自组装纳米材料在基因治疗和细胞培养中的应用研究
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摘要
基因传递系统是基因治疗中的重要组成部分，缺少安全有效的基因载体是阻碍基因治疗临床试验成功的主要因素。在非病毒基因载体中聚乙烯亚胺（PEI）因具有“质子海绵效应”是研究的最为广泛的阳离子聚合物基因载体。根据文献报道，PEI的基因转染效率和毒性与其分子量密切相关。高分子量的PEI如PEI（25kDa）因具有较高的正电荷密度而具有较高的转染效率，但同时过高的电荷密度和分子本身的不可降解性也导致其细胞毒性比较大，体内应用受到限制。低分子量PEI（<2kDa）毒性很小却基本没有基因转染效率。因此如何利用无毒的低分子量PEI设计出低毒高效的基因载体在近年来受到广泛关注。很多学者通过PEI分子的PEG化修饰来实现降低载体细胞毒性和增强载体血清相容性的目的。
与传统的将PEG分子接到聚合物或纳米粒子外围的修饰手段不同，在本论文第二章中我们将PEG分子作为主链，接枝小分子PEI合成基因载体。实验中首先通过麦克尔加成反应，将聚乙二醇二丙烯酸酯（PEGDA，258Da）与二硫苏糖醇（DTT）反应，得到含有可降解酯键的线性聚合物PEG-DTT，然后以羰基二咪唑（CDI）作为接头将PEI（800Da）连接到聚合物PEG-DTT上。通过控制PEGDA和DTT的比例（从1.2：1到1：1.2）得到五种不同分子量和结构的基因载体(PEG-DTT)-g-PEIs；通过凝胶渗透色谱（GPC）、氢核磁共振谱（1H-HMR）和傅里叶变换红外光谱（FTIR）对载体的分子量和结构进行了表征；研究了载体的毒性及其与DNA形成的复合物粒径和电位；并对该基因载体的体内外基因转染效率进行了评价。实验结果表明：(PEG-DTT)-g-PEIs/DNA复合物的粒径小于200nm，电位在+20-40mV；载体(PEG-DTT)-g-PEIs与PEI（25kDa）相比具有较低的细胞毒性；对HeLa、HepG2、MCF-7和COS-7四种肿瘤细胞系的转染效率都高于PEI（25kDa），并且转染效率不受高浓度血清（30%）的抑制；荷瘤裸鼠的瘤内基因转染结果说明该载体对HepG2肿瘤的转染效果优于PEI（25kDa）。这些结果表明(PEG-DTT)-g-PEIs系列基因载体具有很好的应用前景。
为了得到具有更高转染效率的肿瘤靶向基因载体，在第三章中我们尝试通过核酸适配体筛选技术获得肿瘤细胞特异性的核酸适配体。
因短肽类化合物具有易合成、低成本且能大量制备、易与各类生物活性分子结合、降解可控等优点，短肽类水凝胶具有很好的生物学应用前景。其中，因其含水量高、能够形成类似于细胞外基质的三维网络而被广泛用于细胞培养和组织工程。在细胞培养和组织工程用水凝胶中，存在着从胶体中分离培养细胞困难的问题。因此设计能够在外界刺激下实现从凝胶到溶液的转变的响应型水凝胶对于在水凝胶中培养的细胞的分离及后续的实验研究具有重要意义。
在第四章中我们合成了几种含有金刚烷分子的多肽Ada-GFFYKn-ss-K(4-n)-CONH_2，能够被还原剂谷胱甘肽（GSH）或二硫苏糖醇（DTT）还原而形成水凝胶，且形成的水凝胶能够对β-环糊精或其衍生物产生凝胶-溶液的响应。小鼠胚胎成纤维细胞（NIH3T3）在胶上生长状态良好，并能够利用胶体对甲基-β-环糊精的响应特点实现NIH3T3细胞的快速分离，且这种分离方式对细胞活力无不利影响。这些研究结果说明这种响应型金刚烷-多肽水凝胶在水凝胶中培养细胞的进一步分析研究方面具有很大的应用潜能。
Gene delivery system is an important part of gene therapy, and the lack of safeand effective gene vectors is one of the major factors to hinder successful clinicaltrials of gene therapy. Poly(ethylene imine)(PEI) is one of the most efficient andwidely studied non-viral gene carriers in vitro and in vivo due to its “proton spongeeffect”, which can buffer the environment of the endosome and cause the release ofcomplexes into the cytoplasm. The gene transfection efficiency and cytotoxicity ofPEI are closely dependent on its macromolecular structure and molecular weightwhich have reported by many researchers. In general, high molecular weight PEI (25kDa) has a high transfection activity, but also has high toxicity due to its highpositive charge density and nondegradable property, which limits its application inclinical treatment. In contrast, low molecular weight PEI(LMW PEI,<2kDa)exhibits a much lower toxicity, but is transfection inefficient due to inefficient DNAcondensation. So, the designation of gene vectors with lower toxicity and higherefficiency based on non-toxic LMW PEIs has attracted widespread attentions. Someresearch groups have synthesized various poly(ethylene glycol)(PEG) modifiedLMW PEIs to enhance the transfection efficiency and the serum compatibility ofLMW PEI.
