基因治疗药物中基因传递载体的应用基础研究
|
摘要
根据自主知识产权的专利工艺路线,合成具有分支结构、分子量30kD的阳离子聚合物,以此为基础构建sofast基因载体,用于大分子核酸的体外和体内的基因传递。通过sofast/DNA复合物形成、粒径、zeta电位、抗核酸酶能力、酸碱缓冲能力、结合核酸能力,以及基因融合肽dilNF-7和工作介质盐浓度的影响等分析,对sofast基因载体的转染机制做了初步的探讨。在体外试验中,采用sofast基因载体将质粒pEGFPN1、pCMV-lac Z和pGL3分别转染到HEK297细胞,通过所表达的绿色荧光蛋白、β-半乳糖苷酶和荧光素酶的检测,证实其具有高转染效率:通过HUV-EC等众多细胞株的转染,结果表明其广泛适用于众多原代培养细胞和转化细胞株的转染:采用MTT法进行其在最高效转染时的细胞毒性研究,结果表明细胞存活率高于90%,证实其细胞毒性极低;通过sofast基因载体抗血清特性研究,表明其具有抗血清特性,可以直接加到细胞培养基中,转染前后无需更换培养基,简化转染程序;通过sofast基因载体稳定性试验,结果表明sofast基因载体性质极其稳定,适合常温运送,4℃较长时间(3年以上)储存。在体内试验研究中,急性毒性试验、亚急性毒性试验、慢性毒性试验、半致死量测定、过敏试验以及热源检测等均表明sofast基因载体体内应用毒性极低,生物兼容性好;通过豚鼠尾静脉注射sofast/pEGFPN1复合物在体内表达试验,结果表明sofast基因载体体内应用仍然具有较高的转染效率,略优于目前市场占有率最高的阳离子脂质体Lipofectamine 2000。因此,所构建的sofast基因载体是一种高转染效率、低细胞毒性、稳定性好,且适用细胞类型较广泛的基因载体,适合体内外基因转染应用,是新一代阳离子聚合物基因载体的代表。而其简单,快捷的试验步骤,同样具有很好的优越性。
在成功构建sofast阳离子聚合物用于大分子核酸基因传递基础上,自主合成一带巴西烯酸侧链、分子量50kD的脂质-阳离子聚合物(lipid-cationic polymer),构建lipid-cationic polymer siRNA基因传递载体,专用于体内外小分子siRNA基因传递。通过lipid-cationic polymer/siRNA复合物形成、粒径、zeta电位、抗核酸酶能力、酸碱缓冲能力、结合核酸能力,以及基因融合肽diINF-7和质子泵抑制剂的影响等分析,对lipid-cationic polymer基因载体的转染机制做了初步的探讨。结果表明lipid-cationic polymer以阳离子聚合物为基本骨架,在阳离子聚合物侧链交联上巴西烯酸,同时具备阳离子聚合物和阳离子脂质体的某些特性,发挥运载siRNA功能。采用lipid-cationic polymer基因载体将针对GFP的siRNA转染到HT1080-EGFP和HeLa-EGFP细胞,结果绿色荧光蛋白抑制率分别为73%和72%,高于lipofectamine2000的抑制率:进一步的特异性、细胞毒性、生物毒性、生物兼容性、可降解性、理化性质稳定性等诸多特性的研究,表明所构建的脂质-阳离子聚合物介导的RNAi基因沉默技术是安全、特异和稳定的。采用靶向环氧化酶-2(COX-2)基因的siRNA特异诱导COX-2基因转录后沉默,mRNA水平的变化提示基因载体的有效性。进一步应用自己制备的COX-2多克隆抗体和单克隆抗体进行West-blot Test和免疫组化分析,从蛋白表达水平证实了基因载体介导的基因沉默是有效的。因此,lipid-cationicpolymer基因载体可作为胚胎发育、病毒感染(如SARS、肝炎)、肿瘤发生、药物筛选、基因功能及基因治疗研究的技术平台,并可望拓宽基因治疗药物中基因传递载体这一长期困扰基因治疗技术成熟的瓶颈。
此外,我们还对肿瘤患者的调节型免疫复合物的免疫调节作用进行了研究。
According to the independent intellectual property patent process route,a branched and 30KD cationic polymer was synthesized,which the sofast gene carrier was constructed based on.The sofast gene carrier can be applied as big molecular nucleic acids carrier both in vitro and in vivo.In this paper we investigated its transfection mechanism as a gene carrier through formation of sofast/DNA complex,particle size,zeta potential analysis,anti-nuclease assays,buffering capacity assays,DNA combining assayes and effect of diINF-7 and salt concentration of working solutions.The in vivtro asssays results showed that the sofast gene carrier had high transfection efficiency,can be applied to various cell lines transfection.It also had the property of low cytotoxicity,anti-serum capacity,long-time stability(4℃for 3 years) and simple operation.In in vivo assayes, acute toxicity test,sbuacute and chronic toxicity test,LD50 assays,allergic assays and pyrogen assays were taken.The results indicated the sofast gene carrier had low in vivo cytotoxicity.The in vivo transfection assays results showed that its tansfection efficiency was higher than cationic-liposome Lipofectamine 2000 which prevailed in the market. So the sofast gene carrier is an new kinds of easy handling,widely-fitting with the property of high efficiency,low toxicity,long stability,lipid-cationic polymer gene carrier.
Based on the construction of sofast gene carrier,we synthesized 50KD brassidic acid branched lipid-cationic polymer,then constructed the lipid-cationic polymer siRNA gene carrier to mediated siRNA transfection both in vitro and in vivo.In this paper we investigated its transfection mechanism as a gene carrier through formation of sofast/DNA complex,particle size,zeta potential analysis,anti-nuclease assays,buffering capacity assays,DNA combining assayes and effect of diINF-7 and proton pump inhibitor. It showed that the lipid cationic polymer gene carrier is composed of the cationic polymer backbone and the branched brassidic acid.So it bore the characteristics of cationic polymer and cationic liposome.It's transfection efficiency is higher than the Lipofectamine 2000.Further specificity test,cytotoxicity test,bio-compatibility test, degradation test,stability test and suitable cell line test indicated that the lipid-cationic polymer gene carrier mediated siRNA transfection is safe,efficient,specific and stable. The siRNA induced silence after the transcriptiom of cox-2 showed the effectiveness of gene carrier in mRNA level.The western blotting analysis and immunohistochemistry analysis using self-made COX-2 polyclonal and monoclonal antibodies showed the effectiveness of the gene carrier mediated gene silence in protein expression level.So the lipid-cationic polymer gene carrier can be applied in areas of embryo development,virus infection,carcinogenesis,drug screening,gene function and genetic therapy etc.And it is hoped that the lipid-cationic polymer gene carrier can break the bottle neck in genetic therapy the gene carrier in gene therapeutic drugs.
在成功构建sofast阳离子聚合物用于大分子核酸基因传递基础上,自主合成一带巴西烯酸侧链、分子量50kD的脂质-阳离子聚合物(lipid-cationic polymer),构建lipid-cationic polymer siRNA基因传递载体,专用于体内外小分子siRNA基因传递。通过lipid-cationic polymer/siRNA复合物形成、粒径、zeta电位、抗核酸酶能力、酸碱缓冲能力、结合核酸能力,以及基因融合肽diINF-7和质子泵抑制剂的影响等分析,对lipid-cationic polymer基因载体的转染机制做了初步的探讨。结果表明lipid-cationic polymer以阳离子聚合物为基本骨架,在阳离子聚合物侧链交联上巴西烯酸,同时具备阳离子聚合物和阳离子脂质体的某些特性,发挥运载siRNA功能。采用lipid-cationic polymer基因载体将针对GFP的siRNA转染到HT1080-EGFP和HeLa-EGFP细胞,结果绿色荧光蛋白抑制率分别为73%和72%,高于lipofectamine2000的抑制率:进一步的特异性、细胞毒性、生物毒性、生物兼容性、可降解性、理化性质稳定性等诸多特性的研究,表明所构建的脂质-阳离子聚合物介导的RNAi基因沉默技术是安全、特异和稳定的。采用靶向环氧化酶-2(COX-2)基因的siRNA特异诱导COX-2基因转录后沉默,mRNA水平的变化提示基因载体的有效性。进一步应用自己制备的COX-2多克隆抗体和单克隆抗体进行West-blot Test和免疫组化分析,从蛋白表达水平证实了基因载体介导的基因沉默是有效的。因此,lipid-cationicpolymer基因载体可作为胚胎发育、病毒感染(如SARS、肝炎)、肿瘤发生、药物筛选、基因功能及基因治疗研究的技术平台,并可望拓宽基因治疗药物中基因传递载体这一长期困扰基因治疗技术成熟的瓶颈。
此外,我们还对肿瘤患者的调节型免疫复合物的免疫调节作用进行了研究。
According to the independent intellectual property patent process route,a branched and 30KD cationic polymer was synthesized,which the sofast gene carrier was constructed based on.The sofast gene carrier can be applied as big molecular nucleic acids carrier both in vitro and in vivo.In this paper we investigated its transfection mechanism as a gene carrier through formation of sofast/DNA complex,particle size,zeta potential analysis,anti-nuclease assays,buffering capacity assays,DNA combining assayes and effect of diINF-7 and salt concentration of working solutions.The in vivtro asssays results showed that the sofast gene carrier had high transfection efficiency,can be applied to various cell lines transfection.It also had the property of low cytotoxicity,anti-serum capacity,long-time stability(4℃for 3 years) and simple operation.In in vivo assayes, acute toxicity test,sbuacute and chronic toxicity test,LD50 assays,allergic assays and pyrogen assays were taken.The results indicated the sofast gene carrier had low in vivo cytotoxicity.The in vivo transfection assays results showed that its tansfection efficiency was higher than cationic-liposome Lipofectamine 2000 which prevailed in the market. So the sofast gene carrier is an new kinds of easy handling,widely-fitting with the property of high efficiency,low toxicity,long stability,lipid-cationic polymer gene carrier.
Based on the construction of sofast gene carrier,we synthesized 50KD brassidic acid branched lipid-cationic polymer,then constructed the lipid-cationic polymer siRNA gene carrier to mediated siRNA transfection both in vitro and in vivo.In this paper we investigated its transfection mechanism as a gene carrier through formation of sofast/DNA complex,particle size,zeta potential analysis,anti-nuclease assays,buffering capacity assays,DNA combining assayes and effect of diINF-7 and proton pump inhibitor. It showed that the lipid cationic polymer gene carrier is composed of the cationic polymer backbone and the branched brassidic acid.So it bore the characteristics of cationic polymer and cationic liposome.It's transfection efficiency is higher than the Lipofectamine 2000.Further specificity test,cytotoxicity test,bio-compatibility test, degradation test,stability test and suitable cell line test indicated that the lipid-cationic polymer gene carrier mediated siRNA transfection is safe,efficient,specific and stable. The siRNA induced silence after the transcriptiom of cox-2 showed the effectiveness of gene carrier in mRNA level.The western blotting analysis and immunohistochemistry analysis using self-made COX-2 polyclonal and monoclonal antibodies showed the effectiveness of the gene carrier mediated gene silence in protein expression level.So the lipid-cationic polymer gene carrier can be applied in areas of embryo development,virus infection,carcinogenesis,drug screening,gene function and genetic therapy etc.And it is hoped that the lipid-cationic polymer gene carrier can break the bottle neck in genetic therapy the gene carrier in gene therapeutic drugs.
引文
[1]Huang L,Viroonchatapan E.Introduction,in:Huang M.Wagner(Eds),Non-viral vector for gene therapy[M].New York:Academic Press.1999;22.
[2]Hideki I,Bassem NM,Zhang WJ,et al.Lipid-mediated ex vivo gene transfer of viral interleukin 10 in rat lung allotransplantation[J].J.Thorac.Cardiovasc.Surg.2001;122:29-38.
[3]Dai Y,Roman M,Naviaux RK,et al.Gene therapy via primary myoblasts:long term expression of factorⅨprotein following transplantation in vivo[J].P roe Natl Acad Sci USA.1992;89:10892-10895.
[4]Stolberg SG.The biotech death of Jesse Gelsinger[J].N Y Times Mag.1999;136-140.
[5]Li Z,Dullmann J,Schiedlmeier B,et al.Murine leukemia induced by retroviral gene marking[J].Science.2002;296:497.
[6]Marshall E.Gene therapy a suspect in leukemia-like disease[J].Science.2002;298:34-35.
[7]Boyce N.Trial halted after gene shows up in semen[J].Nature.2001;414:677-678.
[8]Kaiser J.Seeking the cause of induced leukemias in X-SCID trial[J].Science.2003;299:495.
