, and a non-acid-labile polyamidine (PAmd) copolymer was also synthesized for comparison using a triethylene glycol diamine monomer. Both copolymers were easily dissolved in water, and can efficiently bind and condense plasmid DNA at neutral pH, forming nano-scale polyplexes. The physicochemical properties of the polyplexes have been studied using dynamic light scattering, gel electrophoresis, ethidium bromide exclusion, and heparin competition. The average size of the polyplexes was dependent on the amidine:phosphate (N:P) ratio of the polymers to DNA. Polyplexes containing the acid-labile POEAmd or the non-acid-labile PAmd showed similar average particle size, comparable strength of condensing DNA, and resistance to electrostatic destabilization. They also share similar metabolic toxicity to cells as measured by MTT assay. Importantly, the acid-labile polyplexes undergo accelerated polymer degradation at mildly acid-pHs, resulting in increasing particle size and the release of intact DNA plasmid. Polyplexes from both types of polyamidines caused distinct changes in the scattering properties of Baby Hamster Kidney (BHK-21) cells, showing swelling and increasing intracellular granularity. These cellular responses are uniquely different from other cationic polymers such as polyethylenimine and point to stress-related mechanisms specific to the polyamidines. Gene transfection of BHK-21 cells was evaluated by flow cytometry. The positive yet modest transfection efficiency by the polyamidines (acid-labile and non-acid-labile alike) underscores the importance of balancing polymer degradation and DNA release with endosomal escape. Insights gained from studying such acid-labile polyamidine-based DNA carriers and their interaction with cells may contribute to improved design of practically useful gene delivery systems. 相似文献
15.
Synthesis and characterization of cleavable cationic surfactants with a 1,3-dioxane ring 总被引:8,自引:0,他引:8
Guan-Wu Wang Xian-You Yuan You-Cheng Liu Xue-Gong Lei Qing-Xiang Guo 《Journal of the American Oil Chemists' Society》1995,72(1):83-87
A series of cationic cleavable surfactants was prepared by condensation of 2-alkyl-1,3-propanediols with 3-bromopropanal,
followed by reaction with triethylamine. Each surfactant is a mixture of two diastereomers, and their precursors’ stereochemical
assignments were based on1H nuclear magnetic resonance spectra and melting points. The critical micelle concentrations, Krafft points and destructibility
of these surfactants were determined. 相似文献
16.
以玉米淀粉为原料,以3-氯-2-羟丙基三甲基氯化铵(CHPTMAC)为阳离子醚化剂,以NaOH为催化剂,制备了天然高分子多糖基染料吸附剂阳离子淀粉(CS),用于对活性染料的吸附。对醚化反应机理进行了系统研究,并考察了反应条件对CS取代度(DS)及反应效率(RE)的影响。采用RAM、XRD、SEM对产物进行表征。吸附实验表明,当DS为0.12,染料溶液pH为8时,CS对活性红195、活性金黄K-2RA的吸附量分别为21.0和20.4 mg·g-1,去除率可达84.1%和81.6%,好于无机吸附材料活性炭。还进行了CS染料吸附材料的再生实验,4次再生后仍有较高的吸附量,表明CS染料吸附材料具有较强的可再生性能,可循环使用。该天然基染料吸附剂CS有望成为无机吸附剂及合成树脂吸附剂的理想替代品,用于工业染料废水的处理中。 相似文献
17.
Xiong MP Bae Y Fukushima S Forrest ML Nishiyama N Kataoka K Kwon GS 《ChemMedChem》2007,2(9):1321-1327
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. 相似文献
18.
Li-Ngee Ho Hiroyasu Nishiguchi Katsutoshi Nagaoka Yusaku Takita 《Journal of Porous Materials》2006,13(3):237-244
A series of lanthanide (LA) phosphate were prepared by using N-(2-hydroxyethyl) ethylenediane-N,N′,N′-triacetic acid (H3hedtra) as a chelating agent. The obtained samples were characterized by using X-ray diffraction (XRD), nitrogen adsorption-desorption
isotherm, thermal analysis (TG-DTA), transmission electron microscope (TEM) and TPD-ammonia desorption. The results showed
that samples prepared through chelating agent route possessed smaller particle size which led to higher specific surface area
with increased acidic sites compared with the reference samples prepared free of H3hedtra. It was also found that the acidic strength increased gradually from the light lanthanide phosphate to heavy lanthanide
phosphate. Besides, pore size of the samples could be controlled by altering the mole ratio of the lanthanide(LA): H3hedtra. Pore size distribution of the samples became narrower through synthesis in the presence of H3hedtra. The precursor sol complex was investigated by FTIR and XRD and mesopore formation mechanism had been discussed. 相似文献
19.
A series of new smectic and cholesteric liquid crystalline elastomers was prepared by graft polymerization of mesogenic monomer with the chiral and nonmesogenic crosslinking agent using polymethylhydrosiloxane as backbone. The chemical structures of the monomers and polymers obtained were confirmed by Fourier transform infrared (FTIR), proton nuclear magnetic resonance spectra (1H‐NMR). The mesomorphic properties were investigated by differential scanning calorimetry (DSC), polarizing optical microscopy (POM), and X‐ray diffraction measurements (XRD). M1 showed smectic (SB, SC, SA) and nematic phases during the heating and the cooling cycles. Polymer P0 and elastomer P1 exhibited smectic B phase, elastomers P2–P5 showed smectic A phase, P6 and P7 showed cholesteric phase, and P8 displayed stress‐induced birefringence. The elastomers containing less than 15 mol % M2 displayed elasticity and reversible phase transition with wide mesophase temperature ranges. Experimental results demonstrated that the glass transition temperatures decreased first and then increased; melting temperatures and the isotropization temperatures and the mesophase temperature ranges decreased with increasing content of crosslinking unit. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 97: 498–506, 2005 相似文献
20.
Li-Ngee Ho Hiroyasu Nishiguchi Katsutoshi Nagaoka Yusaku Takita 《Journal of Porous Materials》2006,13(3-4):237-244
A series of lanthanide (LA) phosphate were prepared by using N-(2-hydroxyethyl) ethylenediane-N,N′,N′-triacetic acid (H3hedtra) as a chelating agent. The obtained samples were characterized by using X-ray diffraction (XRD), nitrogen adsorption-desorption isotherm, thermal analysis (TG-DTA), transmission electron microscope (TEM) and TPD-ammonia desorption. The results showed that samples prepared through chelating agent route possessed smaller particle size which led to higher specific surface area with increased acidic sites compared with the reference samples prepared free of H3hedtra. It was also found that the acidic strength increased gradually from the light lanthanide phosphate to heavy lanthanide phosphate. Besides, pore size of the samples could be controlled by altering the mole ratio of the lanthanide(LA): H3hedtra. Pore size distribution of the samples became narrower through synthesis in the presence of H3hedtra. The precursor sol complex was investigated by FTIR and XRD and mesopore formation mechanism had been discussed. 相似文献