In chapter2, combining the advantages of LMW PEI and PEG, we synthesizeda new class of degradable non-viral gene vectors,(PEG-DTT)-g-PEI copolymers.Rather than using PEG as an external layer to shield the particles, as in previousreports, here PEG was used as the internal core of the copolymers and LMW PEIwas grafted to (PEG-DTT) main chain. We expected the structure to showdiminished aggregation and improved stealthiness in the bloodstream. First, aMichael addition reaction between poly(ethylene glycol) diacrylates (PEGDA,258Da) and D,L-dithiothreitol (DTT) was carried out to generate a linear degradablepolymer (PEG-DTT) having a terminal thiol, methacrylate and pendant hydroxylfunctional groups. Five PEG-DTT analogs were synthesized by varying the molar ratio of diacrylates to thiols from1.2:1to1:1.2. Then PEI (800Da) was grafted ontothe main chain of the PEG-DTTs using1,1’-carbonyldiimidazole as the linker. Theabove reaction gave rise to a new class of non-viral gene vectors,(PEG-DTT)-g-PEIcopolymers. The molecular weights and structures of the copolymers werecharacterized by gel permeation chromatography;1H nuclear magnetic resonanceand Fourier transform infrared spectroscopy. Then the cytotoxicities of thecopolymers and the particle size and zeta potential of the copolymer/DNAcomplexes were studied. The transfection efficiency of five polymers was evaluatedin vitro and in vivo. The size of the nanoparticles was <200nm and the surfacecharge of the nanoparticles, expressed as the zeta potential, was between+20and+40mV. Cytotoxicity assays showed that the copolymers exhibited much lowercytotoxicities than high molecular weight PEI (25kDa). Transfection was performedin cultured HeLa, HepG2, MCF-7and COS-7cells in vitro. The copolymers showedhigher transfection efficiencies than PEI (25kDa) tested in four cell lines. Thepresence of serum (up to30%) had no inhibitory effect on the transfection efficiency.The higher transfection efficiencies than PEI (25kDa) was also found in HepG2tumor-beared nude mice. These results indicate that this new class of non-viral genevectors may be a promising gene carrier that is worth further investigation.
In order to get more efficient gene carriers, we did some attempts of tumorspecific aptamers selection in chapter3. The selected aptamers could be conjugatedto the above synthesized (PEG-DTT)-g-PEIs to generated tumor targeted nonviralgene vectors.
Due to the advantages of easy synthesis, low cost, easy combination withvarious bioactive molecules and controllable degradation, polypeptide-basedhydrogels have a good prospects for biological applications. They could formthree-dimensional networks similar to the extracellular matrix and are widely used incell culture and tissue engineering. It will be greatly beneficial to develop hydrogelsthat can be converted to clear solutions by an external biocompatible stimulus,because hydrogels with this unique property can facilitate separation and furtheranalysis of cells postculture.
