基于PEG及聚磷酸酯的刷形嵌段共聚物的合成与应用
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摘要
基因治疗对治疗各种基因疾病（包括遗传性疾病、感染性疾病和癌症等）具有潜在的疗效，有着重要的发展前景。安全、高效、稳定的基因载体是基因治疗中的一个重要方向。基因载体的制备和控制释放涉及材料学、分子生物学、医学及高分子化学等领域，具有重要的理论意义和潜在的应用价值，非病毒阳离子型基因载体因其具有较高的负载效率而受到广泛的关注。本论文利用亲水性刷形聚合物的诸多优点，即具有表面防污、屏蔽电荷、降低复合物的自聚集、降低载体毒性、延长载体在体内的循环时间、且使载体具有抗蛋白非特异吸附性能，结合磁性纳米粒子、还原敏感二硫键、生物可降解聚磷酸酯、荧光分子香豆素的优点，设计合成了一系列刷形聚合物，用于构建多重响应性基因载体。对刷形聚合物的结构设计、合成表征、生物相容性以及作为基因载体的性能进行了研究。论文的主要内容分为以下几个方面：
(1)利用聚阳离子修饰的磁性纳米子、刷形聚阴离子以及DNA，通过静电作用，构建磁响应性复合基因载体。首先采用氧阴离子引发聚合，制备含胆固醇的阳离子聚合物，即末端含胆固醇的聚[甲基丙烯酸-2-(N,N-二甲氨基)乙酯]（Chol-PDMAEMA），再通过配体交换法，获得阳离子聚合物修饰的磁性纳米粒子，用于缩合DNA；通过原子转移自由基聚合（ATRP）和后修饰反应，制备含巯基（-SH）的刷形阴离子嵌段共聚物聚（聚乙二醇单甲醚甲基丙烯酸酯）-b-聚甲基丙烯酸（PPEGMA-b-PMAASH），与上述磁性阳离子载体作用，形成复合物载体，在双氧水或空气中O2作用下，-SH交联成二硫键（S-S），可将包载的DNA固定于聚合物载体中，提高了载体在血液循环过程中的稳定性，当载体到达细胞内还原环境中，在细胞内谷胱甘肽作用下，二硫键断裂，释放出包裹的DNA。利用核磁共振氢谱（1H NMR）和凝胶渗透色谱（GPC）对聚合物进行表征。通过琼脂糖凝胶电泳、zeta电位、动态激光光散射仪（DLS）、透射电镜（TEM）、细胞毒性测试，抗蛋白吸附测试以及转染测试对载体进行评价。
(2)利用单电子转移活性自由基聚合（SET-LRP）和开环聚合（ROP）法，制备侧链接枝生物可降解聚磷酸酯的刷形嵌段共聚物(PHEMA-g-PEEP)-b-PDMAEMA。首先利用两步SET-LRP反应，获得甲基丙烯酸羟乙酯（HEMA）与甲基丙烯酸-2-(N,N-二甲氨基)乙酯（DMAEMA）的两嵌段共聚物PHEMA-b-PDMAEMA；再利用嵌段共聚物中PHEMA侧基上的羟基，对环状磷酸酯单体（EEP）进行开环接枝聚合，获得(PHEMA-g-PEEP)-b-PDMAEMA。利用1HNMR、31PNMR、红外光谱（FT-IR）和GPC对聚合物的结构进行表征。采用荧光探针法测试聚合物的临界聚集浓度（CAC）值，并且，通过琼脂糖凝胶电泳、zeta电位、DLS、TEM、细胞毒性以及体外转染测试对其作为基因载体的性质进行了评价。
(3)结合开环聚合（ROP）、原子转移自由基聚合（ATRP）和点击化学（Click）反应，制备基于PEG刷形聚合物的荧光/pH响应的酸敏感型嵌段共聚物CE-PCL-a-(PDMAEMA-co-PPEGMA)。首先利用荧光分子7-（2’-羟基-3’-氯）丙烷-4-甲基香豆素（CE）的羟基开环单体己内酯（-CL），获得CE-PCL，接着，对CE-PCL端基的羟基进行修饰，使端基成为具有酸敏感缩醛基的缩醛-叠氮基团；另一方面，利用ATRP法合成端基为炔基的PPEGMA和PDMAEMA的刷形无规共聚物。通过“Click”反应，将上述两个嵌段共聚物的叠氮基团和炔基进行反应，获得酸敏感型嵌段共聚物CE-PCL-a-(PDMAEMA-co-PPEGMA)。这种具有荧光性的共聚物在水中可以自组装形成胶束，可以同时包载药物和基因,发挥协同作用,用于癌症治疗。利用1HNMR、FT-IR和GPC对聚合物进行结构表征。通过荧光探针法测定聚合物的临界聚集浓度（CAC），利用琼脂糖凝胶电泳、zeta电位、DLS、TEM、细胞毒性测试、药物释放以及内吞、转染测试等对所构建的载体及载体的荧光性能进行了评价。
(4)利用两步原子转移自由基聚合（ATRP）法和后修饰反应，制备半乳糖修饰的阳离子型刷形共聚物P(PEGMEMA-co-PEGMAGal)-b-PDMAEMA。首先，通过ATRP法制备单体聚乙二醇单甲醚甲基丙烯酸酯（PEGMEMA）和聚乙二醇甲基丙烯酸酯（PEGMA）的无规共聚物P(PEGMEMA-co-PEGMA)，再将其作为大分子引发剂，引发阳离子型单体DMAEMA进行ATRP反应，获得三组分两嵌段的阳离子型刷形共聚物P(PEGMEMA-co-PEGMA)-b-PDMAEMA。进一步地，利用PPEGMA侧链上的羟基键合肝靶向分子半乳糖，获得半乳糖修饰的阳离子型刷形嵌段共聚物P(PEGMEMA-co-PEGMAGal)-b-PDMAEMA。通过1H NMR、FT-IR以及GPC测试对聚合物的结构、分子量及分子量分布进行表征，通过凝胶阻滞电泳测试，研究了阳离子型刷形嵌段共聚物结合DNA的能力，利用zeta电位研究载体的表面电荷、通过细胞毒性试验测试了载体的生物相容性，并且对比了半乳糖修饰的阳离子型刷形嵌段共聚物P(PEGMEMA-co-PEGMAGal)-b-PDMAEMA与DNA形成的复合物对HeLa（子宫颈癌）和HepG2（肝癌）细胞的转染能力。
