心血管内靶向定位基因递送体系—载基因支架的实验研究
摘要
经皮腔内冠状动脉成形术(Percutaneous Transluminal Coronary Angioplasty，PTCA)是冠状动脉硬化性心脏病的主要治疗手段，但PTCA术后血管再狭窄的发生率高达15—60％，迄今仍是临床亟待解决的难题。转基因技术的飞速发展为血管再狭窄的基因治疗奠定了基础。心血管内基因治疗的成功必须依靠有效的治疗基因，安全的载体和可以把基因(和载体)递送到血管内靶部位的递送体系。心血管内基因治疗的特殊性在于很难把基因专一性递送到血管组织而不进入血液循环系统。以往的研究大多数采用球囊导管向血管内灌注基因(和载体)，研究表明，灌注到血管内的载体大部分随血流进入全身循环系统，到达病灶局部的基因很少，达不到治疗效果。
血管内支架携带基因有其独特的优势，可以在植入支架的同时将基因递送到心血管内的病灶部位，借助支架与血管壁的紧密接触，使基因被局部血管组织吸收，随着基因的缓慢释放，达到长期的基因转染和表达。基因载体分为病毒载体和非病毒载体。病毒载体转染效率高，但安全性方面存在潜在的危险性。非病毒载体安全性好，易于制备，近年来倍受关注。阳离子脂质体和壳聚糖是目前研究最广泛的非病毒载体，显示出了一定的优越性。
本课题针对心血管基因治疗的主要技术难题，采用血管支架为基因递送平台，将抗DNA抗体—质粒DNA—阳离子脂质体三元复合纳米基因载体和壳聚糖基因纳米粒两种非病毒载体结合在支架上，并通过体内外试验验证这一新型血管内基因递送体系的有效性和可行性。
本文第一章对PTCA术后再狭窄的发病机理及治疗现状进行了综述。
本文具体研究内容如下：
1．制备了新型抗DNA抗体—质粒DNA—阳离子脂质体三元复合纳米基因载体(DAC)，筛选出了最佳配方，并初步进行了细胞摄取及细胞基因转染实验。结果发现，抗DNA抗体—质粒DNA—阳离子脂质体可以自组装为360nm左右的球形粒子，与传统的质粒DNA—阳离子脂质体二元基因载体(DC组)相比，DAC体系对质粒DNA(28.5±1.3％vs13.6±0.9％，p＜0.01)的包封率明显增加，并且明显地提高了细胞基因转染效率(41.8％vs10.2％，p＜0.01)。采用双重荧光标记联合共聚焦显微观察发现抗DNA抗体可促进质粒DNA进入细胞核。使用胶原对金属支架表面进行涂层，通过化学和免疫双重偶联的方法将上述DAC载体固定化在支架表面。使用放射性同位素分别标记抗DNA抗体和质粒DNA来测定支架结合量及释放曲线。用细胞培养及动物体内植入实验验证了这一新型基因递送体系的转基因效果。结果显示，支架表面通过化学交联的胶原涂层具有很好的均一性
PTCA (Percutaneous Transluminal Coronary Angioplasty ) has become one of the most important strategies to treat coronary artery diseases. However, restenosis has been observed in pathological and clinical studies, and poses a formidable problem (15-60%). The gene therapy for restenosis has progressed for the development of transgenic technique. The most challenging issues for successful application of gene therapy to human diseases concern: (1) the choice of the relevant therapeutic gene, (2) the choice of promoter and regulatory sequences driving expression of the transgene; and (3) the vector used for delivery of the transgene into cells (that is, for transduction of target cells). The difficulties in the development of an effective percutanous gene deliver system to the diseased site without distal spread have proven to be a major hurdle to the advancement of vascular gene therapy. In the past decades, balloon catheters have been used for vector delivery. However, catheter-based gene delivery systems fail to limit systemic biodistribution of vector to circulation and distal organs.
Endovascular stents represent an ideal platform for localized vascular gene therapy for vascular diseases due to their permanent scaffolding structure. Because of long-term residue within the vessel, the gene tethered on the stent could release slowly and access the vascular cells directly. There are essentially two classes of gene therapy vectors: nonviral vectors and viral vectors. Viruses are efficient in transducing cells. However, the safety concerns regarding the use of virus in humans make nonviral delivery systems an attractive alternative. Nonviral vectors are particularly suitable with respect to simplicity of use, ease of large-scale production and lack of specific immune response. Recently, several novel nonviral vectors have been developed that approach viruses with respect to transfection efficiency. Among them, cationic lipid and chitosan have been extensively studied for gene vectors.