[9]胡春生.基因治疗的“3Y”问题与原则[J].遗传.2003;25(5):577-580.
[10]Pan RY,Xiao X,Chen SL,et al.Disease-inducible transgene expression from a recombinant adeno-associated virus vector in a rat arthritis model[J].J Virol.1999;73:3410-3417.
[11]Aderson WF.Human gene therapy[J].Nature.1998;392:25-30.
[12]Luo D,Saltzman WM.Synthetic DNA delivery system[J].Nat Biotechnol.2000;18:33-37.
[13]EI-Aneed A.An overview of current delivery systems in cancer gene therapy[J].J Control Release.2004; 94:1-14.
[14] Arai T,Matrsurnoto K,Saitoh L,et al.A new system for antigen:High tilter vesicular stomatits virus G rptein-praeudotyped retrovirus vector induction by introduction of Cre recombinase into stable prepacksging cell linke[J].J Virol. 1998; 72(2): 1115-1121
[15] Martin F, Neil S, Kupsch J,et al.Retrovirus targeting by tropism restriction to melanomn cells[J].J Virol.1999; 73(8):6923-6929.
[16] Song JJ,Lee B,Chang JW,et al.Optimization of vesicular stomatitis virus-G pseudotyed feline immunodeficiency virus vector for minimized cytotoxicity with efficient gene transfer.Virus Res,2003,93(1):25-30.
[17] Schowalter DB,Himeda CL,Winther BL,et al.Implication of interfering antibody formation and apoptosis as two different menchanism lending to variable duration of adenovirus-mediated transgene express in immune-competent mice[J].J Virol. 1999;73(6):4755-4766.
[18] Belousova N,Korokhow N,Krendelshchikova V,et al.Genetically targeted adenovirus vector directed to CD40-expressing cells.J Virol. 2003; 77(21): 11367-11377.
[19] Krepper F, Luther TT, Semkova I, et al.Long-term transgene expression in the RPE after gene transfer with a high-capacity adenovirus vector[J].Invest Ophthalmol Vis Sci. 2002; 43(6): 1965-1970.
[20] Snvasbva A.Delivery system for gene therapy:adeno-associated virus[J].Stem Cell Boil Gene Ther.1998; 6:257-285.
[21] Gao GP, Lu FM. Sanmiguel JC. et al.Rep/Cap gene amplification and high-yield Production of AAV in an A549 cell line expressing Rep/Cap [J].Mol Ther. 2002; 5(5): 644-649.
[22] Chaudhary VK, Jinno Y, FitzGerald D, et al.Pseudomonas exotoxin contains a specific sequence at the carboxyl terminus that is required for cytotoxicity [J].Proc Natl Acad Sci. 1990; 87:308-312.
[23] Masanori O. In Vivo Cytotoxic Activities of Recombinant Immunotoxin 8H9(Fv)-PE38 against Breast Cancer,Osteosarcoma and Neuroblastoma [J].Cancer Res. 2004; 64: 419-1424.
[24] Zhu Z, DeLuca NA, Schaffer PA. Overexpression of the herpes simplex virus type 1 immediate-early regulatory protein, ICP27, is responsible for the aberrant localization of ICPO and mutant forms of ICP4 in ICP4 mutant virus-infected cells [J].J Virol. 1996; 70:5346-5356.
[25] Smith RL,Geller AI,Escudero KW,et al.Long-term expression in sensory neurons in tissue culture from herpes simplex virus type 1(HSV-1)promoters in an HSV-1-derived vector [J].J Virol.1995; 69:4593-4599.
[26] Goins WF,Sternberg LR,Croen KD,et al.A novel latency-active promoter is contained within the herpes simplex virus type 1 UL flanking repeats [J].J virol. 1994; 68:2239-2252.
[27] Watanabe T,Watanabe S,Noda T,et al.Exploitation of nucleic acid packaging signals to generate a novel influenza virus-based vector stably expressing two foreign genes [J].J Virol. 2003; 77(19):10575-10583.
[28] Huang Z,Elankumaran S,Panda A,et al.Recombinant Newcastle disease virus as a vaccine vector [J].Poult Sci.2003;82(6):899-906
[29] Fischer T,Planz O.Stitz L,et al.Ovel recombinant parapox-virus cectors induce protective humoral and cellular immunity against lethal herpesvirus challenge infection in mice [J].J Virol. 2003; 77(17):9312-9323.
[30] Simon RH,Engelhardt JF,Yang Y, et al.Adenovirus-mediated gene transfer of the CFTR gene to the lung of non-human primates:atosicity study [J].Hum Gene Tuer. 1993; 4:771-780.
[31] Donahue RE,Kessler SW,Bodine D,et al.Helper virus induced T cell lymphoma in non-human primates after retroviral gene transfer [J].J Exp Biol. 1992; 176: 1125-1135.
[32] Xiang ZQ,Yang Y,Wilson JM,et al.A replication defective human adenovirus recombdinant serves as a highly efficacious vaccine carrier [J].Virology.1996; 219: 220-227.
[33] Knowles MR,Hohneker RW,Zhou Z,et al.A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patient with cystic fibrosis [J].New Engl J Med.1995; 333:823-831.
[34] Wolff JA,Malone RW,Williams P,et al.Direct gene transfer into mouse muscle in vivo[J].Science. 1990; 247:1465-1468.
[35] Liu F,Song Y,Liu D,et al.Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA[J].Gene Therapy.1999; 6:1258-1266.
[36] Nishi T,Dev SB, Yoshizatok.Treatment of cancer using pulsedelectric field in combination with chemotherapeutic agents or genes [J].Hum Cell.1997; 10:81-86.
[37] Zhang L,Li L,Hoffman GA,et al.Depth-targeted efficient gene delivery and expression in the skin by pulsed electric fields:an approach to gene therapy of skin aging and other diseases [J].Biochem Biophys Res Commun. 1996; 220:633-636.
[38] Feigner PL,Gadek TR,Holm M,et al.Lipofection:a highly efficient,lipid-mediated DNA-transfection procedure [J].Proc Natl Acad Sci USA.1987; 84:7413-7417.
[39] Andrew M.Gene therapy:the first decade [J].Tibtech March. 2000; 18:119-128.
[40] Legendre JY,Trzeciak B,Deuschle U,et al.N-acyl-(α,γ-diaminobutyric acid)n hydrazide as an efficient gene transfer vectorin mammalian cells in culture [J].Pharm Res.l997;14:619-624.
[41]Boussif O, Lezoualc'HF, Zanta MA, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo:polyethylenimine [J].Proc Natl Acad Sci USA.1995; 92:7279-7301.
[42] Roy K,Mao HQ,Huang SK,et al.Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy [J].Nature Med.l999;5:387-391.
[43] Nakada Y,Fattal E,Foulquier M,et al.Pharmacokinetics andbiodistribution of oligonucleotide adsorbed onto poly(isobutyl2cyanoacrylate)nanoparticles after intravenous administration in mice [J].Pharm Res.l996;13(1):38-43.
[44] Godard G,Boutorine AS,Saison BE,et al.Antisense effects of cholesterol-oligode oxynucleotide conjugates associated with poly (alkylcyanoacrylate)nanoparticles [J].Eur J Biochem. 1995; 232(2):404-410.
[45] 陈云弟,曾溢滔．反义基因治疗[J]．生物工程进展．2000；20：23-26．
[46] Kren BT,Bandyopadhyay P,Steer CJ,et al.In vivo site-directed mutagenesis of the factor Ⅸ gene by chimeric RNA/DNA oligonucleotides[J].Nat ure Med.1998;4:285-290.
[47]Li S,Tseng WC,Stolz DB,et al.Dynamic changes in the characteristics of cationic lipidic vectors after exposure to mouse serum:implications for intravenous lipofection[J].Gene Therapy.1999;6:585-594.
[48]MillerAD.Human gene therapy comes of age[J].Nature.1992;357:455-460.
[49]Mulligan RC.The basie science of gene therapy[J].Seience.1993;260:926-932.
[50]Kabanov AV.Taking Polycation gene delivery systems from invitro to in vivo[J].PharmSei Teehnol Today.1999;2:365-372.
[51]SatoT,KawakamiT,ShirakawaN,et al.Preparation and characterization of DNA-lipoglutamate complexes[J].Bull Chem Soc JPn.1995;68:2709-2715.
[52]陈建海.纳米技术在基因治疗中的应用现状[J].中国药学杂志.2004;39:481-483.
[53]OuPicky D,Howard KA,Konak C,et al.Steric stabilization of Poly-L-lysine/DNA complexes by the covalent attachment of semitelechelie poly N-(2-hydroxypropyl)methacrylamide[J].Bioconjugate Chem.2000;11:492-501.
[54]Bielinska AU,Yen A,Wu HL,et al.Application of membrane-based dendrimer/DNA comoplexes for solid phase transfection in vitro and in vivo[J].Biomaterials.2000;21:877-887.
[55]Mumper RJ,Duguid JG,Anwer K,et al.Polyvinyl derivatives as novel interactive polymers for controlled gene delivery to muscle[J].Pharm Res.1996;12:701-709.
[56]Leong KW,Mao HQ,Truong-Le VL,et al.DNA-polycation nanospheres as non-viral gene delivery vehicles[J].J Control Release.1998;53:183-193.
[57]Isobe H,Sugiyama S,Fukui K,et al.Atomic force microscope studies on condensation of plasmid DNA with functionalized fullerenes[J].Angew Chem Int Ed.2001;40:3364-3367.
[58]Pouton CW,Seymour LW.Key issues in non-viral gene delivery[J].Adv Drug Deliv Rev.2001;34:3-19.
[59]Laemmli UK.Characterization of DNA condensation induced by poly(ethylene oxide) and polylysine[J].Proc Natl Acad Sci USA.1975;72:4288-4292.
[60] Kwoh DY,Coffme CC, Lollo CP,et al. Stabilization of poly-L-lysine/DNA polyplexes for in vio gene delivery to the liver [J]. Biochim Biophys Acta. 1999; 1444: 171-190.
[61] Liu G, Molas M, Grossmann GA, et al. Biological properties of poly-L- lysine-DNA complexes generated by cooperative binding of the polycation [J]. J Biol Chem. 2001; 276:34379-34387.
[62] Ogris M, Brunner S, Schuller S, et al. PEGylated DNA/transferring-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery[J]. Gene Ther.1999; 6: 595-605.
[63] Garnett MC. Gene-delivery systems using cationic polymers [J]. Crit Rev Ther Drug Carr Syst. 1999; 16: 147-207.
[64] Petersen H, Fechner PM, Martin AL, et al. Polyethylenimine-graft-poly(ethylene glycol) copolymers: influence of copolymer block structure on DNA complexation and biological activities as gene delivery system [J]. Bioconjug Chem. 2002; 13: 845-854.
[65] Lim YB, Kim Ch, Kim K, et al. Development of a safe gene delivery system using biodegradable polymer, poly [alpha-(4-aminobutyl)-L- glycolic acid [J]. J Am Chem Soc . 2000; 122: 6524-6525.
[66] Ahn CH, Chae SY, Bae YH, et al. Biodegradable poly(ethylenimine) for plasmid DNA delivery [J]. J Control Release. 2002; 80: 273-282.
[67] Kim YH, Park JH, Lee M, et al. Polyethylenimine with acid-labile linkages as a biodegradable gene carrier [J]. J Control Release .2005; 103: 209-219.
[68] Wang J, Mao HQ, Leong KW. A novel biodegradable gene carrier based on polyphosphoester [J].J Am Chem Soc. 2001;123: 8155-8156.
[69] Kircheis R, Wightman L, Wagner E .Design and gene delivery activity of modified polyethylenimines [J]. Advanced Drug Delivery Reviews. 2001; 53: 341-358.
[70] Petersen H, Kunath K, Martin AL, et al. Star-shaped poly(ethyleneglycol)- block polyethylenimine copolymers enhance DNA condensation of low molecular weight polyethylenimines [J]. Bivmacromolecules. 2002; 3 :926-936.
[71] Erbacher P, Remy JS, Behr JP. Gene transfer with synthetic virus-like particles via the integrin-mediated endocytosis pathway [J]. Gene Ther.1999; 6:138-145.
[72] Bian ZM, Elner SG, Yoshida A et al. Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade [J]. Exp Eye Res. 2003; 76: 573-583.
[73] Wu SS, Yamauchi K, Rozengurt E. Bombesin and angiotensin II rapidly stimulate Src phosphorylation at Tyr-418 in fibroblasts and intestinal epithelial cells through a PP2-insensitive pathway [J]. Cell Signal. 2005; 17:93-102.
