阳离子脂质体基因转染能力及其环境效应研究
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摘要
基因治疗是癌症等疾病的有效治疗手段,高效、安全的基因载体是基因治疗成功的关键技术之一。阳离子脂质体因其安全性高、易生产、低免疫原性以及基因递送的有效性日益受到广泛关注,基于阳离子脂质体的复合载体也显示出良好的发展前景。新的类脂分子不断涌现,研究结构与转染效率的构效关系,细胞递送机制对于提高转染效率和指导类脂分子的合成以及化学修饰具有重要意义。
论文以4类新型季铵盐表面活性剂为阳离子类脂制备脂质体,采用TEM, DLS,凝胶电泳对脂质体进行物化性质表征。结果表明,脂质体平均粒径为100-300nm,脂质体与DNA结合能力强。以GFP和荧光素酶为报告基因,进行了转染能力评价。结果显示,部分阳离子脂质体对Hela和Hep-2细胞可实现高效转染。构效关系研究表明,C3系列双子型双电荷头部的基因载体相对于单子型单电荷C1系列以及增加延伸区的单电荷C2系列和双电荷C4系列具有较高的细胞转染能力,其中,化合物C3-12的基因转染能力较高。
构建了低分子量壳聚糖/脂质体/pDNA三元非共价键新型复合载体,显著提高了脂质体的基因递送核酸能力。凝胶延滞和AFM实验表明,复合载体与pDNA结合能力强,可完全延滞pDNA。脂质体/壳聚糖/pDNA复合载体形态呈现未完全压缩的球形,短棒状和不规则的聚集块。非紧密包裹的复合物形态可能有利于提高基因转运能力。复合载体中,脂质体/pDNA以及壳聚糖/pDNA比例对转染效率影响较大,同时壳聚糖没有增加脂质体的细胞毒性,甚至可以减少某些脂质体的细胞毒性。基于脂质体和壳聚糖的复合载体具有较强的核酸递送能力和较低的细胞毒性,是基因治疗的潜在新型非病毒基因载体。
通过分子标记,利用倒置荧光显微镜考察了C3系列脂质体的跨膜过程,利用CLSM对脂质体/聚合物/pDNA复合载体的基因转运机理进行了研究。结果表明,壳聚糖提高了基因载体的核输送能力,4h后pDNA可以进入细胞核。
论文使用的新型类脂分子为季铵盐表面活性剂,这些化合物排放入水体,对水生生物可能会产生毒害作用。本文对四类阳离子类脂共12个化合物进行了环境生态效应评估,对其毒性和生物降解性进行了研究。对此类新兴污染物的环境生态效应及作用机理研究将指导基于环境考虑的高效、低毒的类脂分子设计合成。
首先对四类阳离子类脂12个化合物进行了Hela和MCF-7的细胞毒性研究,脂质体在两种人体癌细胞中的细胞毒性普遍较低,优化条件下,细胞存活率均在75%以上,添加壳聚糖可以降低阳离子基因载体的细胞毒性。其次,通过栅藻、裙带菜配子体和发光细菌毒性测试验证类脂具有生物毒性效应。对于栅藻,12个化合物的48和72h的ICso值除了C2-1472h为2.69mg/L外,其余均小于2mg/L。高浓度阳离子类脂可抑制光合作用,过氧化物酶活性,降低生存能力。对于裙带菜配子体,在低浓度(<1.5mg/L)时,部分化合物对裙带菜配子体的生长起到刺激作用,但随着时间的增长,其刺激作用慢慢减弱,转变为抑制作用。C3-12毒性最强,C2-14毒性最弱。48、72h的IC50分别为1.59mg/L、1.85mg/L及8.90mg/L、16.01mg/L。对于发光细菌而言,基因载体浓度低时,促进发光细菌生长,而高浓度抑制发光。构效关系研究表明,基因载体毒性大小递减一般顺序为：对于相同的头部基团和类似的分子结构,随着疏水链增长,毒性下降；头部毒性大小为：双电荷>单电荷。其毒性主要源于电荷效应。
季铵盐在环境中可长期存在,其降解对于维持环境低浓度至关重要。利用活性污泥法进行了类脂分子生物降解度的测定。结果表明,氨基甲酸酯型季氨盐基因载体生物降解能力强。96小时最终降解(TOC)显示,对于12碳尾载体C3-12为69.0%,C1-12为61.1%,C2-12为73.7%,C4-12为68.7%。对于相同头部基团类脂分子的降解率规律为,随着疏水链增长,降解率下降。
论文研究表明,部分新型类脂分子具有较高核酸递送能力,同时,基于脂质体开发的新型壳聚糖/脂质体/pDNA新型复合载体,显著提高了核酸递送能力。两者均为基因治疗提供具有潜力的新型非病毒载体。对于类脂结构与高效核酸递送能力的研究以及基于环境考虑的类脂结构与毒性和生物降解能力的相关性研究将对发展新的高效、低毒、可生物降解新的类脂分子提供理论依据和参考。
Gene therapy is expected to be an effective method to treat cancer and other diseases. The success of gene therapy highly depends on the development of effective and secure delivery vectors. Cationic liposome has advantages of safety, easy production, much lower immunotoxicity and effectiveness in gene delivery. Therefore, much attention has been paid to cationic liposome. Research has shown that the complex vector can be used with good prospect. New lipid molecules were synthesized continuously. Research about relationship between chemical structure with higher transfection efficiency and intracellular pathway of liposome would have significance in lipid synthesis and modification.