To resolve the difficult problem of vascular gene therapy, we attached DAC system and chitosan-plasmid DNA nanoparticles on coronary stents to assesss the feasibility and effectivity of this novel gene delivery system.
In chapter 1, the recent progress of the research topic was reviewed.
血管内支架携带基因有其独特的优势，可以在植入支架的同时将基因递送到心血管内的病灶部位，借助支架与血管壁的紧密接触，使基因被局部血管组织吸收，随着基因的缓慢释放，达到长期的基因转染和表达。基因载体分为病毒载体和非病毒载体。病毒载体转染效率高，但安全性方面存在潜在的危险性。非病毒载体安全性好，易于制备，近年来倍受关注。阳离子脂质体和壳聚糖是目前研究最广泛的非病毒载体，显示出了一定的优越性。
本课题针对心血管基因治疗的主要技术难题，采用血管支架为基因递送平台，将抗DNA抗体—质粒DNA—阳离子脂质体三元复合纳米基因载体和壳聚糖基因纳米粒两种非病毒载体结合在支架上，并通过体内外试验验证这一新型血管内基因递送体系的有效性和可行性。
本文第一章对PTCA术后再狭窄的发病机理及治疗现状进行了综述。
本文具体研究内容如下：
1．制备了新型抗DNA抗体—质粒DNA—阳离子脂质体三元复合纳米基因载体(DAC)，筛选出了最佳配方，并初步进行了细胞摄取及细胞基因转染实验。结果发现，抗DNA抗体—质粒DNA—阳离子脂质体可以自组装为360nm左右的球形粒子，与传统的质粒DNA—阳离子脂质体二元基因载体(DC组)相比，DAC体系对质粒DNA(28.5±1.3％vs13.6±0.9％，p＜0.01)的包封率明显增加，并且明显地提高了细胞基因转染效率(41.8％vs10.2％，p＜0.01)。采用双重荧光标记联合共聚焦显微观察发现抗DNA抗体可促进质粒DNA进入细胞核。使用胶原对金属支架表面进行涂层，通过化学和免疫双重偶联的方法将上述DAC载体固定化在支架表面。使用放射性同位素分别标记抗DNA抗体和质粒DNA来测定支架结合量及释放曲线。用细胞培养及动物体内植入实验验证了这一新型基因递送体系的转基因效果。结果显示，支架表面通过化学交联的胶原涂层具有很好的均一性
PTCA (Percutaneous Transluminal Coronary Angioplasty ) has become one of the most important strategies to treat coronary artery diseases. However, restenosis has been observed in pathological and clinical studies, and poses a formidable problem (15-60%). The gene therapy for restenosis has progressed for the development of transgenic technique. The most challenging issues for successful application of gene therapy to human diseases concern: (1) the choice of the relevant therapeutic gene, (2) the choice of promoter and regulatory sequences driving expression of the transgene; and (3) the vector used for delivery of the transgene into cells (that is, for transduction of target cells). The difficulties in the development of an effective percutanous gene deliver system to the diseased site without distal spread have proven to be a major hurdle to the advancement of vascular gene therapy. In the past decades, balloon catheters have been used for vector delivery. However, catheter-based gene delivery systems fail to limit systemic biodistribution of vector to circulation and distal organs.
Endovascular stents represent an ideal platform for localized vascular gene therapy for vascular diseases due to their permanent scaffolding structure. Because of long-term residue within the vessel, the gene tethered on the stent could release slowly and access the vascular cells directly. There are essentially two classes of gene therapy vectors: nonviral vectors and viral vectors. Viruses are efficient in transducing cells. However, the safety concerns regarding the use of virus in humans make nonviral delivery systems an attractive alternative. Nonviral vectors are particularly suitable with respect to simplicity of use, ease of large-scale production and lack of specific immune response. Recently, several novel nonviral vectors have been developed that approach viruses with respect to transfection efficiency. Among them, cationic lipid and chitosan have been extensively studied for gene vectors.
To resolve the difficult problem of vascular gene therapy, we attached DAC system and chitosan-plasmid DNA nanoparticles on coronary stents to assesss the feasibility and effectivity of this novel gene delivery system.
In chapter 1, the recent progress of the research topic was reviewed.
引文
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