[74] Vittal R, Horowitz JC, Moore BB, et al. Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury [J]. Am J Pathol .2005; 166: 367-375.
[75] Merdan T, Kunath K, Fischer D, et al. Intracellular processing of poly(ethylene imine)/ribozyme complexes can be observed in living cells by using confocal laser scanning microscopy and inhibitor experiments [J]. Pharm Res .2002; 19: 140-146.
[76] Pollard H, Remy JS, Loussouarn G, et al. Polyethylenimine but not cationic lipids promote transgene delivery to the nucleus in mammalian cells [J]. J Biol Chem.1998; 273:7507-511.
[77] Moret I, Esteban PJ, Guillem VM, et al. Stability of PEI-DNA and DOTAPDNA complexes: effect of alkaline pH, heparin and serum [J]. J Controlled Rel .2001; 76:169-181.
[78] Bieber T, Meissner W, Kostin S, et al. Intracellular route and transcriptional competence of polyethylenimine-DNA complexes [J]. J Controlled Rel .2002; 82: 441-454.
[79] Brunner S, Sauer T, Carotta S, et al. Cell cycle dependence of gene transfer by lipoplex, polyplex and recombinant adenovirus [J]. Gene. 2000; 7: 401-407.
[80] Brunner S, Furtbauer E, Sauer T, et al. Overcoming the nuclear barrier: cell cycle independent nonviral gene transfer with linear polyethylenimine or electroporation [J]. Mol Ther .2002; 5:80-86.
[81] Fischer D, Li Y, Ahlemeyer B, et al. In vitor cytotoxicity testjing of polycations: influence of polymer structure on cell viability and hemolysis [J]. Biomaterials. 2003; 24:1121.
[82] Gebhart CL, Kabanov AV. Evaluation of polyplexes as gene transfer agents [ J ]. J Control Release. 2001; 73 (2 - 3): 401.
[83] Guo S, Kemphues K J. par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser / Thr kinase that is asymmetrically distributed [J]. Cell. 1995; 81: 611-620.
[84] Fire A, Xu S, Montomery MK, et al. Potent and specific genetic in-terference by double-stranded RNA in Caenorhabditis elegans[J]. Nature.1998; 391: 806-811.
[85] Bass BL.Double-stranded RNA as a template for gene silence[J]. Cell. 2000; 101: 235-238.
[86] Cerutti L, Mian N. Bateman A. Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain[J]. Trends Biochem Sci. 2000; 25: 481-482.
[87] Bernstein E, Caudy AA, Hammond SM, et al. Role for a bidentate ribonucleasein the initiation step of RNA interference [J]. Nature. 2001; 409: 363-366.
[88] Ketting RF, Fischer SE, Bernstein E, et al. Dicer function in RNA interference and synthesis of small RNA involved in development timing in c. elegans[J]. Gene Dev. 2001; 15: 2654-2659.
[89] Hammond SM, Berstein E, Beach D, et al. An RNA-directed nuclease mediates posttranscriptional gene silencing in Drosophila cells[J]. Nature. 2000; 404: 293-296.
[90] Kamath R S, Martinez-Campos M, Zipperlen P,et al.Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans[J].Genome Biology. 2000; 2:1-10.
[91] Nykanen A, Hally B, Zamore P D. ATP requirements and small interfering RNA structure in the RNA interference pathway[J]. Cell. 2001; 107: 300-321.
[92] Palauqui J C, Elmayan T, Pollien J M, et al. Systemic acquired silencing: transgene specific posttranscriptional silencing is transmitted by grafting from silenced stocks to non-silenced scions[J]. EMBO J. 1997; 16: 4738-4745.
[93] Sijen T. On the role of RNA amplification in dsRNA-trigered gene silencing[J]. Cell. 2001; 107: 465-476.
[94] Schiebel W. Isolation of an RNA-directed RNA polymerase-specific cDNA clone from tomato[J]. Plant Cell. 1998; 10: 2087-2101.
[95] McManus MT, Sharp PA. Gene silencing in mammals by small interfering RNAs[J]. Nat Rev Genet.2002; 3(10):737-747.
[96] HarborthJ, Elbashir S M, Bechert K, et al.Identification of essential genes in cultured mammalian cells using small interfering RNAs[J]. Cell Sci. 2001; 114(24): 4557-4565.
[97] Tuschl T,Zamore P D, Lehmann R, et al. Targeted mRNA degradation by double-stranded RNA in vitro[J]. Genes&Dev. 1999; 13: 3191-3197.
[98] Beinstein E, CaudyAA, Hammond SM, et al. Role for a bidentate ribonuclease in the initiation step of RNA interference [J]. Nature. 2001; 409: 363-366.(102)
[99] Svoboda P, Stein P, Hayashi H, et al. Selective reduction of dormant material mRNAs in mouse oocytes bv RNA interference [J]. Development. 2000; 127: 4147-4156.
[100] Nam NH, Parang K. Current targets for anticancer drug discovery[J] Curr Drug Targets.2003; 4:159-179.
[101] Aoki Y, Cioca D, Oidaim H, et al. RNA interference may be more potent than antisense RNA in human cancer cell lines[J]. Clin Exp Pharmacol Physiol. 2003; 30:96-102.
[102] Cioca DP, Aoki Y, Kiyosawa K. RNA interference is a functional pathway with therapeutic potential in human myeloid leukemia cell lines[J]. Cancer Gene Ther. 2003; 10:125-133.
[103] Siegmund D, Hadwiger P, Pfizenmaier K, et al. Selective inhibition Of FLICE-like inhibitory protein expression with interfering RNA oligonu-deotides is sufficient to sensitize tumor cells for TRAIL-induced apoptosis[J]. Mol Med, 2002; 8: 725-732.
[104]Kohler G,Milstein C.Continuous cultures of fused cells secreting antibody of Predefined specificity[J].Nature.1975;256:495 - 497.
[105]胡春艳,刘全忠.单克隆抗体制备技术及应用的研究进展[J].安徽预防医学杂志.2008;14(3):116-118.
[106]Riechmann L,Clark M,Waldmann H,et al.Reshaping human antibodies for therapy[J].Nature.1988;332:323 - 327.
[107]Batra SK,Niswonger ML,Wikstrand C J,et al.Mouse/human chimeric Me1214antibody genomic cloning of the variable region genes,linkage to human constant region genes,expression,and characterization[J].Hybridoma.1994;13:87- 97.
[108]Nguyen DT,Amess J A,Doughty H,et al.IDEC2C2B8 anti-CD20(rituximab)immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphopro life rative disorders:evaluation of response on 48 patients[J].Eur J Haemat ol.1999;62:76-82.
[109]Ross J S,Fletcher JA.The HER-2/neuoncogene in breast cancer:prognostic factor predictive factor and targer for therapy[J].Stem Cells.1998;16:413 -428.
[110]Mendelsohn J.Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy[J].Clin Cancer Res.1997;3:2703-2707.
[111]Friedman PN,Chace DF,Trail PA,et al.Antitumor activity of the singlec hain immunotoxin BR96 sFv-PE40 against established breast and lung tumor xenografts[J].Immunol.1993;150:3054-3061.
[112]Kreitman RJ,Wang QC,FitzGerald DJ,et al.Complete regression of human Bcell lymphoma xenografts in mice treated with recombinant anti-CD22immunotox in RFB4(dsFv) 2PE38 at doses tolerated by cynomolgusmonkeys[J].Int Cancer.1999;81:148 -155.
[113]Milenic DE,Yokota T,Filpula DR,et al.Construction binding properties,metabolism,and tumor targeting of a single chain Fv derived from the pancarcinoma monoclonal antibody CC49[J].Cancer Res.1991;51:6363 - 6371.
[114]Yokota TY,Mlinic DE,Whitlow M,et al.Rapid tumor penetration f a single chain Fv and comparion with other immunoglobulin forms[J].Cancer Res.1992;52:3403-3408.
[115] Chaudhary VK, Batra JK, Gallo MG, et al. A rapid method of clining functional varable-region antibody genes in Escherichia coli as single chain immunotoxins [J]. Proc NatlAcad SciUSA.1990; 87: 1066-1070.
[116] Zhao CY. Preparation of single chain variable fragment of MG-7mAb by phage display technology [J]. World J Gastroenterology. 2001; 7 (4): 510-514.
[117] Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science.1985; 228: 1315-1317.
[118] Hanes J, Pluckthun A .In vitro selection and evolution of functional proteins by using ribosome display[J].Proc Natl Acad Sci USA. 1997;94(10):4937-4942.
[119] Sgro C. Side effects of a monoclonal antibody, muromonab CD3 /orthoclone OKT3: bibliographic review[J].Toxicology.1995; 105:23-29.
[120] Goldblatt F, Isenberg DA. New therapies for rheumatoid arthritis[J], Clin Exp Immunol. 2005; 140(2): 195-204.
[121] Bayry, Jagadeesh. Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases: rationale and mechanisms of action[J]. Nature Clinical Practice Rheumatology [J]. 2007; 3 (5): 262 - 272.
[122] Ludwig, Dale L.Monoclonal antibody therapeutics and apoptosis[J]. Oncogene.2003; 22 (56): 9097 - 9106.
[123] Kopp, Christoph W, Steiner MD, et al. Abciximab Reduces Monocyte Tissue Factor in Carotid Angioplasty and Stenting[J]. Stroke.2003; 34(11):2560-2567.
[124] Peng XX, Ye XT, Wang SY. Identification of novel immunogenic proteins of Shigella flexneri 2a by proteomic methodologies[J]. Vaccine, 2004,22: 2750-2756.
[125] Peng XX, Zhang JY, Wang SY, Lin ZL, Zhang WY. Immuno-capture PCR for Detection of Aeromonas hydrophila[J]. J. Microbiol. Methods. 2002; 49(3):335-338.
[126] Peng XX, Wu YJ, Wang SY. Acute phase response (APR)-related proteome of loach skin to injury[J]. Proteomics, 2004; 4:3989-3997.
[127] Xu CX, Lin XM., Ren HX, Zhang YL, Wang SY, Peng XX. Analysis of outer membrane proteome of Escherichia coli related to resistance to ampicillin and tetracycline[J]. Proteomics, 2006, 6: 462-473.
[128] Huang C, Lin X, Wu L, Zhang D, Liu D, Wang S, Peng X. Systematic identification of the subproteome of Escherichia coli cell envelope reveals the interaction network of membrane proteins and membrane-associated peripheral proteins[J]. J Proteome Res, 2006, 5: 3268-3276.
[129] Goding S. Computed tomography in the diagnosis of paritod gland tumors.Br J Radiol, 1982,55:182.
[130] Boussif O, Zanta M A, Behr J P. Optimized galenics improve in vitro gene transfer with cationic molecules up to a thousand-fold[J]. Gene Ther. 1996;3:1074-1080.
[131] Kircheis R,Wightman L,Schreibe r A, et al. Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application. Gene Ther 2001; 8: 28-40.
[132] Baker A, Cotten M. Delivery of bacterial artificial chromosomes into mammalian cells with psoralen-inactivated adenovirus carrier[J]. Nucleic Acids Res. 1997; 25 (10): 1950-1956.
[133] Campeau P, Chapdelaine P, Seigneurin-Venin S, et al. Transfection of large plasmids in primary human Myoblasts[J]. Gene Therapy .2001 ;8:1387-1394.
[134] Antoine K, Christian L, Emmanuel C, et al. Polyethylenimine-mediated gene delivery: a mechanistic study [J]. THE JOURNAL OF GENE MEDICINE J Gene Med.2001;3: 135-144.
[135] Wightman L, Kircheis R, Rossler V, et al. Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo[J]. Gene Med. 2001 ;3: 362-372.
[136] Goula D, Remy JS, Erbacher P, et al. Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system[J]. Gene Ther. 1998; 5 :712-717.
[137] Ogris M, Steinlein P, Kursa M, et al.The size of DNA/transferrin-PEI complexes is an important factor for gene expression in cultured cells[J]. Gene Ther. 1998; 5: 1425-1433.
[138] Blessing T, Kursa M, Holzhauser R, et al.Different strategies for formation of pegylated EGF-conjugated PEI/DNA complexes for targeted gene delivery[J].Bioconjugate Chem.2001;12:529-537.
[139]Cotton M,Wagner E,Birnstiel ML.Receptor-mediated transport of DNA into eukaryotic cells,Methods Enzymol[J].217(1993) 618-644.
[140]Sosnowski B A,Gonzalez A M,Chandler L A,et al.Targeting DNA to cells with basic fibroblast growth factor(FGF2)[J]J.Biol.Chem.1996;271:33647-33653.