Four types of cationic lipids-quaternary ammonium based-surfactants gene delivery vectors were used to prepare cationic liposomes. They were characterized by TEM, dynamic light scattering and gel retarding. The average particle sizes of liposomes were changed from100to300nm. The liposomes could bind DNA efficiently. The transfection efficiency of liposome/pDNA complexes was investigated by using GFP and luciferase as marker gene, which showed higher transfection efficiency in Hela and Hep-2cells. Structure-activity relationship research showed that lipid of gemini headgroup and12carbon hydrocarbon tails of C3lipid used for gene delivery obtained higher transfection efficiency than monovalent C2and multivalent C4lipids.
The novel type of stable ternary complexes was formed by mixing low molecular weight chitosan with cationic liposome/pDNA lipoplex via non-covalent conjugation for the efficient delivery of plasmid DNA. They were characterized by atomic force microscopy (AFM), gel retarding. The complexes could bind pDNA effectively and retard it completely. Lipopolyplexes were in uncompacted spheroids, short rod-and irregular lump. Uncompacted complex morphology would increase gene delivery ability. Liposome/pDNA and chitosan/pDNA weight ratio affected transfection efficiency. Chitosan could decrease cell toxicity of liposomes. Chitosan enhanced gene delivery of cationic liposome effectively with low cell toxicity and new ternary complex would be used as novel non-vial vector.
Liposomes C3were marked by NDB-PE, which could enter cell through membrane efficiently. The intracellular trafficking and mechanism of ternary complexes were examined by confocal laser scanning microscopy. Rapid pDNA delivery to the nucleus was obtained after4h transfection by chitosan enhanced cationic liposome.
Cationic lipids used in this paper belong to quaternary ammonium compounds (QACs). Most uses of QACs led to their release into wastewater treatment systems or the environment and were harm to organisms in water body. However, little information was available on the ecological properties of lipid-based surfactants. Four series and twelve compounds were used to evaluate their ecological properties. Biological toxicity and biodegradation ability were studied in this paper. Based on environmental considerations, high efficiency and low toxicity molecular design would obtain support form these data.
Four series of cationic liposomes and twelve compounds were used to evaluate Hela and MCF-7cell toxicity. Lower cell toxicity was obtained and cell viability was higher than75%. Chitosan could decrease cell toxicity of liposomes. Acute toxicity tests on freshwater algae Scenedusmus obliquus and as well as on saltwater algae Undaria pinnatifida gametophates and luminescent bacteria were carried out to assess the aquatic toxicity of the cationic surfactant based lipid. IC50value of Scenedusmus sp were below2mg/L at48h and72h except for C2-14(72h, IC50was2.69mg/L). Higher concentration lipids could inhibit photosynthesis and POD activity, thus decrease algae survival ability. On Undaria pinnatifida gametophates, lower concentration lipids could stimulate gametophate growth and higher concentration lipids inhibit its growth. C3-12obtained the highest toxicity at48and72h with IC501.59mg/L and8.90mg/L, whereas C2-14obtained the lowest toxicity at48and72h with IC501.85mg/L and16.01mg/L. About luminescent bacteria, Lower dose of lipids increased the growth of bacteria and higher dose inhibited luminescence. Study of relationship between structure and activity showed that for the same head group and similar molecular structure, the toxicity became decreased with longer as the chain length increased. Lipids of multivalent headgroup had higher toxicity than that of monovalent headgroup. The toxicity mainly belonged to charge effects.
QACs were persistent in the environment. Biodegradation of lipid vector would be imperative in reducing surfactants concentration in urban wastewater close to the back-ground levels. Ultimate biodegradation was examined by activated sludge method. TOC results showed that the (?)ltimate biodegradation of C3-12, Cl-12, C2-12, and C4-12with the same carbon tails were69.0%,61.1%,73.7%and68.7%. The biodegradation efficiency decreased with hydrophobic chain length increased of the same lipid headgroup.