Gene therapy has been generally acknowledged as a promising treatment fornumerous hard curable diseases, including genetic diseases, infectious diseases, andcancer. Safety, efficiency and stability play the most challenging role in gene therapy.Preparation and controlled release of gene vector concern the materials science,molecular biology, medicine and polymer chemistry and other fields with importanttheoretical significance and potential applications. Non-viral cationic gene vectors arepromising due to their easily-adjustable and controlled structures, high condensationability. This thesis is mainly focused on the design and synthesis of PEGylated orpolyphosphoester (PPE) based brush-type copolymers for fabricating multi-responsivegene vectors, combining the advantages of brush-type copolymers, disulfide bond,magnetic nanoparticles, biodegradable PPE and fluorescent coumarin. It is reportedthat brush-type hydrophilic units on the surface of vectors can enhance their resistanceagainst self-aggregation, and nonspecific adsorption with proteins or serum-drivencomponents, also it can enhance the solubility of polyplexes and prolong the lifetime inblood circulation because the abundant periphery highly flexible chains stericallyprevent undesirable interactions of the vectors with negatively-charged components inbloodstream. The present work can be summarized as follows:
(1) A novel magnetic-responsive complex composed of polycation, DNA andpolyanion has been constructed via electrostatic interaction. The magneticnanoparticles (MNPs) were first coated with a polycation, poly[2-(dimethylamino)ethyl methacrylate] end-capped with cholesterol moiety(Chol-PDMAEMA), and then binded with DNA through electrostatic interaction, thecomplexes were further interacted with the brush-type polyanion, namelypoly[poly(ethylene glycol)methyl ether methacrylate]-block-poly[methacrylic acidcarrying partial mercapto groups](PPEGMA-b-PMAASH). The resulting magneticparticle/DNA/polyion complexes could be stabilized by oxidizing the mercapto groupsto form cross-linking shell with bridging disulfide (S-S) betweenPPEGMA-b-PMAASHmolecular chains. The interactions among DNA,Chol-PDMAEMA coated MNPs and PPEGMA-b-PMAASHwere studied by agarosegel retardation assay. The complexes were fully characterized by means of zetapotential, transmission electron microscopy (TEM), dynamic light scattering (DLS)measurements, cytotoxicity assay, anti-nonspecific protein adsorption and in vitrotransfection tests.