[141]李刚辉,沈一丁,费贵强,等.阳离子互穿聚合物网络对纸张的增强作用[J].中国造纸.2005;24(4):13-16.
[142]唐善法,李利民,罗平亚.阳离子聚合物对聚合物驱污水中HPAM的去除作用及机理[J].石油天然气学报.2007;29(4):119-124.
[143]Wandrey C,Hemandez- Barajas J,Hunkerler D.Diallyildimethylammonium chloride and its polymers[J].Adv.Polym.Sci..1999;145:123- 182.
[144]Richmond J M.Surfatant science,cationtic:oranic chemistry[M].Marcel Dekker.,Inc.,Newyork.1990;34-36.
[145]Churg Daniel K.Flocculants for bauxite[J].Macromolecules.1995;28:276- 281.
[146]Mikiharu Y.Rapidly dissolving water- soluble actrylamide polymers[J].Water and Waste Treatment.1993;47(6):401- 409.
[147]Verma IM,Somia N.Gene therepy promises problem and prospects[J].Nature,1997;389:239 - 241.
[148]Hill IR,Gamett MC,Bignotti F,et al.Determination of protection from serum nuclease activity by DNA-Polyelectrolyte complexes using an electrophoretic method[J].Anal Biochem,2001;291(1):62 - 65.
[149]Brown MD,Schatzlein AG,Uchegbu IF.Gene delivery with synthetic(non viral)carriers[J].Int J Pharm.2001;229:1-21.
[150]Suh J,Paik H J,Hwang B K.Ionization of polyethylenimine and polyallylamine at various pHs.Bioorg[J].Chem.1994;22:318-327.
[151]Tang M X,Szoka F C.The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complex[J].Gene Ther.1997;4:823-832.
[152]Midoux P,MonsignyM.Efficient gene transfer by hystidylated polylysine/pDNA complexes[J].ioconjugate Chem.1999;10:406 - 411.
[153]Park YJ,Liang JF,Ko KS,et al.Low molecular weight protamine as an efficient and nontoxic gene carder:in vitro study[J].J GeneMed,2003,5:700 - 711.
[154]Sun X,Zhang ZR.Preparation of lipid-protamine/DNA complexes and evaluation of their transfection efficiencies in vitro[J].Acta Pharm Sin.2004;39:792 - 796.
[155]Godbey WT,Wu KK,Mikos AG..Poly(ethylenimine) and its role in gene delivery [J].J Control Release.1999;60:149-160.
[156]Fretz MM,Mastrobattista E,Koning GA,et al.Strategies for cytosolic delivery of liposomal macromolecules[J].Int.J.Pharm.2005;298:305-309.
[157]Wadia J S,Dowdy S F.Protein transduction technology[J].CurrOp in Biotechnol,2002;13(1):52 - 56.
[158]李志琴,俞彰,凌诒萍.NSF在细胞分泌中的作用[J].生理科学进展.2001;2(1):77-79.
[159]张弗盈,王文杰.膜融合中的SNAREs及其相关蛋白研究进展[J].医学综述.2004;10(12):734-736.
[160]Ruiyong Y,Paul P,Diana GM,et al.A Role for the Disintegrin Domain of Cyritestin,a Sperm Surface Protein Belonging to the ADAM Family,in Mouse Sperm- Egg Plasma Membrane Adhesion and Fusion.[J].Cell Biol.1997;137:105- 112.
[161]段晓刚,张红国,刘睿智,等.哺乳动物精卵黏附和融合的分子基础[J].生命的化学。2006;26(5):392-395.
[162]Wolfert MA,Seymour LW.Chloroquine and amphipathic peptide helixes show synergistic transfection in vitro[J].Gene Ther.1998;5:409-414.
[163]Wagner E.Application of membrane-active peptides for non-viral gene delivery,Adv[J].Drug Deliv.Rev.1999;38:279-289.
[164]Subbarao NK,Parente RA,Szoka FC,et al.pH-dependent bilayer destabilization by an amphipathic peptide[J].Biochemistry.1987;26:2964-2972.
[165]Plank C,Oberhauser B,Mechtler K,et al.The influence of endosome disruptive peptides on gene transfer using synthetic virus-like gene transfer systems[J].J.Biol.Chem.1994;269:12918-12924.
[166] Strobattista E. Functional characterization of an endosome disruptive peptide and its application in cytosolic delivery of immunoliposome-entrapped proteins [J]. J. Biol. Chem. 2002;277: 27135-27143.
[167] Ferkol T, Pellicena PA, Eckman E, et al. Immunologic responses to gene transfer into mice via the polymeric immunoglobulin receptor[J].Gene Ther. 1996;3 (8): 669-678.
[168] McLachlan G, Stevenson B J, Davidson DJ, et al.Bacterial DNA is implicated in the inflammatory response to delivery of DNA/DOTAP to mouse lungs[J].Gene Ther. 2000;7(5):384-392.
[169] Nabel G J, Nabel E G, Yang Z Y, et al. Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans [J].Proc. Natl. Acad. Sci. 1993; 90: 11307-11311.
[170] Plautz G E, Yang Z Y, Wu B Y, Gao X., et al. Immunotherapy of malignancy by in vivo gene transfer into tumors [J]. Proc. Natl. Acad. Sci. 1993; 90: 4645-4649.
[171] Boletta A, Benigni A, Lutz J, et al. Nonviral gene delivery to the rat kidney with polyethylenimine[J]. Hum. Gene Ther. 1997; 8: 1243-1251.
[172] Ferrari S, Pettenazzo A, Behr J P, et al.ExGen 500 is an efficient vector for gene delivery to lung epithelial cells in vitro and in vivo[J]. Gene Ther. 1997; 4:1100-1106.
[173] Kircheis R, Schuller S, Brunner S, et al. Polycation-based DNA complexes for tumor-targeted gene delivery in vivo [J]. J. Gene Med. 1999; 1:111-120.
[174] Kircheis R, Wagner E. Polycation /DNA complexes for in vivo gene delivery[J]. Gene Ther. Regul. 20001 (1): 95-114.
[175] Plank C, Mechtler K, Szoka F, et al. Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery [J]. Hum. Gene Ther. 1996;7 :1437-1446.
[176] Papahadjopoulos D, Allen T M, Gabizon A, et al.Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy [J]. Proc. Natl. Acad. Sci. 1991; 88: 11460-11464.
[177] Mahato RI, Kawabata K, Nomura T, et al. Physicochemical and pharmacokinetic characteristics of plasmid DNA/ cationic liposome complexes[J]. J. Pharmacol. Sci. 1995; 84: 1267-1271.)
[178] Coll JL, Chollet P, Brambilla E, et al. In vivo delivery to tumors of DNA complexed with linear polyethylenimine [J]. Hum. Gene Then 1999; 10 (10):1659-1666.
[179] Finsinger D, Remy J S, Erbacher P, Koch C, et al. Protective copolymers for nonviral gene vectors: synthesis, vector characterization and application in gene delivery [J]. Gene Ther. 2000; 7 (11): 1183-1192.
[180] Dash PR, Read ML, Fisher KD, et al. Decreased binding to proteins conjuand cells of polymeric gene delivery vectors surface modified with a multivalent hydrophilic polymer and retargeting through attachment of transferrin[J]. J. Biol. Chem. 2000; 275 (6):3793-3802.
[181] Nguyen HK, Lemieux P, Vinogradov SV, et al. Evaluation of polyether polyethyleneimine graft copolymers as gene transfer agents[J]. Gene Ther. 2000; 7 (2): 126-138.
[182] David V Morrissey. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs [J]. Nature Biotechnology. 2005; 23: 1002 - 1007.
[183] Fountaine TM, Wood MJ, Wade-Martins R. Delivering RNA interference to the mammalian brain [J].Curr Gene Ther. 2005; 5(4):399-410.
[184] Verma I M, Somia N. Gene therapy-promises, problems and prospects [J]. Nature. 1997; 389: 239-242.
[185] Arhsall E. Gene therapy death prompts review of adenovirus vector. Science [J], 2000,286: 2244-2245.
[186] Ishiwata N, Suzuki S, Ando, et al. Characteristics and biodistribution of cationic liposomes and their DNA complexes [J]. J. Control Rel. 2000; 69:139-148.
[187] Filion M C, Phillips N C. Toxicity and immunomodulatory activity of liposomal vectors formulated with cationic lipids toward immune effector cells. Biochim Biophys Acta[J].1997;1329: 345-356.
[188] Filion M C, Phillips N C. Major limitations in the use of cationic liposomes for DNA delivery [J].Int. J. Pharm. 1998; 162:159-170.
[189]杨天赐,陈明桥,黄革玲.新一代阳离子聚合物基因载体的(梭华-Sofast)转染效果研究[J].厦门大学学报(自然科学版).2004;43(4):572-577.
[190]Ledley F D.Nonviral gene therapy:the promise of genes as pharmaceutical products[J].Hum.Gene Ther.1995;6(9):1129-1144.
[191]Lollo C P,Banaszczyk M G,Chiou H C.Obstacles and advances in non-viral gene delivery[J].Curt.Opin.Mol.Ther.2000;2(2):136-142.)
[192]Hengge UR.,Walker PS,Vogel JC.Expression of naked DNA in human,pig,and mouse skin[J].J.Clin.Invest.1996;97:2911-2916.
[193]Yang NS,Burkholder J,Roberts B,et al.In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment[J].Proc.Natl.Acad.Sci.1990;87:9568-9572.
[194]Heller R,Jarosteski M,Atkin A,et al.In vivo gene electroporation and expression in rat liver[J].FEBS Lett.1996;389:225-228.
[195]Mathiesen I.Electropermeabilization of skeletal muscle enhances gene transfer in vivo[J].Gene Ther.1999;6:508-514.
I196]Behr J P.Gene transfer with synthetic cationic amphiphiles:prospects for gene therapy.Bioconjug[J].Chem.1994;5:382-389.
[197]Felgner J H,Kumar R,Sridhar CN,et al.Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations[J].J.Biol.Chem.1994;269:2550-2561.
[198]Kichler A.Gene transfer with modified polyethylenimines[J].J.Gene Med.2004;6:3-10.
[199]Wagner E,Kircheis R,Walker GE Targeted nucleic acid delivery into tumors:new avenues for cancer therapy[J].Biomed.Pharmacother.2004;58(3):152-161.
[200]Park TG,Jeong JH,Kim SW.Current status of polymeric gene delivery systems[J].Adv.Drug Deliv.Rev.2006;58(4):467-486.
[201]Lungwitz U,Breunig M,Blunk T,et al.Polyethyleniminebased non-viral gene delivery systems[J].Eur.J.Pharm.Biopharm.2005;60(2):247-266.
[202]Neu M,Fischer D,Kissel T,et al.Recent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivatives[J].J.Gene Med.2005;7 (8): 992-1009.)
[203] Ishiwata N, Suzuki S, Ando, et al. Characteristics and biodistribution of cationic liposomes and their DNA complexes[J]. Control Rel. 2000; 69: 139-148.
[204] Fumitaka T, Yoshiko M, Shunjin, et al. Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo [J]. PNAS. 2005; 102 (34): 12177-12182.
[205] Susan L,Uprichard D. The therapeutic potential of RNA interference [J]. FEBS Lett. 2005; 579 (12): 5996 - 6007.
[206] Leung RK, Whittaker PA. RNA interference: from gene silencing to gene specific therapeutics [J]. Pharm acol Ther. 2005; 107 (2):222 - 239.
[207] Tebes SJ, Kruk PA. The genesis of RNA interference, its potential clinical applications, and implications in gynecologiccancer [J]. Gynecol Oncol. 2005; 99 (3): 736-741.
[208] Aigner A. Gene silencing through RNA interference (RNAi) in vivo: Strategies based on the direct application of siRNAs[J]. J B iotechnol.2006; 124 (1): 12-25.
[209] Lieberman J, Song E, Lee SK, et al. Interfering with disease: opportunities and roadblocks to harnessing RNA interference [J]. Trends MolMed.2003; 9 (9): 397 - 403.
[210] Tompkins SM, Tumpey TM, Epstein SL, et al. Protection against lethal influenza virus challenge by RNA interference in vivo [ J ]. PNAS, 2004,101 (23): 8682 - 8686.
[211] Frank Y, Martin CW, Lupy. Harnessing in vivo siRNA delivery for drug discovery and therapeutic development [J]. DDT. 2006; 11(1/2): 67 - 72.
[212] Martin CW, Lupy. Nanoparticles delivery RNAi therapy [J]. Nanotoday.2005; 8 (8): 34-41.
[213] Dannenberg AJ, Altorki NK, Boyle JO, et al.Cyclo-oxygenase:a pharmacological target for the prevention of cancer.Lancet Oncol[J].2001; 2(9): 544-551.