New synthesized lipid molecules had higher gene delivery ability. Novel chitosan/liposome/pDNA ternary complexes significantly improved gene delivery ability. Both types of non-viral gene vector had potential ability used for gene therapy. The study of lipid structure and activity of gene delivery, toxicity, and biodegradation allowed the development of lipid design for high efficiency, low toxicity and high biodegradation efficiency and provided theory basis and reference for lipid synthesis.
论文以4类新型季铵盐表面活性剂为阳离子类脂制备脂质体,采用TEM, DLS,凝胶电泳对脂质体进行物化性质表征。结果表明,脂质体平均粒径为100-300nm,脂质体与DNA结合能力强。以GFP和荧光素酶为报告基因,进行了转染能力评价。结果显示,部分阳离子脂质体对Hela和Hep-2细胞可实现高效转染。构效关系研究表明,C3系列双子型双电荷头部的基因载体相对于单子型单电荷C1系列以及增加延伸区的单电荷C2系列和双电荷C4系列具有较高的细胞转染能力,其中,化合物C3-12的基因转染能力较高。
构建了低分子量壳聚糖/脂质体/pDNA三元非共价键新型复合载体,显著提高了脂质体的基因递送核酸能力。凝胶延滞和AFM实验表明,复合载体与pDNA结合能力强,可完全延滞pDNA。脂质体/壳聚糖/pDNA复合载体形态呈现未完全压缩的球形,短棒状和不规则的聚集块。非紧密包裹的复合物形态可能有利于提高基因转运能力。复合载体中,脂质体/pDNA以及壳聚糖/pDNA比例对转染效率影响较大,同时壳聚糖没有增加脂质体的细胞毒性,甚至可以减少某些脂质体的细胞毒性。基于脂质体和壳聚糖的复合载体具有较强的核酸递送能力和较低的细胞毒性,是基因治疗的潜在新型非病毒基因载体。
通过分子标记,利用倒置荧光显微镜考察了C3系列脂质体的跨膜过程,利用CLSM对脂质体/聚合物/pDNA复合载体的基因转运机理进行了研究。结果表明,壳聚糖提高了基因载体的核输送能力,4h后pDNA可以进入细胞核。
论文使用的新型类脂分子为季铵盐表面活性剂,这些化合物排放入水体,对水生生物可能会产生毒害作用。本文对四类阳离子类脂共12个化合物进行了环境生态效应评估,对其毒性和生物降解性进行了研究。对此类新兴污染物的环境生态效应及作用机理研究将指导基于环境考虑的高效、低毒的类脂分子设计合成。
首先对四类阳离子类脂12个化合物进行了Hela和MCF-7的细胞毒性研究,脂质体在两种人体癌细胞中的细胞毒性普遍较低,优化条件下,细胞存活率均在75%以上,添加壳聚糖可以降低阳离子基因载体的细胞毒性。其次,通过栅藻、裙带菜配子体和发光细菌毒性测试验证类脂具有生物毒性效应。对于栅藻,12个化合物的48和72h的ICso值除了C2-1472h为2.69mg/L外,其余均小于2mg/L。高浓度阳离子类脂可抑制光合作用,过氧化物酶活性,降低生存能力。对于裙带菜配子体,在低浓度(<1.5mg/L)时,部分化合物对裙带菜配子体的生长起到刺激作用,但随着时间的增长,其刺激作用慢慢减弱,转变为抑制作用。C3-12毒性最强,C2-14毒性最弱。48、72h的IC50分别为1.59mg/L、1.85mg/L及8.90mg/L、16.01mg/L。对于发光细菌而言,基因载体浓度低时,促进发光细菌生长,而高浓度抑制发光。构效关系研究表明,基因载体毒性大小递减一般顺序为：对于相同的头部基团和类似的分子结构,随着疏水链增长,毒性下降；头部毒性大小为：双电荷>单电荷。其毒性主要源于电荷效应。
季铵盐在环境中可长期存在,其降解对于维持环境低浓度至关重要。利用活性污泥法进行了类脂分子生物降解度的测定。结果表明,氨基甲酸酯型季氨盐基因载体生物降解能力强。96小时最终降解(TOC)显示,对于12碳尾载体C3-12为69.0%,C1-12为61.1%,C2-12为73.7%,C4-12为68.7%。对于相同头部基团类脂分子的降解率规律为,随着疏水链增长,降解率下降。
论文研究表明,部分新型类脂分子具有较高核酸递送能力,同时,基于脂质体开发的新型壳聚糖/脂质体/pDNA新型复合载体,显著提高了核酸递送能力。两者均为基因治疗提供具有潜力的新型非病毒载体。对于类脂结构与高效核酸递送能力的研究以及基于环境考虑的类脂结构与毒性和生物降解能力的相关性研究将对发展新的高效、低毒、可生物降解新的类脂分子提供理论依据和参考。
Gene therapy is expected to be an effective method to treat cancer and other diseases. The success of gene therapy highly depends on the development of effective and secure delivery vectors. Cationic liposome has advantages of safety, easy production, much lower immunotoxicity and effectiveness in gene delivery. Therefore, much attention has been paid to cationic liposome. Research has shown that the complex vector can be used with good prospect. New lipid molecules were synthesized continuously. Research about relationship between chemical structure with higher transfection efficiency and intracellular pathway of liposome would have significance in lipid synthesis and modification.