In order to achieve this goal, in chapter4we report several responsive small molecular hydrogels based on adamantane-peptides whose gel to clear solutionphase transition can be achieved by addition of β-cyclodextrin (β-CD)derivatives.The small molecular hydrogels are formed by our recently developed method ofdisulfide bond cleavage by glutathione (GSH). Mouse fibroblast3T3cells attach andgrow well at the surface of hydrogels. Furthermore,3T3cells postculture can berecovered from the gels by the addition of a β-CD derivative due to formation ofclear solutions by the adamantane-β-CD interaction. The culture on hydrogels andrecovery process do not cause obvious efects on behaviors of3T3cells. The resultsindicate that small molecular hydrogels based on adamantane-peptides have greatpotentials in research fields where further analysis of cells is needed.
与传统的将PEG分子接到聚合物或纳米粒子外围的修饰手段不同，在本论文第二章中我们将PEG分子作为主链，接枝小分子PEI合成基因载体。实验中首先通过麦克尔加成反应，将聚乙二醇二丙烯酸酯（PEGDA，258Da）与二硫苏糖醇（DTT）反应，得到含有可降解酯键的线性聚合物PEG-DTT，然后以羰基二咪唑（CDI）作为接头将PEI（800Da）连接到聚合物PEG-DTT上。通过控制PEGDA和DTT的比例（从1.2：1到1：1.2）得到五种不同分子量和结构的基因载体(PEG-DTT)-g-PEIs；通过凝胶渗透色谱（GPC）、氢核磁共振谱（1H-HMR）和傅里叶变换红外光谱（FTIR）对载体的分子量和结构进行了表征；研究了载体的毒性及其与DNA形成的复合物粒径和电位；并对该基因载体的体内外基因转染效率进行了评价。实验结果表明：(PEG-DTT)-g-PEIs/DNA复合物的粒径小于200nm，电位在+20-40mV；载体(PEG-DTT)-g-PEIs与PEI（25kDa）相比具有较低的细胞毒性；对HeLa、HepG2、MCF-7和COS-7四种肿瘤细胞系的转染效率都高于PEI（25kDa），并且转染效率不受高浓度血清（30%）的抑制；荷瘤裸鼠的瘤内基因转染结果说明该载体对HepG2肿瘤的转染效果优于PEI（25kDa）。这些结果表明(PEG-DTT)-g-PEIs系列基因载体具有很好的应用前景。
为了得到具有更高转染效率的肿瘤靶向基因载体，在第三章中我们尝试通过核酸适配体筛选技术获得肿瘤细胞特异性的核酸适配体。
因短肽类化合物具有易合成、低成本且能大量制备、易与各类生物活性分子结合、降解可控等优点，短肽类水凝胶具有很好的生物学应用前景。其中，因其含水量高、能够形成类似于细胞外基质的三维网络而被广泛用于细胞培养和组织工程。在细胞培养和组织工程用水凝胶中，存在着从胶体中分离培养细胞困难的问题。因此设计能够在外界刺激下实现从凝胶到溶液的转变的响应型水凝胶对于在水凝胶中培养的细胞的分离及后续的实验研究具有重要意义。
在第四章中我们合成了几种含有金刚烷分子的多肽Ada-GFFYKn-ss-K(4-n)-CONH_2，能够被还原剂谷胱甘肽（GSH）或二硫苏糖醇（DTT）还原而形成水凝胶，且形成的水凝胶能够对β-环糊精或其衍生物产生凝胶-溶液的响应。小鼠胚胎成纤维细胞（NIH3T3）在胶上生长状态良好，并能够利用胶体对甲基-β-环糊精的响应特点实现NIH3T3细胞的快速分离，且这种分离方式对细胞活力无不利影响。这些研究结果说明这种响应型金刚烷-多肽水凝胶在水凝胶中培养细胞的进一步分析研究方面具有很大的应用潜能。
Gene delivery system is an important part of gene therapy, and the lack of safeand effective gene vectors is one of the major factors to hinder successful clinicaltrials of gene therapy. Poly(ethylene imine)(PEI) is one of the most efficient andwidely studied non-viral gene carriers in vitro and in vivo due to its “proton spongeeffect”, which can buffer the environment of the endosome and cause the release ofcomplexes into the cytoplasm. The gene transfection efficiency and cytotoxicity ofPEI are closely dependent on its macromolecular structure and molecular weightwhich have reported by many researchers. In general, high molecular weight PEI (25kDa) has a high transfection activity, but also has high toxicity due to its highpositive charge density and nondegradable property, which limits its application inclinical treatment. In contrast, low molecular weight PEI(LMW PEI,<2kDa)exhibits a much lower toxicity, but is transfection inefficient due to inefficient DNAcondensation. So, the designation of gene vectors with lower toxicity and higherefficiency based on non-toxic LMW PEIs has attracted widespread attentions. Someresearch groups have synthesized various poly(ethylene glycol)(PEG) modifiedLMW PEIs to enhance the transfection efficiency and the serum compatibility ofLMW PEI.