[214] Howe LR, Dannenberg AJ.A role for cyclooxygenase-2 inhibitors in the prevention and treatment of cancer [J].Semin Oncol. 2002; 29(3):111-119.
[215] Dannenberg AJ, Altoki NK, Boyle JO, et al. Cyclooxygenase-2: a pharmacological target for the prevention of cancer [J].Lanet Oncol. 2001; 2(9):544
[216] McCarthy CJ, Carofford LJ, Greenson J, et al. Cyclooxygenase-2 expression in gastric antral mucosa befor and after eradication of Helicobacter pylori infection [J].Am J Gastroenterol. 1999;94: 1218.
[217] Mestre JR., Mackrell PJ, Rivadeneira DE, et al. Redundancy in the signaling pathways and promoter elements regulating cyclooxygenase-2 gene expression in endotoxintreated macrophage/monocytic cells [J].Bio Chem.2001; 276: 3977.
[218] Kishi K, Petersen S, Petersen C, et al. Preferential enhancement of tumor radio response by a cyclooxygenase-2 inhibitor [J]. Cancer Res. 2000; 60:1326-1331.
[219] Hida T, Kozaki K, Muramatsu H, et al. Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines [J]. Clin Cancer Res. 2000; 6:2006-2011.
[220] Tianci Yang, Hui Li, Ge-ning Huang, et al. Detection of IgM and IgG complexes provides new insight intoimmune regulation of patients with malignancies: A randomized controlled trial[J]. INTERNATIONAL IMMUNOPHARMACOLOGY. 2007; 7(11) : 1433-1441.
[221] Marita Chakhtoura, Ghassan Al-Awar, Alexander M. Human leukocyte antigen (HLA) associations, antibody titers and circulating immune complexes in patients with cystic echinococcosis[J].Acta Parasitologica.2007; 52(4):414-418.
[222] Tokushige K, Hasegawa K, Yamauchi K, Hayashi N. Analysis of natural killer cells and interleukin-15 in patients with acute and fulminant hepatitis. Hepatol Res 2002;23:31-37.
[223] Stahl D, Sibrowski W. IgG2 containing IgM-IgG immune complexes predominate in normal human plasma, but not in plasma of patients with warm autoimmune haemolytic anaemia. Eur J Haematol.2006;77 (3): 191-202.
[224] Khanna SS, Karjodkar FR. Circulating immune complexes and trace elements (copper, iron and selenium) as markers in oralpre cancer and cancer: a randomised, controlled clinical trial. Head & Face Medicine 2006;2:33.
[225]A.J.Schuerweghl,E.J.Dombrechtl,W.J.Stevensl,et al.Synovial fluid and peripheral blood immune complexes of patients with rheumatoid arthritis induce apoptosis in cytokine-activated chondrocytes[J].Rheumatology International.2007;27(10):901-909.
[226]Peng X X,Wan Y G,Huang Z M,et al.Relationship of circulating immunoglobuliti class-specific immune complexes binding complement to hepatocellular injury in patients infected hepatitis A virus[J].Hepatol.1994;24(11):9-11.
[227]彭宣宪,方亮.应用酶联免疫吸附试验检测不同类型乙型肝炎中激活补体类HBsAg免疫复合物[J].病毒学报,1989,5(1):62-67.
[228]杨天赐,王三英,王怀蓉,等.甲亢患者双特异性免疫复合物的研究[J].厦门大学学报(自然科学版).2001;40(08):995-999.
[229]杨天赐,苏新辉,彭宣宪,等.甲亢患者的体液免疫研究[J].中国公共卫生学报.1998;17(04):204-206.
[230]Sanying Wang,Tianci Yang,Jianying Zhang,et al.C3/Ig and Ig/C3 two component determined circulating immune complexes(TCIC) in patients with HCV infection[J].FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY.2003;36(3):77-82.
[231]彭宣宪,张建营,万雅各,等.不同类型乙型肝炎血清IgA特异性激活补体类免疫复合物的研究(J).病毒学报,1993,9(4):325-330.
[232]杨天赐,王三英,万雅各,等.健康人C3/Ig双特异性免疫复合物与体液免疫的相关性[J].厦门大学学报(自然科学版).1999;38(05):776-779.
[233]Peng XX,Huang XF,Zhou YL,et al.Urine HBsAg of IgG two component determined immune complexes in patients with hepatitis B[J].Hepatol;1997,27(3):22-24.
[234]Peng X X,Tao Y Z,Wainberg M A,et al.Immunoglobulin and complement complexes in blood following infect ion with human immunodeficiency virus type 1[J].Clin Diagnos Lab Immunol,1996,3(1):128- 132.
[235]彭宣宪.双特异性免疫复合物的研究进展[J].上海免疫学杂志.1996;16(5):315-317.
[236]Sanying Wang,Tianci Yang,Jianying Zhang,et al.Analysis of Ig/Ig two componentdetermined circulating immune complexes(TCIC) provide new insights into host immunity[J].INTERNATIONAL IMMUNOPHARMACOLOGY 2003;3(3):1549-1555.
[237]王三英,杨天赐,彭宣宪.Ig/Ig双特异性免疫复合物定量及免疫调节作用[J].中国公共卫生.2002;18(06):712-714.
[238]彭宣宪,王三英,杨天赐.异类Ig/Ig双特异性免疫复合物的检测及其意义[J].中国公共卫生学报.1999;18(06):321-323.
[239]Bentley GA.Three dimensional structure of an id-iotope - anti - idiotope complex.Nature 1990;348:254.
[240]毕爱华(主编).医学免疫学.北京:人民军医出版社,1995:41
[241]彭宣宪.健康IgA特异性激活补体类循环免疫复合物的研究.中国免疫学杂志1993;9(3):170
[242]彭宣宪.健康人IgM特异性激活补体类循环免疫复合物的研究.中国公共卫生学报1994;13(1):45
[2]Hideki I,Bassem NM,Zhang WJ,et al.Lipid-mediated ex vivo gene transfer of viral interleukin 10 in rat lung allotransplantation[J].J.Thorac.Cardiovasc.Surg.2001;122:29-38.
[3]Dai Y,Roman M,Naviaux RK,et al.Gene therapy via primary myoblasts:long term expression of factorⅨprotein following transplantation in vivo[J].P roe Natl Acad Sci USA.1992;89:10892-10895.
[4]Stolberg SG.The biotech death of Jesse Gelsinger[J].N Y Times Mag.1999;136-140.
[5]Li Z,Dullmann J,Schiedlmeier B,et al.Murine leukemia induced by retroviral gene marking[J].Science.2002;296:497.
[6]Marshall E.Gene therapy a suspect in leukemia-like disease[J].Science.2002;298:34-35.
[7]Boyce N.Trial halted after gene shows up in semen[J].Nature.2001;414:677-678.
[8]Kaiser J.Seeking the cause of induced leukemias in X-SCID trial[J].Science.2003;299:495.
[9]胡春生.基因治疗的“3Y”问题与原则[J].遗传.2003;25(5):577-580.
[10]Pan RY,Xiao X,Chen SL,et al.Disease-inducible transgene expression from a recombinant adeno-associated virus vector in a rat arthritis model[J].J Virol.1999;73:3410-3417.
[11]Aderson WF.Human gene therapy[J].Nature.1998;392:25-30.
[12]Luo D,Saltzman WM.Synthetic DNA delivery system[J].Nat Biotechnol.2000;18:33-37.
[13]EI-Aneed A.An overview of current delivery systems in cancer gene therapy[J].J Control Release.2004; 94:1-14.
[14] Arai T,Matrsurnoto K,Saitoh L,et al.A new system for antigen:High tilter vesicular stomatits virus G rptein-praeudotyped retrovirus vector induction by introduction of Cre recombinase into stable prepacksging cell linke[J].J Virol. 1998; 72(2): 1115-1121
[15] Martin F, Neil S, Kupsch J,et al.Retrovirus targeting by tropism restriction to melanomn cells[J].J Virol.1999; 73(8):6923-6929.
[16] Song JJ,Lee B,Chang JW,et al.Optimization of vesicular stomatitis virus-G pseudotyed feline immunodeficiency virus vector for minimized cytotoxicity with efficient gene transfer.Virus Res,2003,93(1):25-30.
[17] Schowalter DB,Himeda CL,Winther BL,et al.Implication of interfering antibody formation and apoptosis as two different menchanism lending to variable duration of adenovirus-mediated transgene express in immune-competent mice[J].J Virol. 1999;73(6):4755-4766.
[18] Belousova N,Korokhow N,Krendelshchikova V,et al.Genetically targeted adenovirus vector directed to CD40-expressing cells.J Virol. 2003; 77(21): 11367-11377.
[19] Krepper F, Luther TT, Semkova I, et al.Long-term transgene expression in the RPE after gene transfer with a high-capacity adenovirus vector[J].Invest Ophthalmol Vis Sci. 2002; 43(6): 1965-1970.
[20] Snvasbva A.Delivery system for gene therapy:adeno-associated virus[J].Stem Cell Boil Gene Ther.1998; 6:257-285.
[21] Gao GP, Lu FM. Sanmiguel JC. et al.Rep/Cap gene amplification and high-yield Production of AAV in an A549 cell line expressing Rep/Cap [J].Mol Ther. 2002; 5(5): 644-649.
[22] Chaudhary VK, Jinno Y, FitzGerald D, et al.Pseudomonas exotoxin contains a specific sequence at the carboxyl terminus that is required for cytotoxicity [J].Proc Natl Acad Sci. 1990; 87:308-312.
[23] Masanori O. In Vivo Cytotoxic Activities of Recombinant Immunotoxin 8H9(Fv)-PE38 against Breast Cancer,Osteosarcoma and Neuroblastoma [J].Cancer Res. 2004; 64: 419-1424.
[24] Zhu Z, DeLuca NA, Schaffer PA. Overexpression of the herpes simplex virus type 1 immediate-early regulatory protein, ICP27, is responsible for the aberrant localization of ICPO and mutant forms of ICP4 in ICP4 mutant virus-infected cells [J].J Virol. 1996; 70:5346-5356.
[25] Smith RL,Geller AI,Escudero KW,et al.Long-term expression in sensory neurons in tissue culture from herpes simplex virus type 1(HSV-1)promoters in an HSV-1-derived vector [J].J Virol.1995; 69:4593-4599.
[26] Goins WF,Sternberg LR,Croen KD,et al.A novel latency-active promoter is contained within the herpes simplex virus type 1 UL flanking repeats [J].J virol. 1994; 68:2239-2252.
[27] Watanabe T,Watanabe S,Noda T,et al.Exploitation of nucleic acid packaging signals to generate a novel influenza virus-based vector stably expressing two foreign genes [J].J Virol. 2003; 77(19):10575-10583.
[28] Huang Z,Elankumaran S,Panda A,et al.Recombinant Newcastle disease virus as a vaccine vector [J].Poult Sci.2003;82(6):899-906
[29] Fischer T,Planz O.Stitz L,et al.Ovel recombinant parapox-virus cectors induce protective humoral and cellular immunity against lethal herpesvirus challenge infection in mice [J].J Virol. 2003; 77(17):9312-9323.
[30] Simon RH,Engelhardt JF,Yang Y, et al.Adenovirus-mediated gene transfer of the CFTR gene to the lung of non-human primates:atosicity study [J].Hum Gene Tuer. 1993; 4:771-780.
[31] Donahue RE,Kessler SW,Bodine D,et al.Helper virus induced T cell lymphoma in non-human primates after retroviral gene transfer [J].J Exp Biol. 1992; 176: 1125-1135.
[32] Xiang ZQ,Yang Y,Wilson JM,et al.A replication defective human adenovirus recombdinant serves as a highly efficacious vaccine carrier [J].Virology.1996; 219: 220-227.
[33] Knowles MR,Hohneker RW,Zhou Z,et al.A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patient with cystic fibrosis [J].New Engl J Med.1995; 333:823-831.
[34] Wolff JA,Malone RW,Williams P,et al.Direct gene transfer into mouse muscle in vivo[J].Science. 1990; 247:1465-1468.
[35] Liu F,Song Y,Liu D,et al.Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA[J].Gene Therapy.1999; 6:1258-1266.
[36] Nishi T,Dev SB, Yoshizatok.Treatment of cancer using pulsedelectric field in combination with chemotherapeutic agents or genes [J].Hum Cell.1997; 10:81-86.
[37] Zhang L,Li L,Hoffman GA,et al.Depth-targeted efficient gene delivery and expression in the skin by pulsed electric fields:an approach to gene therapy of skin aging and other diseases [J].Biochem Biophys Res Commun. 1996; 220:633-636.