(2) A novel kind of pH-sensitive brush-tpye copolymer,[poly(2-hydroxyethylmethacrylate)-graft-poly(ethylethylene phosphate)]-block-poly[2-(dimethylamino)ethyl methacrylate][(PHEMA-g-PEEP)-b-PDMAEMA] with biodegradablepolyphosphoester as the side chains were synthesized via a combination ofsingle-electron transfer living radical polymerization (SET-LRP) and ring-openingpolymerization (ROP). The chemical structures were characterized by1H NMR,31PNMR, FT-IR, and GPC measurements.(PHEMA-g-PEEP)-b-PDMAEMA canself-assembled into aggregates served as a gene carrier. The brush-like PPE chainsprovide the carrier with good biocompatibility and biodegradability, as well as longcirculation lifetime. The interaction of (PHEMA-g-PEEP)-b-PDMAEMA and DNAwas studied by agarose gel retardation assay, and the formed complexes were furtherinvestigated by means of zeta potential, DLS and TEM measurements. In addition, thein vitro cytotoxicity and transfection tests were also investigated.
(3) In this part, we report on a novel acid-cleavable and fluorescent cationic blockcopolymer CE-PCL-a-(PDMAEMA-co-PPEGMA) by a combination of atom transferradical polymerization (ATRP), ring-opening polymerization (ROP) and “Click”reaction. The cationic block copolymer CE-PCL-a-(PDMAEMA-co-PPEGMA) canself-assemble into micelles to load drug and DNA simultaneously to form complexeswith the brush-type PPEGMA on the surface. The drugs and DNA can be releasedafter the acetal linkage was cleaved under intracellular acid conditions. We studiedthese micelles as the drug and gene co-delivery vector by employing gel retardationassay, zeta potential, DLS, TEM, and subsequently its in vitro drug release, in vitrocytotoxicity and transfection efficiency were tested. Fluorescence spectrometer wasused to evaluate the fluorescence of complex for detecting and locating the carrier.
(4) A series of brush copolymer P(PEGMEMA-co-PEGMAGal)-b-PDMAEMAmodified by liver targeted galactose were prepared by two-step ATRP technique andesterification reaction activated by N, N’-carbonyldiimidazole (CDI) and furthermodified by galactosamine. The brush-type hydrophilic polymer can enhance theresistance against self-aggregation, prolong the lifetime in blood circulation andprevent non-specific adsorption of proteins. Meanwhile, the pH responsivePDMAEMA segment can be protonized to carry positive charges to condense DNA. Inaddition, the galactose ligands can enhance the endocytosis of complex by hepatocyteto increase the transfection efficiency. The chemical structures ofP(PEGMEMA-co-PEGMAGal)-b-PDMAEMA were characterized by1H NMR, FT-IR,and GPC measurements. The binding capacity of this cationic copolymer with DNAwas investigated by agarose gel electrophoresis, zeta potential, in vitro cytotoxicity andtransfection assay was tested.
(1)利用聚阳离子修饰的磁性纳米子、刷形聚阴离子以及DNA，通过静电作用，构建磁响应性复合基因载体。首先采用氧阴离子引发聚合，制备含胆固醇的阳离子聚合物，即末端含胆固醇的聚[甲基丙烯酸-2-(N,N-二甲氨基)乙酯]（Chol-PDMAEMA），再通过配体交换法，获得阳离子聚合物修饰的磁性纳米粒子，用于缩合DNA；通过原子转移自由基聚合（ATRP）和后修饰反应，制备含巯基（-SH）的刷形阴离子嵌段共聚物聚（聚乙二醇单甲醚甲基丙烯酸酯）-b-聚甲基丙烯酸（PPEGMA-b-PMAASH），与上述磁性阳离子载体作用，形成复合物载体，在双氧水或空气中O2作用下，-SH交联成二硫键（S-S），可将包载的DNA固定于聚合物载体中，提高了载体在血液循环过程中的稳定性，当载体到达细胞内还原环境中，在细胞内谷胱甘肽作用下，二硫键断裂，释放出包裹的DNA。利用核磁共振氢谱（1H NMR）和凝胶渗透色谱（GPC）对聚合物进行表征。通过琼脂糖凝胶电泳、zeta电位、动态激光光散射仪（DLS）、透射电镜（TEM）、细胞毒性测试，抗蛋白吸附测试以及转染测试对载体进行评价。
