磁性阳离子脂质体介导CD-TK双自杀融合基因靶向治疗肝癌的实验研究
摘要
目的:本课题探讨由CMV启动子、AFP增强子组成的高活性嵌合启动子,通过融合启动子的调控提高融合自杀基因CD/TK在靶细胞表达的特异性;并以生物相容性好的磁性阳离子脂质体为载体,将该自杀基因靶向导入肝癌细胞中,以达到提高基因治疗靶向性及安全性的目的。
方法:本研究利用反相蒸发法法制备一种100nm大小、分散均匀的磁性阳离子脂质体,采用PCR、RT-PCR、融合PCR、酶切、连接等技术构建由CMV启动子、AFP增强子驱动的融合自杀基因AFPE-pTK-IRES-CD表达载体,并以该磁性阳离子脂质体为载体将PAFPE-pTK-IRES-CD质粒表达载体转染肝癌HepG2细胞系进行体外实验研究,荧光显微镜、流式细胞仪检测纳米的转染效率,分别用RT-PCR、Western-blot杂交等方法检测鉴定CD/TK融合自杀基因在HepG2细胞内的表达;MTT法检测5-FC、GCV对HepG2细胞的毒性;
MTT法、克隆形成实验检测自杀基因前药系统对表达自杀基因的HepG2细胞的杀伤效应;绘制细胞生长曲线反映该系统对HepG2细胞生长的影响;免疫组化及免疫荧光检测治疗前后自杀基因蛋白表达水平的变化;用高效液相色谱(HPLC)法测定处理前后前体药物5-FC向5-FU转化效率的变化;
结果:在经过正交优化实验后,磁性阳离子脂质体能与质粒DNA有效结合,通过复合体吸附在细胞膜上并进入细胞内,增加进入细胞内DNA量,提高基因转染的效率,并且质粒DNA与磁性阳离子脂质体形成的复合体能有效的抵抗血清中酶类对DNA分子的降解,有效的保护DNA分子的完整性;用绿色荧光蛋白(GFP)基因作报告基因,与磁性阳离子脂质体结合后转染常规培养的HepG2细胞,用荧光显微镜及流式细胞仪检测,发现磁性阳离子脂质体具有较高的转染效率;
5-FC和GCV在高浓度(5-FC>60μg/ml,GCV>0.6μg/ml)时,对HepG2细胞亦有一定的杀伤作用;对于CD/TK阳性HepG2细胞,当5-FC的浓度为40μg/ml和80μg/ml时,细胞存活率分别是69.23%和18.02%;同时,结果显示,CD/TK阳性HepG2细胞在两种前体药物5-FC和GCV同时存在的条件下,并没有大多数文献报告的显示出协同杀瘤作用,其作用反而低于单独使用5-FC;200μg/ml,5-FC处理CD/TK阳性HepG2细胞24小时后,用高效液相色谱法测定细胞上清中5-Fu浓度是188μg/ml,5-Fc向5-Fu转化效率是94%;旁杀效应实验显示,在200μg/ml5-FC存在时,只要PAFPE-pTK-IRES-CD质粒有20%的转染效率,细胞的相对存活率将下降为49.6%,说明该融合自杀基因前药系统具有强大的“旁杀效应”。这说明磁性阳离子脂质体介导的自杀基因前药治疗均有明显的抑瘤作用。
结论:
1)磁性阳离子脂质体能有效介导PAFPE-pTK-IRES-CD自杀基因质粒载体转染HepG2细胞,且未显示明显毒副作用,因此该磁性阳离子脂质体可能成为一种新型的用于基因治疗的非病毒载体。
2)5-FC与GCV对CD/TK阳性细胞均有明显杀伤作用,但二者无协同作用,其作用弱于单独5-FC而强于GCV。
3)该融合自杀基因前药系统具有强大的“旁杀效应”
4)该融合自杀基因前药系统,当前体药物浓度5-FC<200μg/ml,GCV<50μg/ml,在此浓度下,对不含自杀基因的HepG2细胞毒性很低。
5)体外实验结果显示,以磁性阳离子脂质体为载体介导AFP调控下的自杀基因在肿瘤的治疗中显示良好的靶向杀伤效应。
Objective:To study the chimeric promoter with high activity which is composed with CMV promoter and AFP enhancer;the specificity of the fused suicide gene CD/TK increases or not,which expressed in target cell by the regulation of fused promoter;and by magnetic cationic liposome with good biocompatibility as a carrier,suicide gene transfect into hepatoma cells,to observe the probability of enhancing target and safety of gene therapy.