[38] Feigner PL,Gadek TR,Holm M,et al.Lipofection:a highly efficient,lipid-mediated DNA-transfection procedure [J].Proc Natl Acad Sci USA.1987; 84:7413-7417.
[39] Andrew M.Gene therapy:the first decade [J].Tibtech March. 2000; 18:119-128.
[40] Legendre JY,Trzeciak B,Deuschle U,et al.N-acyl-(α,γ-diaminobutyric acid)n hydrazide as an efficient gene transfer vectorin mammalian cells in culture [J].Pharm Res.l997;14:619-624.
[41]Boussif O, Lezoualc'HF, Zanta MA, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo:polyethylenimine [J].Proc Natl Acad Sci USA.1995; 92:7279-7301.
[42] Roy K,Mao HQ,Huang SK,et al.Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy [J].Nature Med.l999;5:387-391.
[43] Nakada Y,Fattal E,Foulquier M,et al.Pharmacokinetics andbiodistribution of oligonucleotide adsorbed onto poly(isobutyl2cyanoacrylate)nanoparticles after intravenous administration in mice [J].Pharm Res.l996;13(1):38-43.
[44] Godard G,Boutorine AS,Saison BE,et al.Antisense effects of cholesterol-oligode oxynucleotide conjugates associated with poly (alkylcyanoacrylate)nanoparticles [J].Eur J Biochem. 1995; 232(2):404-410.
[45] 陈云弟,曾溢滔．反义基因治疗[J]．生物工程进展．2000；20：23-26．
[46] Kren BT,Bandyopadhyay P,Steer CJ,et al.In vivo site-directed mutagenesis of the factor Ⅸ gene by chimeric RNA/DNA oligonucleotides[J].Nat ure Med.1998;4:285-290.
[47]Li S,Tseng WC,Stolz DB,et al.Dynamic changes in the characteristics of cationic lipidic vectors after exposure to mouse serum:implications for intravenous lipofection[J].Gene Therapy.1999;6:585-594.
[48]MillerAD.Human gene therapy comes of age[J].Nature.1992;357:455-460.
[49]Mulligan RC.The basie science of gene therapy[J].Seience.1993;260:926-932.
[50]Kabanov AV.Taking Polycation gene delivery systems from invitro to in vivo[J].PharmSei Teehnol Today.1999;2:365-372.
[51]SatoT,KawakamiT,ShirakawaN,et al.Preparation and characterization of DNA-lipoglutamate complexes[J].Bull Chem Soc JPn.1995;68:2709-2715.
[52]陈建海.纳米技术在基因治疗中的应用现状[J].中国药学杂志.2004;39:481-483.
[53]OuPicky D,Howard KA,Konak C,et al.Steric stabilization of Poly-L-lysine/DNA complexes by the covalent attachment of semitelechelie poly N-(2-hydroxypropyl)methacrylamide[J].Bioconjugate Chem.2000;11:492-501.
[54]Bielinska AU,Yen A,Wu HL,et al.Application of membrane-based dendrimer/DNA comoplexes for solid phase transfection in vitro and in vivo[J].Biomaterials.2000;21:877-887.
[55]Mumper RJ,Duguid JG,Anwer K,et al.Polyvinyl derivatives as novel interactive polymers for controlled gene delivery to muscle[J].Pharm Res.1996;12:701-709.
[56]Leong KW,Mao HQ,Truong-Le VL,et al.DNA-polycation nanospheres as non-viral gene delivery vehicles[J].J Control Release.1998;53:183-193.
[57]Isobe H,Sugiyama S,Fukui K,et al.Atomic force microscope studies on condensation of plasmid DNA with functionalized fullerenes[J].Angew Chem Int Ed.2001;40:3364-3367.
[58]Pouton CW,Seymour LW.Key issues in non-viral gene delivery[J].Adv Drug Deliv Rev.2001;34:3-19.
[59]Laemmli UK.Characterization of DNA condensation induced by poly(ethylene oxide) and polylysine[J].Proc Natl Acad Sci USA.1975;72:4288-4292.
[60] Kwoh DY,Coffme CC, Lollo CP,et al. Stabilization of poly-L-lysine/DNA polyplexes for in vio gene delivery to the liver [J]. Biochim Biophys Acta. 1999; 1444: 171-190.
[61] Liu G, Molas M, Grossmann GA, et al. Biological properties of poly-L- lysine-DNA complexes generated by cooperative binding of the polycation [J]. J Biol Chem. 2001; 276:34379-34387.
[62] Ogris M, Brunner S, Schuller S, et al. PEGylated DNA/transferring-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery[J]. Gene Ther.1999; 6: 595-605.
[63] Garnett MC. Gene-delivery systems using cationic polymers [J]. Crit Rev Ther Drug Carr Syst. 1999; 16: 147-207.
[64] Petersen H, Fechner PM, Martin AL, et al. Polyethylenimine-graft-poly(ethylene glycol) copolymers: influence of copolymer block structure on DNA complexation and biological activities as gene delivery system [J]. Bioconjug Chem. 2002; 13: 845-854.
[65] Lim YB, Kim Ch, Kim K, et al. Development of a safe gene delivery system using biodegradable polymer, poly [alpha-(4-aminobutyl)-L- glycolic acid [J]. J Am Chem Soc . 2000; 122: 6524-6525.
[66] Ahn CH, Chae SY, Bae YH, et al. Biodegradable poly(ethylenimine) for plasmid DNA delivery [J]. J Control Release. 2002; 80: 273-282.
[67] Kim YH, Park JH, Lee M, et al. Polyethylenimine with acid-labile linkages as a biodegradable gene carrier [J]. J Control Release .2005; 103: 209-219.
[68] Wang J, Mao HQ, Leong KW. A novel biodegradable gene carrier based on polyphosphoester [J].J Am Chem Soc. 2001;123: 8155-8156.
[69] Kircheis R, Wightman L, Wagner E .Design and gene delivery activity of modified polyethylenimines [J]. Advanced Drug Delivery Reviews. 2001; 53: 341-358.
[70] Petersen H, Kunath K, Martin AL, et al. Star-shaped poly(ethyleneglycol)- block polyethylenimine copolymers enhance DNA condensation of low molecular weight polyethylenimines [J]. Bivmacromolecules. 2002; 3 :926-936.
[71] Erbacher P, Remy JS, Behr JP. Gene transfer with synthetic virus-like particles via the integrin-mediated endocytosis pathway [J]. Gene Ther.1999; 6:138-145.
[72] Bian ZM, Elner SG, Yoshida A et al. Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade [J]. Exp Eye Res. 2003; 76: 573-583.
[73] Wu SS, Yamauchi K, Rozengurt E. Bombesin and angiotensin II rapidly stimulate Src phosphorylation at Tyr-418 in fibroblasts and intestinal epithelial cells through a PP2-insensitive pathway [J]. Cell Signal. 2005; 17:93-102.
[74] Vittal R, Horowitz JC, Moore BB, et al. Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury [J]. Am J Pathol .2005; 166: 367-375.
[75] Merdan T, Kunath K, Fischer D, et al. Intracellular processing of poly(ethylene imine)/ribozyme complexes can be observed in living cells by using confocal laser scanning microscopy and inhibitor experiments [J]. Pharm Res .2002; 19: 140-146.
[76] Pollard H, Remy JS, Loussouarn G, et al. Polyethylenimine but not cationic lipids promote transgene delivery to the nucleus in mammalian cells [J]. J Biol Chem.1998; 273:7507-511.
[77] Moret I, Esteban PJ, Guillem VM, et al. Stability of PEI-DNA and DOTAPDNA complexes: effect of alkaline pH, heparin and serum [J]. J Controlled Rel .2001; 76:169-181.
[78] Bieber T, Meissner W, Kostin S, et al. Intracellular route and transcriptional competence of polyethylenimine-DNA complexes [J]. J Controlled Rel .2002; 82: 441-454.
[79] Brunner S, Sauer T, Carotta S, et al. Cell cycle dependence of gene transfer by lipoplex, polyplex and recombinant adenovirus [J]. Gene. 2000; 7: 401-407.
[80] Brunner S, Furtbauer E, Sauer T, et al. Overcoming the nuclear barrier: cell cycle independent nonviral gene transfer with linear polyethylenimine or electroporation [J]. Mol Ther .2002; 5:80-86.
[81] Fischer D, Li Y, Ahlemeyer B, et al. In vitor cytotoxicity testjing of polycations: influence of polymer structure on cell viability and hemolysis [J]. Biomaterials. 2003; 24:1121.
[82] Gebhart CL, Kabanov AV. Evaluation of polyplexes as gene transfer agents [ J ]. J Control Release. 2001; 73 (2 - 3): 401.
[83] Guo S, Kemphues K J. par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser / Thr kinase that is asymmetrically distributed [J]. Cell. 1995; 81: 611-620.
[84] Fire A, Xu S, Montomery MK, et al. Potent and specific genetic in-terference by double-stranded RNA in Caenorhabditis elegans[J]. Nature.1998; 391: 806-811.
[85] Bass BL.Double-stranded RNA as a template for gene silence[J]. Cell. 2000; 101: 235-238.
[86] Cerutti L, Mian N. Bateman A. Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain[J]. Trends Biochem Sci. 2000; 25: 481-482.
[87] Bernstein E, Caudy AA, Hammond SM, et al. Role for a bidentate ribonucleasein the initiation step of RNA interference [J]. Nature. 2001; 409: 363-366.
[88] Ketting RF, Fischer SE, Bernstein E, et al. Dicer function in RNA interference and synthesis of small RNA involved in development timing in c. elegans[J]. Gene Dev. 2001; 15: 2654-2659.
[89] Hammond SM, Berstein E, Beach D, et al. An RNA-directed nuclease mediates posttranscriptional gene silencing in Drosophila cells[J]. Nature. 2000; 404: 293-296.
[90] Kamath R S, Martinez-Campos M, Zipperlen P,et al.Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans[J].Genome Biology. 2000; 2:1-10.
[91] Nykanen A, Hally B, Zamore P D. ATP requirements and small interfering RNA structure in the RNA interference pathway[J]. Cell. 2001; 107: 300-321.
[92] Palauqui J C, Elmayan T, Pollien J M, et al. Systemic acquired silencing: transgene specific posttranscriptional silencing is transmitted by grafting from silenced stocks to non-silenced scions[J]. EMBO J. 1997; 16: 4738-4745.
[93] Sijen T. On the role of RNA amplification in dsRNA-trigered gene silencing[J]. Cell. 2001; 107: 465-476.
[94] Schiebel W. Isolation of an RNA-directed RNA polymerase-specific cDNA clone from tomato[J]. Plant Cell. 1998; 10: 2087-2101.
[95] McManus MT, Sharp PA. Gene silencing in mammals by small interfering RNAs[J]. Nat Rev Genet.2002; 3(10):737-747.
[96] HarborthJ, Elbashir S M, Bechert K, et al.Identification of essential genes in cultured mammalian cells using small interfering RNAs[J]. Cell Sci. 2001; 114(24): 4557-4565.
[97] Tuschl T,Zamore P D, Lehmann R, et al. Targeted mRNA degradation by double-stranded RNA in vitro[J]. Genes&Dev. 1999; 13: 3191-3197.
[98] Beinstein E, CaudyAA, Hammond SM, et al. Role for a bidentate ribonuclease in the initiation step of RNA interference [J]. Nature. 2001; 409: 363-366.(102)
[99] Svoboda P, Stein P, Hayashi H, et al. Selective reduction of dormant material mRNAs in mouse oocytes bv RNA interference [J]. Development. 2000; 127: 4147-4156.
[100] Nam NH, Parang K. Current targets for anticancer drug discovery[J] Curr Drug Targets.2003; 4:159-179.
[101] Aoki Y, Cioca D, Oidaim H, et al. RNA interference may be more potent than antisense RNA in human cancer cell lines[J]. Clin Exp Pharmacol Physiol. 2003; 30:96-102.
[102] Cioca DP, Aoki Y, Kiyosawa K. RNA interference is a functional pathway with therapeutic potential in human myeloid leukemia cell lines[J]. Cancer Gene Ther. 2003; 10:125-133.
[103] Siegmund D, Hadwiger P, Pfizenmaier K, et al. Selective inhibition Of FLICE-like inhibitory protein expression with interfering RNA oligonu-deotides is sufficient to sensitize tumor cells for TRAIL-induced apoptosis[J]. Mol Med, 2002; 8: 725-732.
[104]Kohler G,Milstein C.Continuous cultures of fused cells secreting antibody of Predefined specificity[J].Nature.1975;256:495 - 497.