(2)利用单电子转移活性自由基聚合（SET-LRP）和开环聚合（ROP）法，制备侧链接枝生物可降解聚磷酸酯的刷形嵌段共聚物(PHEMA-g-PEEP)-b-PDMAEMA。首先利用两步SET-LRP反应，获得甲基丙烯酸羟乙酯（HEMA）与甲基丙烯酸-2-(N,N-二甲氨基)乙酯（DMAEMA）的两嵌段共聚物PHEMA-b-PDMAEMA；再利用嵌段共聚物中PHEMA侧基上的羟基，对环状磷酸酯单体（EEP）进行开环接枝聚合，获得(PHEMA-g-PEEP)-b-PDMAEMA。利用1HNMR、31PNMR、红外光谱（FT-IR）和GPC对聚合物的结构进行表征。采用荧光探针法测试聚合物的临界聚集浓度（CAC）值，并且，通过琼脂糖凝胶电泳、zeta电位、DLS、TEM、细胞毒性以及体外转染测试对其作为基因载体的性质进行了评价。
(3)结合开环聚合（ROP）、原子转移自由基聚合（ATRP）和点击化学（Click）反应，制备基于PEG刷形聚合物的荧光/pH响应的酸敏感型嵌段共聚物CE-PCL-a-(PDMAEMA-co-PPEGMA)。首先利用荧光分子7-（2’-羟基-3’-氯）丙烷-4-甲基香豆素（CE）的羟基开环单体己内酯（-CL），获得CE-PCL，接着，对CE-PCL端基的羟基进行修饰，使端基成为具有酸敏感缩醛基的缩醛-叠氮基团；另一方面，利用ATRP法合成端基为炔基的PPEGMA和PDMAEMA的刷形无规共聚物。通过“Click”反应，将上述两个嵌段共聚物的叠氮基团和炔基进行反应，获得酸敏感型嵌段共聚物CE-PCL-a-(PDMAEMA-co-PPEGMA)。这种具有荧光性的共聚物在水中可以自组装形成胶束，可以同时包载药物和基因,发挥协同作用,用于癌症治疗。利用1HNMR、FT-IR和GPC对聚合物进行结构表征。通过荧光探针法测定聚合物的临界聚集浓度（CAC），利用琼脂糖凝胶电泳、zeta电位、DLS、TEM、细胞毒性测试、药物释放以及内吞、转染测试等对所构建的载体及载体的荧光性能进行了评价。
(4)利用两步原子转移自由基聚合（ATRP）法和后修饰反应，制备半乳糖修饰的阳离子型刷形共聚物P(PEGMEMA-co-PEGMAGal)-b-PDMAEMA。首先，通过ATRP法制备单体聚乙二醇单甲醚甲基丙烯酸酯（PEGMEMA）和聚乙二醇甲基丙烯酸酯（PEGMA）的无规共聚物P(PEGMEMA-co-PEGMA)，再将其作为大分子引发剂，引发阳离子型单体DMAEMA进行ATRP反应，获得三组分两嵌段的阳离子型刷形共聚物P(PEGMEMA-co-PEGMA)-b-PDMAEMA。进一步地，利用PPEGMA侧链上的羟基键合肝靶向分子半乳糖，获得半乳糖修饰的阳离子型刷形嵌段共聚物P(PEGMEMA-co-PEGMAGal)-b-PDMAEMA。通过1H NMR、FT-IR以及GPC测试对聚合物的结构、分子量及分子量分布进行表征，通过凝胶阻滞电泳测试，研究了阳离子型刷形嵌段共聚物结合DNA的能力，利用zeta电位研究载体的表面电荷、通过细胞毒性试验测试了载体的生物相容性，并且对比了半乳糖修饰的阳离子型刷形嵌段共聚物P(PEGMEMA-co-PEGMAGal)-b-PDMAEMA与DNA形成的复合物对HeLa（子宫颈癌）和HepG2（肝癌）细胞的转染能力。
Gene therapy has been generally acknowledged as a promising treatment fornumerous hard curable diseases, including genetic diseases, infectious diseases, andcancer. Safety, efficiency and stability play the most challenging role in gene therapy.Preparation and controlled release of gene vector concern the materials science,molecular biology, medicine and polymer chemistry and other fields with importanttheoretical significance and potential applications. Non-viral cationic gene vectors arepromising due to their easily-adjustable and controlled structures, high condensationability. This thesis is mainly focused on the design and synthesis of PEGylated orpolyphosphoester (PPE) based brush-type copolymers for fabricating multi-responsivegene vectors, combining the advantages of brush-type copolymers, disulfide bond,magnetic nanoparticles, biodegradable PPE and fluorescent coumarin. It is reportedthat brush-type hydrophilic units on the surface of vectors can enhance their resistanceagainst self-aggregation, and nonspecific adsorption with proteins or serum-drivencomponents, also it can enhance the solubility of polyplexes and prolong the lifetime inblood circulation because the abundant periphery highly flexible chains stericallyprevent undesirable interactions of the vectors with negatively-charged components inbloodstream. The present work can be summarized as follows:
(1) A novel magnetic-responsive complex composed of polycation, DNA andpolyanion has been constructed via electrostatic interaction. The magneticnanoparticles (MNPs) were first coated with a polycation, poly[2-(dimethylamino)ethyl methacrylate] end-capped with cholesterol moiety(Chol-PDMAEMA), and then binded with DNA through electrostatic interaction, thecomplexes were further interacted with the brush-type polyanion, namelypoly[poly(ethylene glycol)methyl ether methacrylate]-block-poly[methacrylic acidcarrying partial mercapto groups](PPEGMA-b-PMAASH). The resulting magneticparticle/DNA/polyion complexes could be stabilized by oxidizing the mercapto groupsto form cross-linking shell with bridging disulfide (S-S) betweenPPEGMA-b-PMAASHmolecular chains. The interactions among DNA,Chol-PDMAEMA coated MNPs and PPEGMA-b-PMAASHwere studied by agarosegel retardation assay. The complexes were fully characterized by means of zetapotential, transmission electron microscopy (TEM), dynamic light scattering (DLS)measurements, cytotoxicity assay, anti-nonspecific protein adsorption and in vitrotransfection tests.