Methods:magnetic cationic liposomes were prepared by reverse phase evaporation,the expression vector of AFPE-pTK-IRES-CD as a fused suicide gene was construct by PCR,RT-PCR,fusion PCR, restriction enzyme and ligation etc.In vitro experiment was through transfect pAFPE-pTK-IRES-CD plasmid expression vector into HepG2 cell line using magnetic cationic liposomes as a vector.The transfection efficiency was detected by fluorescence microscope and flow cytometer, the express of CD/TK fused suicide gene in HepG2 cell was detected by RT-PCR and Western-blot.The toxicity of 5-FC and GCV on HepG2 cells was detected by MTT.The killing effect of suicide gene prodrug system on HepG2 cells expressed the suicide gene was detected by MTT and clone formation experiment.The effect of this system on the growth of HepG2 cells was observed by cell growth curve.The change of express level of the suicide gene before and after treatment was detected by immunohistochemistry and immunofluorescence.The change of transfection efficiency from prodrug 5-FC to 5-FU was detected by HPLC before and after treatment.
Results:Magnetic cationic liposomes could conjugate with plasmid DNA as the complex,it absorbed on the cell membrane and went into cells,increased DNA quantities into cells and increased the efficiency of gene transfection.The complex could inhibit well the DNA degradation by the enzyme in blood serum and protect well the integrality of DNA molecule.When HepG2 cells were transfected after Green fluorescent protein(GFP) as a reporter gene combined with magnetic cationic liposomes,it found that it had higher transfection efficiency.5-FC and GCV in a high concentration(5-FC＞60μg/mL GCV＞0.6μg/ml) had some killing effect for HepG2 cells.For CD/TK+ HepG2 cells,when the 5-FC concentration was 40μg/ml and 80μg/ml,cell survival rates were 69.23% and 18.02%respectively.And for CD/TK+ HepG2 cells,under the condition of simultaneous existence for two prodrugs 5-FC and GCV, synergism effect was not found which reported by many studies,and the effect was lower than 5-FC alone.CD/TK+ HepG2 cells were treated 24h with 200μg/ml 5-FC,5-Fu concentration in cell supernatant was 168μg/ml,the transformation efficiency was 94%from 5-Fc to 5-Fu. Under 200μg/ml 5-FC,when pAFPE-pTK-IRES-CD plasmid had more 20%transfection efficiency,the relative survival rate of the cells decreased to 49.6%,this revealed that magnetic cationic liposomes-mediated suicide gene prodrug treatment had evident effect on tumor inhibition.
Conclusions:Magnetic cationic liposomes can mediate well the transfection of suicide gene pAFPE-pTK-IRES-CD plasmid into HepG2 cells for,and have no evident toxicity and side effects,so it may be a new non-viral vector for gene therapy.5-FC and GCV have evident killing effect for CD/TK+ cells,but no synergism;and the effect is lower than that of 5-FC alone,but stronger than that of GCV.The fused suicide gene prodrug system has strong bystander killing effect,and as prodrug 5-FC＜200μg/ml,GCV＜50μg/ml,its toxicity is very low for HepG2 cells with no suicide gene.In vitro experiment reveals that magnetic cationic liposomes-mediated suicide gene under regulation by AFP has good targeted killing effect for tumor therapy.
方法:本研究利用反相蒸发法法制备一种100nm大小、分散均匀的磁性阳离子脂质体,采用PCR、RT-PCR、融合PCR、酶切、连接等技术构建由CMV启动子、AFP增强子驱动的融合自杀基因AFPE-pTK-IRES-CD表达载体,并以该磁性阳离子脂质体为载体将PAFPE-pTK-IRES-CD质粒表达载体转染肝癌HepG2细胞系进行体外实验研究,荧光显微镜、流式细胞仪检测纳米的转染效率,分别用RT-PCR、Western-blot杂交等方法检测鉴定CD/TK融合自杀基因在HepG2细胞内的表达;MTT法检测5-FC、GCV对HepG2细胞的毒性;
MTT法、克隆形成实验检测自杀基因前药系统对表达自杀基因的HepG2细胞的杀伤效应;绘制细胞生长曲线反映该系统对HepG2细胞生长的影响;免疫组化及免疫荧光检测治疗前后自杀基因蛋白表达水平的变化;用高效液相色谱(HPLC)法测定处理前后前体药物5-FC向5-FU转化效率的变化;
结果:在经过正交优化实验后,磁性阳离子脂质体能与质粒DNA有效结合,通过复合体吸附在细胞膜上并进入细胞内,增加进入细胞内DNA量,提高基因转染的效率,并且质粒DNA与磁性阳离子脂质体形成的复合体能有效的抵抗血清中酶类对DNA分子的降解,有效的保护DNA分子的完整性;用绿色荧光蛋白(GFP)基因作报告基因,与磁性阳离子脂质体结合后转染常规培养的HepG2细胞,用荧光显微镜及流式细胞仪检测,发现磁性阳离子脂质体具有较高的转染效率;
5-FC和GCV在高浓度(5-FC>60μg/ml,GCV>0.6μg/ml)时,对HepG2细胞亦有一定的杀伤作用;对于CD/TK阳性HepG2细胞,当5-FC的浓度为40μg/ml和80μg/ml时,细胞存活率分别是69.23%和18.02%;同时,结果显示,CD/TK阳性HepG2细胞在两种前体药物5-FC和GCV同时存在的条件下,并没有大多数文献报告的显示出协同杀瘤作用,其作用反而低于单独使用5-FC;200μg/ml,5-FC处理CD/TK阳性HepG2细胞24小时后,用高效液相色谱法测定细胞上清中5-Fu浓度是188μg/ml,5-Fc向5-Fu转化效率是94%;旁杀效应实验显示,在200μg/ml5-FC存在时,只要PAFPE-pTK-IRES-CD质粒有20%的转染效率,细胞的相对存活率将下降为49.6%,说明该融合自杀基因前药系统具有强大的“旁杀效应”。这说明磁性阳离子脂质体介导的自杀基因前药治疗均有明显的抑瘤作用。