Four types of cationic lipids-quaternary ammonium based-surfactants gene delivery vectors were used to prepare cationic liposomes. They were characterized by TEM, dynamic light scattering and gel retarding. The average particle sizes of liposomes were changed from100to300nm. The liposomes could bind DNA efficiently. The transfection efficiency of liposome/pDNA complexes was investigated by using GFP and luciferase as marker gene, which showed higher transfection efficiency in Hela and Hep-2cells. Structure-activity relationship research showed that lipid of gemini headgroup and12carbon hydrocarbon tails of C3lipid used for gene delivery obtained higher transfection efficiency than monovalent C2and multivalent C4lipids.
The novel type of stable ternary complexes was formed by mixing low molecular weight chitosan with cationic liposome/pDNA lipoplex via non-covalent conjugation for the efficient delivery of plasmid DNA. They were characterized by atomic force microscopy (AFM), gel retarding. The complexes could bind pDNA effectively and retard it completely. Lipopolyplexes were in uncompacted spheroids, short rod-and irregular lump. Uncompacted complex morphology would increase gene delivery ability. Liposome/pDNA and chitosan/pDNA weight ratio affected transfection efficiency. Chitosan could decrease cell toxicity of liposomes. Chitosan enhanced gene delivery of cationic liposome effectively with low cell toxicity and new ternary complex would be used as novel non-vial vector.
Liposomes C3were marked by NDB-PE, which could enter cell through membrane efficiently. The intracellular trafficking and mechanism of ternary complexes were examined by confocal laser scanning microscopy. Rapid pDNA delivery to the nucleus was obtained after4h transfection by chitosan enhanced cationic liposome.
Cationic lipids used in this paper belong to quaternary ammonium compounds (QACs). Most uses of QACs led to their release into wastewater treatment systems or the environment and were harm to organisms in water body. However, little information was available on the ecological properties of lipid-based surfactants. Four series and twelve compounds were used to evaluate their ecological properties. Biological toxicity and biodegradation ability were studied in this paper. Based on environmental considerations, high efficiency and low toxicity molecular design would obtain support form these data.
Four series of cationic liposomes and twelve compounds were used to evaluate Hela and MCF-7cell toxicity. Lower cell toxicity was obtained and cell viability was higher than75%. Chitosan could decrease cell toxicity of liposomes. Acute toxicity tests on freshwater algae Scenedusmus obliquus and as well as on saltwater algae Undaria pinnatifida gametophates and luminescent bacteria were carried out to assess the aquatic toxicity of the cationic surfactant based lipid. IC50value of Scenedusmus sp were below2mg/L at48h and72h except for C2-14(72h, IC50was2.69mg/L). Higher concentration lipids could inhibit photosynthesis and POD activity, thus decrease algae survival ability. On Undaria pinnatifida gametophates, lower concentration lipids could stimulate gametophate growth and higher concentration lipids inhibit its growth. C3-12obtained the highest toxicity at48and72h with IC501.59mg/L and8.90mg/L, whereas C2-14obtained the lowest toxicity at48and72h with IC501.85mg/L and16.01mg/L. About luminescent bacteria, Lower dose of lipids increased the growth of bacteria and higher dose inhibited luminescence. Study of relationship between structure and activity showed that for the same head group and similar molecular structure, the toxicity became decreased with longer as the chain length increased. Lipids of multivalent headgroup had higher toxicity than that of monovalent headgroup. The toxicity mainly belonged to charge effects.
QACs were persistent in the environment. Biodegradation of lipid vector would be imperative in reducing surfactants concentration in urban wastewater close to the back-ground levels. Ultimate biodegradation was examined by activated sludge method. TOC results showed that the (?)ltimate biodegradation of C3-12, Cl-12, C2-12, and C4-12with the same carbon tails were69.0%,61.1%,73.7%and68.7%. The biodegradation efficiency decreased with hydrophobic chain length increased of the same lipid headgroup.
New synthesized lipid molecules had higher gene delivery ability. Novel chitosan/liposome/pDNA ternary complexes significantly improved gene delivery ability. Both types of non-viral gene vector had potential ability used for gene therapy. The study of lipid structure and activity of gene delivery, toxicity, and biodegradation allowed the development of lipid design for high efficiency, low toxicity and high biodegradation efficiency and provided theory basis and reference for lipid synthesis.
引文
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