In chapter2, combining the advantages of LMW PEI and PEG, we synthesizeda new class of degradable non-viral gene vectors,(PEG-DTT)-g-PEI copolymers.Rather than using PEG as an external layer to shield the particles, as in previousreports, here PEG was used as the internal core of the copolymers and LMW PEIwas grafted to (PEG-DTT) main chain. We expected the structure to showdiminished aggregation and improved stealthiness in the bloodstream. First, aMichael addition reaction between poly(ethylene glycol) diacrylates (PEGDA,258Da) and D,L-dithiothreitol (DTT) was carried out to generate a linear degradablepolymer (PEG-DTT) having a terminal thiol, methacrylate and pendant hydroxylfunctional groups. Five PEG-DTT analogs were synthesized by varying the molar ratio of diacrylates to thiols from1.2:1to1:1.2. Then PEI (800Da) was grafted ontothe main chain of the PEG-DTTs using1,1’-carbonyldiimidazole as the linker. Theabove reaction gave rise to a new class of non-viral gene vectors,(PEG-DTT)-g-PEIcopolymers. The molecular weights and structures of the copolymers werecharacterized by gel permeation chromatography;1H nuclear magnetic resonanceand Fourier transform infrared spectroscopy. Then the cytotoxicities of thecopolymers and the particle size and zeta potential of the copolymer/DNAcomplexes were studied. The transfection efficiency of five polymers was evaluatedin vitro and in vivo. The size of the nanoparticles was <200nm and the surfacecharge of the nanoparticles, expressed as the zeta potential, was between+20and+40mV. Cytotoxicity assays showed that the copolymers exhibited much lowercytotoxicities than high molecular weight PEI (25kDa). Transfection was performedin cultured HeLa, HepG2, MCF-7and COS-7cells in vitro. The copolymers showedhigher transfection efficiencies than PEI (25kDa) tested in four cell lines. Thepresence of serum (up to30%) had no inhibitory effect on the transfection efficiency.The higher transfection efficiencies than PEI (25kDa) was also found in HepG2tumor-beared nude mice. These results indicate that this new class of non-viral genevectors may be a promising gene carrier that is worth further investigation.
In order to get more efficient gene carriers, we did some attempts of tumorspecific aptamers selection in chapter3. The selected aptamers could be conjugatedto the above synthesized (PEG-DTT)-g-PEIs to generated tumor targeted nonviralgene vectors.
Due to the advantages of easy synthesis, low cost, easy combination withvarious bioactive molecules and controllable degradation, polypeptide-basedhydrogels have a good prospects for biological applications. They could formthree-dimensional networks similar to the extracellular matrix and are widely used incell culture and tissue engineering. It will be greatly beneficial to develop hydrogelsthat can be converted to clear solutions by an external biocompatible stimulus,because hydrogels with this unique property can facilitate separation and furtheranalysis of cells postculture.
In order to achieve this goal, in chapter4we report several responsive small molecular hydrogels based on adamantane-peptides whose gel to clear solutionphase transition can be achieved by addition of β-cyclodextrin (β-CD)derivatives.The small molecular hydrogels are formed by our recently developed method ofdisulfide bond cleavage by glutathione (GSH). Mouse fibroblast3T3cells attach andgrow well at the surface of hydrogels. Furthermore,3T3cells postculture can berecovered from the gels by the addition of a β-CD derivative due to formation ofclear solutions by the adamantane-β-CD interaction. The culture on hydrogels andrecovery process do not cause obvious efects on behaviors of3T3cells. The resultsindicate that small molecular hydrogels based on adamantane-peptides have greatpotentials in research fields where further analysis of cells is needed.
引文
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