结论:
1)磁性阳离子脂质体能有效介导PAFPE-pTK-IRES-CD自杀基因质粒载体转染HepG2细胞,且未显示明显毒副作用,因此该磁性阳离子脂质体可能成为一种新型的用于基因治疗的非病毒载体。
2)5-FC与GCV对CD/TK阳性细胞均有明显杀伤作用,但二者无协同作用,其作用弱于单独5-FC而强于GCV。
3)该融合自杀基因前药系统具有强大的“旁杀效应”
4)该融合自杀基因前药系统,当前体药物浓度5-FC<200μg/ml,GCV<50μg/ml,在此浓度下,对不含自杀基因的HepG2细胞毒性很低。
5)体外实验结果显示,以磁性阳离子脂质体为载体介导AFP调控下的自杀基因在肿瘤的治疗中显示良好的靶向杀伤效应。
Objective:To study the chimeric promoter with high activity which is composed with CMV promoter and AFP enhancer;the specificity of the fused suicide gene CD/TK increases or not,which expressed in target cell by the regulation of fused promoter;and by magnetic cationic liposome with good biocompatibility as a carrier,suicide gene transfect into hepatoma cells,to observe the probability of enhancing target and safety of gene therapy.
Methods:magnetic cationic liposomes were prepared by reverse phase evaporation,the expression vector of AFPE-pTK-IRES-CD as a fused suicide gene was construct by PCR,RT-PCR,fusion PCR, restriction enzyme and ligation etc.In vitro experiment was through transfect pAFPE-pTK-IRES-CD plasmid expression vector into HepG2 cell line using magnetic cationic liposomes as a vector.The transfection efficiency was detected by fluorescence microscope and flow cytometer, the express of CD/TK fused suicide gene in HepG2 cell was detected by RT-PCR and Western-blot.The toxicity of 5-FC and GCV on HepG2 cells was detected by MTT.The killing effect of suicide gene prodrug system on HepG2 cells expressed the suicide gene was detected by MTT and clone formation experiment.The effect of this system on the growth of HepG2 cells was observed by cell growth curve.The change of express level of the suicide gene before and after treatment was detected by immunohistochemistry and immunofluorescence.The change of transfection efficiency from prodrug 5-FC to 5-FU was detected by HPLC before and after treatment.
Results:Magnetic cationic liposomes could conjugate with plasmid DNA as the complex,it absorbed on the cell membrane and went into cells,increased DNA quantities into cells and increased the efficiency of gene transfection.The complex could inhibit well the DNA degradation by the enzyme in blood serum and protect well the integrality of DNA molecule.When HepG2 cells were transfected after Green fluorescent protein(GFP) as a reporter gene combined with magnetic cationic liposomes,it found that it had higher transfection efficiency.5-FC and GCV in a high concentration(5-FC＞60μg/mL GCV＞0.6μg/ml) had some killing effect for HepG2 cells.For CD/TK+ HepG2 cells,when the 5-FC concentration was 40μg/ml and 80μg/ml,cell survival rates were 69.23% and 18.02%respectively.And for CD/TK+ HepG2 cells,under the condition of simultaneous existence for two prodrugs 5-FC and GCV, synergism effect was not found which reported by many studies,and the effect was lower than 5-FC alone.CD/TK+ HepG2 cells were treated 24h with 200μg/ml 5-FC,5-Fu concentration in cell supernatant was 168μg/ml,the transformation efficiency was 94%from 5-Fc to 5-Fu. Under 200μg/ml 5-FC,when pAFPE-pTK-IRES-CD plasmid had more 20%transfection efficiency,the relative survival rate of the cells decreased to 49.6%,this revealed that magnetic cationic liposomes-mediated suicide gene prodrug treatment had evident effect on tumor inhibition.
Conclusions:Magnetic cationic liposomes can mediate well the transfection of suicide gene pAFPE-pTK-IRES-CD plasmid into HepG2 cells for,and have no evident toxicity and side effects,so it may be a new non-viral vector for gene therapy.5-FC and GCV have evident killing effect for CD/TK+ cells,but no synergism;and the effect is lower than that of 5-FC alone,but stronger than that of GCV.The fused suicide gene prodrug system has strong bystander killing effect,and as prodrug 5-FC＜200μg/ml,GCV＜50μg/ml,its toxicity is very low for HepG2 cells with no suicide gene.In vitro experiment reveals that magnetic cationic liposomes-mediated suicide gene under regulation by AFP has good targeted killing effect for tumor therapy.
引文
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