[105]胡春艳,刘全忠.单克隆抗体制备技术及应用的研究进展[J].安徽预防医学杂志.2008;14(3):116-118.
[106]Riechmann L,Clark M,Waldmann H,et al.Reshaping human antibodies for therapy[J].Nature.1988;332:323 - 327.
[107]Batra SK,Niswonger ML,Wikstrand C J,et al.Mouse/human chimeric Me1214antibody genomic cloning of the variable region genes,linkage to human constant region genes,expression,and characterization[J].Hybridoma.1994;13:87- 97.
[108]Nguyen DT,Amess J A,Doughty H,et al.IDEC2C2B8 anti-CD20(rituximab)immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphopro life rative disorders:evaluation of response on 48 patients[J].Eur J Haemat ol.1999;62:76-82.
[109]Ross J S,Fletcher JA.The HER-2/neuoncogene in breast cancer:prognostic factor predictive factor and targer for therapy[J].Stem Cells.1998;16:413 -428.
[110]Mendelsohn J.Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy[J].Clin Cancer Res.1997;3:2703-2707.
[111]Friedman PN,Chace DF,Trail PA,et al.Antitumor activity of the singlec hain immunotoxin BR96 sFv-PE40 against established breast and lung tumor xenografts[J].Immunol.1993;150:3054-3061.
[112]Kreitman RJ,Wang QC,FitzGerald DJ,et al.Complete regression of human Bcell lymphoma xenografts in mice treated with recombinant anti-CD22immunotox in RFB4(dsFv) 2PE38 at doses tolerated by cynomolgusmonkeys[J].Int Cancer.1999;81:148 -155.
[113]Milenic DE,Yokota T,Filpula DR,et al.Construction binding properties,metabolism,and tumor targeting of a single chain Fv derived from the pancarcinoma monoclonal antibody CC49[J].Cancer Res.1991;51:6363 - 6371.
[114]Yokota TY,Mlinic DE,Whitlow M,et al.Rapid tumor penetration f a single chain Fv and comparion with other immunoglobulin forms[J].Cancer Res.1992;52:3403-3408.
[115] Chaudhary VK, Batra JK, Gallo MG, et al. A rapid method of clining functional varable-region antibody genes in Escherichia coli as single chain immunotoxins [J]. Proc NatlAcad SciUSA.1990; 87: 1066-1070.
[116] Zhao CY. Preparation of single chain variable fragment of MG-7mAb by phage display technology [J]. World J Gastroenterology. 2001; 7 (4): 510-514.
[117] Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science.1985; 228: 1315-1317.
[118] Hanes J, Pluckthun A .In vitro selection and evolution of functional proteins by using ribosome display[J].Proc Natl Acad Sci USA. 1997;94(10):4937-4942.
[119] Sgro C. Side effects of a monoclonal antibody, muromonab CD3 /orthoclone OKT3: bibliographic review[J].Toxicology.1995; 105:23-29.
[120] Goldblatt F, Isenberg DA. New therapies for rheumatoid arthritis[J], Clin Exp Immunol. 2005; 140(2): 195-204.
[121] Bayry, Jagadeesh. Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases: rationale and mechanisms of action[J]. Nature Clinical Practice Rheumatology [J]. 2007; 3 (5): 262 - 272.
[122] Ludwig, Dale L.Monoclonal antibody therapeutics and apoptosis[J]. Oncogene.2003; 22 (56): 9097 - 9106.
[123] Kopp, Christoph W, Steiner MD, et al. Abciximab Reduces Monocyte Tissue Factor in Carotid Angioplasty and Stenting[J]. Stroke.2003; 34(11):2560-2567.
[124] Peng XX, Ye XT, Wang SY. Identification of novel immunogenic proteins of Shigella flexneri 2a by proteomic methodologies[J]. Vaccine, 2004,22: 2750-2756.
[125] Peng XX, Zhang JY, Wang SY, Lin ZL, Zhang WY. Immuno-capture PCR for Detection of Aeromonas hydrophila[J]. J. Microbiol. Methods. 2002; 49(3):335-338.
[126] Peng XX, Wu YJ, Wang SY. Acute phase response (APR)-related proteome of loach skin to injury[J]. Proteomics, 2004; 4:3989-3997.
[127] Xu CX, Lin XM., Ren HX, Zhang YL, Wang SY, Peng XX. Analysis of outer membrane proteome of Escherichia coli related to resistance to ampicillin and tetracycline[J]. Proteomics, 2006, 6: 462-473.
[128] Huang C, Lin X, Wu L, Zhang D, Liu D, Wang S, Peng X. Systematic identification of the subproteome of Escherichia coli cell envelope reveals the interaction network of membrane proteins and membrane-associated peripheral proteins[J]. J Proteome Res, 2006, 5: 3268-3276.
[129] Goding S. Computed tomography in the diagnosis of paritod gland tumors.Br J Radiol, 1982,55:182.
[130] Boussif O, Zanta M A, Behr J P. Optimized galenics improve in vitro gene transfer with cationic molecules up to a thousand-fold[J]. Gene Ther. 1996;3:1074-1080.
[131] Kircheis R,Wightman L,Schreibe r A, et al. Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application. Gene Ther 2001; 8: 28-40.
[132] Baker A, Cotten M. Delivery of bacterial artificial chromosomes into mammalian cells with psoralen-inactivated adenovirus carrier[J]. Nucleic Acids Res. 1997; 25 (10): 1950-1956.
[133] Campeau P, Chapdelaine P, Seigneurin-Venin S, et al. Transfection of large plasmids in primary human Myoblasts[J]. Gene Therapy .2001 ;8:1387-1394.
[134] Antoine K, Christian L, Emmanuel C, et al. Polyethylenimine-mediated gene delivery: a mechanistic study [J]. THE JOURNAL OF GENE MEDICINE J Gene Med.2001;3: 135-144.
[135] Wightman L, Kircheis R, Rossler V, et al. Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo[J]. Gene Med. 2001 ;3: 362-372.
[136] Goula D, Remy JS, Erbacher P, et al. Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system[J]. Gene Ther. 1998; 5 :712-717.
[137] Ogris M, Steinlein P, Kursa M, et al.The size of DNA/transferrin-PEI complexes is an important factor for gene expression in cultured cells[J]. Gene Ther. 1998; 5: 1425-1433.
[138] Blessing T, Kursa M, Holzhauser R, et al.Different strategies for formation of pegylated EGF-conjugated PEI/DNA complexes for targeted gene delivery[J].Bioconjugate Chem.2001;12:529-537.
[139]Cotton M,Wagner E,Birnstiel ML.Receptor-mediated transport of DNA into eukaryotic cells,Methods Enzymol[J].217(1993) 618-644.
[140]Sosnowski B A,Gonzalez A M,Chandler L A,et al.Targeting DNA to cells with basic fibroblast growth factor(FGF2)[J]J.Biol.Chem.1996;271:33647-33653.
[141]李刚辉,沈一丁,费贵强,等.阳离子互穿聚合物网络对纸张的增强作用[J].中国造纸.2005;24(4):13-16.
[142]唐善法,李利民,罗平亚.阳离子聚合物对聚合物驱污水中HPAM的去除作用及机理[J].石油天然气学报.2007;29(4):119-124.
[143]Wandrey C,Hemandez- Barajas J,Hunkerler D.Diallyildimethylammonium chloride and its polymers[J].Adv.Polym.Sci..1999;145:123- 182.
[144]Richmond J M.Surfatant science,cationtic:oranic chemistry[M].Marcel Dekker.,Inc.,Newyork.1990;34-36.
[145]Churg Daniel K.Flocculants for bauxite[J].Macromolecules.1995;28:276- 281.
[146]Mikiharu Y.Rapidly dissolving water- soluble actrylamide polymers[J].Water and Waste Treatment.1993;47(6):401- 409.
[147]Verma IM,Somia N.Gene therepy promises problem and prospects[J].Nature,1997;389:239 - 241.
[148]Hill IR,Gamett MC,Bignotti F,et al.Determination of protection from serum nuclease activity by DNA-Polyelectrolyte complexes using an electrophoretic method[J].Anal Biochem,2001;291(1):62 - 65.
[149]Brown MD,Schatzlein AG,Uchegbu IF.Gene delivery with synthetic(non viral)carriers[J].Int J Pharm.2001;229:1-21.
[150]Suh J,Paik H J,Hwang B K.Ionization of polyethylenimine and polyallylamine at various pHs.Bioorg[J].Chem.1994;22:318-327.
[151]Tang M X,Szoka F C.The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complex[J].Gene Ther.1997;4:823-832.
[152]Midoux P,MonsignyM.Efficient gene transfer by hystidylated polylysine/pDNA complexes[J].ioconjugate Chem.1999;10:406 - 411.
[153]Park YJ,Liang JF,Ko KS,et al.Low molecular weight protamine as an efficient and nontoxic gene carder:in vitro study[J].J GeneMed,2003,5:700 - 711.
[154]Sun X,Zhang ZR.Preparation of lipid-protamine/DNA complexes and evaluation of their transfection efficiencies in vitro[J].Acta Pharm Sin.2004;39:792 - 796.
[155]Godbey WT,Wu KK,Mikos AG..Poly(ethylenimine) and its role in gene delivery [J].J Control Release.1999;60:149-160.
[156]Fretz MM,Mastrobattista E,Koning GA,et al.Strategies for cytosolic delivery of liposomal macromolecules[J].Int.J.Pharm.2005;298:305-309.
[157]Wadia J S,Dowdy S F.Protein transduction technology[J].CurrOp in Biotechnol,2002;13(1):52 - 56.
[158]李志琴,俞彰,凌诒萍.NSF在细胞分泌中的作用[J].生理科学进展.2001;2(1):77-79.
[159]张弗盈,王文杰.膜融合中的SNAREs及其相关蛋白研究进展[J].医学综述.2004;10(12):734-736.
[160]Ruiyong Y,Paul P,Diana GM,et al.A Role for the Disintegrin Domain of Cyritestin,a Sperm Surface Protein Belonging to the ADAM Family,in Mouse Sperm- Egg Plasma Membrane Adhesion and Fusion.[J].Cell Biol.1997;137:105- 112.
[161]段晓刚,张红国,刘睿智,等.哺乳动物精卵黏附和融合的分子基础[J].生命的化学。2006;26(5):392-395.
[162]Wolfert MA,Seymour LW.Chloroquine and amphipathic peptide helixes show synergistic transfection in vitro[J].Gene Ther.1998;5:409-414.
[163]Wagner E.Application of membrane-active peptides for non-viral gene delivery,Adv[J].Drug Deliv.Rev.1999;38:279-289.
[164]Subbarao NK,Parente RA,Szoka FC,et al.pH-dependent bilayer destabilization by an amphipathic peptide[J].Biochemistry.1987;26:2964-2972.
[165]Plank C,Oberhauser B,Mechtler K,et al.The influence of endosome disruptive peptides on gene transfer using synthetic virus-like gene transfer systems[J].J.Biol.Chem.1994;269:12918-12924.
[166] Strobattista E. Functional characterization of an endosome disruptive peptide and its application in cytosolic delivery of immunoliposome-entrapped proteins [J]. J. Biol. Chem. 2002;277: 27135-27143.
[167] Ferkol T, Pellicena PA, Eckman E, et al. Immunologic responses to gene transfer into mice via the polymeric immunoglobulin receptor[J].Gene Ther. 1996;3 (8): 669-678.
[168] McLachlan G, Stevenson B J, Davidson DJ, et al.Bacterial DNA is implicated in the inflammatory response to delivery of DNA/DOTAP to mouse lungs[J].Gene Ther. 2000;7(5):384-392.
[169] Nabel G J, Nabel E G, Yang Z Y, et al. Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans [J].Proc. Natl. Acad. Sci. 1993; 90: 11307-11311.
[170] Plautz G E, Yang Z Y, Wu B Y, Gao X., et al. Immunotherapy of malignancy by in vivo gene transfer into tumors [J]. Proc. Natl. Acad. Sci. 1993; 90: 4645-4649.
[171] Boletta A, Benigni A, Lutz J, et al. Nonviral gene delivery to the rat kidney with polyethylenimine[J]. Hum. Gene Ther. 1997; 8: 1243-1251.
[172] Ferrari S, Pettenazzo A, Behr J P, et al.ExGen 500 is an efficient vector for gene delivery to lung epithelial cells in vitro and in vivo[J]. Gene Ther. 1997; 4:1100-1106.
[173] Kircheis R, Schuller S, Brunner S, et al. Polycation-based DNA complexes for tumor-targeted gene delivery in vivo [J]. J. Gene Med. 1999; 1:111-120.
[174] Kircheis R, Wagner E. Polycation /DNA complexes for in vivo gene delivery[J]. Gene Ther. Regul. 20001 (1): 95-114.