(2) A novel kind of pH-sensitive brush-tpye copolymer,[poly(2-hydroxyethylmethacrylate)-graft-poly(ethylethylene phosphate)]-block-poly[2-(dimethylamino)ethyl methacrylate][(PHEMA-g-PEEP)-b-PDMAEMA] with biodegradablepolyphosphoester as the side chains were synthesized via a combination ofsingle-electron transfer living radical polymerization (SET-LRP) and ring-openingpolymerization (ROP). The chemical structures were characterized by1H NMR,31PNMR, FT-IR, and GPC measurements.(PHEMA-g-PEEP)-b-PDMAEMA canself-assembled into aggregates served as a gene carrier. The brush-like PPE chainsprovide the carrier with good biocompatibility and biodegradability, as well as longcirculation lifetime. The interaction of (PHEMA-g-PEEP)-b-PDMAEMA and DNAwas studied by agarose gel retardation assay, and the formed complexes were furtherinvestigated by means of zeta potential, DLS and TEM measurements. In addition, thein vitro cytotoxicity and transfection tests were also investigated.
(3) In this part, we report on a novel acid-cleavable and fluorescent cationic blockcopolymer CE-PCL-a-(PDMAEMA-co-PPEGMA) by a combination of atom transferradical polymerization (ATRP), ring-opening polymerization (ROP) and “Click”reaction. The cationic block copolymer CE-PCL-a-(PDMAEMA-co-PPEGMA) canself-assemble into micelles to load drug and DNA simultaneously to form complexeswith the brush-type PPEGMA on the surface. The drugs and DNA can be releasedafter the acetal linkage was cleaved under intracellular acid conditions. We studiedthese micelles as the drug and gene co-delivery vector by employing gel retardationassay, zeta potential, DLS, TEM, and subsequently its in vitro drug release, in vitrocytotoxicity and transfection efficiency were tested. Fluorescence spectrometer wasused to evaluate the fluorescence of complex for detecting and locating the carrier.
(4) A series of brush copolymer P(PEGMEMA-co-PEGMAGal)-b-PDMAEMAmodified by liver targeted galactose were prepared by two-step ATRP technique andesterification reaction activated by N, N’-carbonyldiimidazole (CDI) and furthermodified by galactosamine. The brush-type hydrophilic polymer can enhance theresistance against self-aggregation, prolong the lifetime in blood circulation andprevent non-specific adsorption of proteins. Meanwhile, the pH responsivePDMAEMA segment can be protonized to carry positive charges to condense DNA. Inaddition, the galactose ligands can enhance the endocytosis of complex by hepatocyteto increase the transfection efficiency. The chemical structures ofP(PEGMEMA-co-PEGMAGal)-b-PDMAEMA were characterized by1H NMR, FT-IR,and GPC measurements. The binding capacity of this cationic copolymer with DNAwas investigated by agarose gel electrophoresis, zeta potential, in vitro cytotoxicity andtransfection assay was tested.
引文
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