[175] Plank C, Mechtler K, Szoka F, et al. Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery [J]. Hum. Gene Ther. 1996;7 :1437-1446.
[176] Papahadjopoulos D, Allen T M, Gabizon A, et al.Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy [J]. Proc. Natl. Acad. Sci. 1991; 88: 11460-11464.
[177] Mahato RI, Kawabata K, Nomura T, et al. Physicochemical and pharmacokinetic characteristics of plasmid DNA/ cationic liposome complexes[J]. J. Pharmacol. Sci. 1995; 84: 1267-1271.)
[178] Coll JL, Chollet P, Brambilla E, et al. In vivo delivery to tumors of DNA complexed with linear polyethylenimine [J]. Hum. Gene Then 1999; 10 (10):1659-1666.
[179] Finsinger D, Remy J S, Erbacher P, Koch C, et al. Protective copolymers for nonviral gene vectors: synthesis, vector characterization and application in gene delivery [J]. Gene Ther. 2000; 7 (11): 1183-1192.
[180] Dash PR, Read ML, Fisher KD, et al. Decreased binding to proteins conjuand cells of polymeric gene delivery vectors surface modified with a multivalent hydrophilic polymer and retargeting through attachment of transferrin[J]. J. Biol. Chem. 2000; 275 (6):3793-3802.
[181] Nguyen HK, Lemieux P, Vinogradov SV, et al. Evaluation of polyether polyethyleneimine graft copolymers as gene transfer agents[J]. Gene Ther. 2000; 7 (2): 126-138.
[182] David V Morrissey. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs [J]. Nature Biotechnology. 2005; 23: 1002 - 1007.
[183] Fountaine TM, Wood MJ, Wade-Martins R. Delivering RNA interference to the mammalian brain [J].Curr Gene Ther. 2005; 5(4):399-410.
[184] Verma I M, Somia N. Gene therapy-promises, problems and prospects [J]. Nature. 1997; 389: 239-242.
[185] Arhsall E. Gene therapy death prompts review of adenovirus vector. Science [J], 2000,286: 2244-2245.
[186] Ishiwata N, Suzuki S, Ando, et al. Characteristics and biodistribution of cationic liposomes and their DNA complexes [J]. J. Control Rel. 2000; 69:139-148.
[187] Filion M C, Phillips N C. Toxicity and immunomodulatory activity of liposomal vectors formulated with cationic lipids toward immune effector cells. Biochim Biophys Acta[J].1997;1329: 345-356.
[188] Filion M C, Phillips N C. Major limitations in the use of cationic liposomes for DNA delivery [J].Int. J. Pharm. 1998; 162:159-170.
[189]杨天赐,陈明桥,黄革玲.新一代阳离子聚合物基因载体的(梭华-Sofast)转染效果研究[J].厦门大学学报(自然科学版).2004;43(4):572-577.
[190]Ledley F D.Nonviral gene therapy:the promise of genes as pharmaceutical products[J].Hum.Gene Ther.1995;6(9):1129-1144.
[191]Lollo C P,Banaszczyk M G,Chiou H C.Obstacles and advances in non-viral gene delivery[J].Curt.Opin.Mol.Ther.2000;2(2):136-142.)
[192]Hengge UR.,Walker PS,Vogel JC.Expression of naked DNA in human,pig,and mouse skin[J].J.Clin.Invest.1996;97:2911-2916.
[193]Yang NS,Burkholder J,Roberts B,et al.In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment[J].Proc.Natl.Acad.Sci.1990;87:9568-9572.
[194]Heller R,Jarosteski M,Atkin A,et al.In vivo gene electroporation and expression in rat liver[J].FEBS Lett.1996;389:225-228.
[195]Mathiesen I.Electropermeabilization of skeletal muscle enhances gene transfer in vivo[J].Gene Ther.1999;6:508-514.
I196]Behr J P.Gene transfer with synthetic cationic amphiphiles:prospects for gene therapy.Bioconjug[J].Chem.1994;5:382-389.
[197]Felgner J H,Kumar R,Sridhar CN,et al.Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations[J].J.Biol.Chem.1994;269:2550-2561.
[198]Kichler A.Gene transfer with modified polyethylenimines[J].J.Gene Med.2004;6:3-10.
[199]Wagner E,Kircheis R,Walker GE Targeted nucleic acid delivery into tumors:new avenues for cancer therapy[J].Biomed.Pharmacother.2004;58(3):152-161.
[200]Park TG,Jeong JH,Kim SW.Current status of polymeric gene delivery systems[J].Adv.Drug Deliv.Rev.2006;58(4):467-486.
[201]Lungwitz U,Breunig M,Blunk T,et al.Polyethyleniminebased non-viral gene delivery systems[J].Eur.J.Pharm.Biopharm.2005;60(2):247-266.
[202]Neu M,Fischer D,Kissel T,et al.Recent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivatives[J].J.Gene Med.2005;7 (8): 992-1009.)
[203] Ishiwata N, Suzuki S, Ando, et al. Characteristics and biodistribution of cationic liposomes and their DNA complexes[J]. Control Rel. 2000; 69: 139-148.
[204] Fumitaka T, Yoshiko M, Shunjin, et al. Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo [J]. PNAS. 2005; 102 (34): 12177-12182.
[205] Susan L,Uprichard D. The therapeutic potential of RNA interference [J]. FEBS Lett. 2005; 579 (12): 5996 - 6007.
[206] Leung RK, Whittaker PA. RNA interference: from gene silencing to gene specific therapeutics [J]. Pharm acol Ther. 2005; 107 (2):222 - 239.
[207] Tebes SJ, Kruk PA. The genesis of RNA interference, its potential clinical applications, and implications in gynecologiccancer [J]. Gynecol Oncol. 2005; 99 (3): 736-741.
[208] Aigner A. Gene silencing through RNA interference (RNAi) in vivo: Strategies based on the direct application of siRNAs[J]. J B iotechnol.2006; 124 (1): 12-25.
[209] Lieberman J, Song E, Lee SK, et al. Interfering with disease: opportunities and roadblocks to harnessing RNA interference [J]. Trends MolMed.2003; 9 (9): 397 - 403.
[210] Tompkins SM, Tumpey TM, Epstein SL, et al. Protection against lethal influenza virus challenge by RNA interference in vivo [ J ]. PNAS, 2004,101 (23): 8682 - 8686.
[211] Frank Y, Martin CW, Lupy. Harnessing in vivo siRNA delivery for drug discovery and therapeutic development [J]. DDT. 2006; 11(1/2): 67 - 72.
[212] Martin CW, Lupy. Nanoparticles delivery RNAi therapy [J]. Nanotoday.2005; 8 (8): 34-41.
[213] Dannenberg AJ, Altorki NK, Boyle JO, et al.Cyclo-oxygenase:a pharmacological target for the prevention of cancer.Lancet Oncol[J].2001; 2(9): 544-551.
[214] Howe LR, Dannenberg AJ.A role for cyclooxygenase-2 inhibitors in the prevention and treatment of cancer [J].Semin Oncol. 2002; 29(3):111-119.
[215] Dannenberg AJ, Altoki NK, Boyle JO, et al. Cyclooxygenase-2: a pharmacological target for the prevention of cancer [J].Lanet Oncol. 2001; 2(9):544
[216] McCarthy CJ, Carofford LJ, Greenson J, et al. Cyclooxygenase-2 expression in gastric antral mucosa befor and after eradication of Helicobacter pylori infection [J].Am J Gastroenterol. 1999;94: 1218.
[217] Mestre JR., Mackrell PJ, Rivadeneira DE, et al. Redundancy in the signaling pathways and promoter elements regulating cyclooxygenase-2 gene expression in endotoxintreated macrophage/monocytic cells [J].Bio Chem.2001; 276: 3977.
[218] Kishi K, Petersen S, Petersen C, et al. Preferential enhancement of tumor radio response by a cyclooxygenase-2 inhibitor [J]. Cancer Res. 2000; 60:1326-1331.
[219] Hida T, Kozaki K, Muramatsu H, et al. Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines [J]. Clin Cancer Res. 2000; 6:2006-2011.
[220] Tianci Yang, Hui Li, Ge-ning Huang, et al. Detection of IgM and IgG complexes provides new insight intoimmune regulation of patients with malignancies: A randomized controlled trial[J]. INTERNATIONAL IMMUNOPHARMACOLOGY. 2007; 7(11) : 1433-1441.
[221] Marita Chakhtoura, Ghassan Al-Awar, Alexander M. Human leukocyte antigen (HLA) associations, antibody titers and circulating immune complexes in patients with cystic echinococcosis[J].Acta Parasitologica.2007; 52(4):414-418.
[222] Tokushige K, Hasegawa K, Yamauchi K, Hayashi N. Analysis of natural killer cells and interleukin-15 in patients with acute and fulminant hepatitis. Hepatol Res 2002;23:31-37.
[223] Stahl D, Sibrowski W. IgG2 containing IgM-IgG immune complexes predominate in normal human plasma, but not in plasma of patients with warm autoimmune haemolytic anaemia. Eur J Haematol.2006;77 (3): 191-202.
[224] Khanna SS, Karjodkar FR. Circulating immune complexes and trace elements (copper, iron and selenium) as markers in oralpre cancer and cancer: a randomised, controlled clinical trial. Head & Face Medicine 2006;2:33.
[225]A.J.Schuerweghl,E.J.Dombrechtl,W.J.Stevensl,et al.Synovial fluid and peripheral blood immune complexes of patients with rheumatoid arthritis induce apoptosis in cytokine-activated chondrocytes[J].Rheumatology International.2007;27(10):901-909.
[226]Peng X X,Wan Y G,Huang Z M,et al.Relationship of circulating immunoglobuliti class-specific immune complexes binding complement to hepatocellular injury in patients infected hepatitis A virus[J].Hepatol.1994;24(11):9-11.
[227]彭宣宪,方亮.应用酶联免疫吸附试验检测不同类型乙型肝炎中激活补体类HBsAg免疫复合物[J].病毒学报,1989,5(1):62-67.
[228]杨天赐,王三英,王怀蓉,等.甲亢患者双特异性免疫复合物的研究[J].厦门大学学报(自然科学版).2001;40(08):995-999.
[229]杨天赐,苏新辉,彭宣宪,等.甲亢患者的体液免疫研究[J].中国公共卫生学报.1998;17(04):204-206.
[230]Sanying Wang,Tianci Yang,Jianying Zhang,et al.C3/Ig and Ig/C3 two component determined circulating immune complexes(TCIC) in patients with HCV infection[J].FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY.2003;36(3):77-82.
[231]彭宣宪,张建营,万雅各,等.不同类型乙型肝炎血清IgA特异性激活补体类免疫复合物的研究(J).病毒学报,1993,9(4):325-330.
[232]杨天赐,王三英,万雅各,等.健康人C3/Ig双特异性免疫复合物与体液免疫的相关性[J].厦门大学学报(自然科学版).1999;38(05):776-779.
[233]Peng XX,Huang XF,Zhou YL,et al.Urine HBsAg of IgG two component determined immune complexes in patients with hepatitis B[J].Hepatol;1997,27(3):22-24.
[234]Peng X X,Tao Y Z,Wainberg M A,et al.Immunoglobulin and complement complexes in blood following infect ion with human immunodeficiency virus type 1[J].Clin Diagnos Lab Immunol,1996,3(1):128- 132.
[235]彭宣宪.双特异性免疫复合物的研究进展[J].上海免疫学杂志.1996;16(5):315-317.
[236]Sanying Wang,Tianci Yang,Jianying Zhang,et al.Analysis of Ig/Ig two componentdetermined circulating immune complexes(TCIC) provide new insights into host immunity[J].INTERNATIONAL IMMUNOPHARMACOLOGY 2003;3(3):1549-1555.
[237]王三英,杨天赐,彭宣宪.Ig/Ig双特异性免疫复合物定量及免疫调节作用[J].中国公共卫生.2002;18(06):712-714.
[238]彭宣宪,王三英,杨天赐.异类Ig/Ig双特异性免疫复合物的检测及其意义[J].中国公共卫生学报.1999;18(06):321-323.
[239]Bentley GA.Three dimensional structure of an id-iotope - anti - idiotope complex.Nature 1990;348:254.
[240]毕爱华(主编).医学免疫学.北京:人民军医出版社,1995:41
[241]彭宣宪.健康IgA特异性激活补体类循环免疫复合物的研究.中国免疫学杂志1993;9(3):170
[242]彭宣宪.健康人IgM特异性激活补体类循环免疫复合物的研究.中国公共卫生学报1994;13(1):45