超支化功能缀合物的构建及纳米医学应用
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摘要
基因与药物载体是近些年来纳米医学研究的重要方向之一。在此领域中，人们利用超支化聚合物具有较多的功能末端、较大的空腔、较低的粘度等优良特性，构建了各种纳米体系，克服了传统载体的许多不足，引起越来越多学者的关注。然而，该领域仍然有很多问题没有解决，例如，阳离子聚合物基因载体存在细胞毒性与转染效率的矛盾；单独基因治疗效果较差；癌症基因治疗中病人因免疫力低下容易遭受细菌感染，进而影响整体治疗效果；癌症病人在化疗过程中，因化疗药物对白细胞的损伤导致免疫力低下，阻碍病人康复等。本研究希望将功能分子缀合进超支化聚合物，构建具有生物功能的超支化缀合物，解决纳米医学领域的上述科学问题。具体研究内容及主要结论为以下四个方面：
1.利用天然小分子构建含糖缀合物作为低毒高效基因载体
糖类分子既可与细胞相互作用，同时也具有较低的细胞毒性。因此，从天然糖基小分子开发低毒高效的基因载体，是克服该类载体毒性与转染效率矛盾的一个很有希望的方向。通过迈克尔加成聚合，制备了阳离子超支化糖缀合聚合物（HPKM）。采用红外、核磁、分子排阻色谱-多角度激光光散射联用和ζ-电位技术等常规表征手段对合成产物进行了化学结构表征。表征结果发现，HPKM的含氮量为7.3%，远低于超支化聚乙烯亚胺的32.6%，且HPKM可以在酸性环境中降解，因此HPKM具有很低的细胞毒性，甚至低于壳聚糖。由于分子结构中存在伯胺、仲胺和叔胺，HPKM呈现良好的质子缓冲能力和DNA压缩能力。体外转染实验表明HPKM介导的转染效率较高，大约是壳聚糖的33倍。这些结果说明，以天然小分子为基础，可以制备低毒高效的超支化糖缀合物基因载体。
2.利用疏水药物分子缀合的阳离子超支化缀合物同时促进基因转染与药效
作为促进基因转染的一种有效方式，阳离子聚合物的疏水修饰受到越来越多的关注。然而，利用疏水药物修饰阳离子聚合物促进基因转染的工作尚未见报道。考虑到疏水药物苯丁酸氮芥的靶标是DNA链，经苯丁酸氮芥修饰的阳离子聚合物既有利于基因转染，又可以增强药效。苯丁酸氮芥缀合的超支化聚合物的各种物理化学表征表明，该缀合物可以有效地将DNA压缩成纳米颗粒。激光共聚焦显微镜技术及流式细胞仪研究发现，该缀合物能快速进入细胞核，因此药效明显强于相同浓度的单药。相对于未经修饰的阳离子聚合物，疏水药物缀合的聚合物的转染性能有较大提高。该工作构建的可控释放载体能够同时促进药效与基因转染，给药物与基因共传递纳米体系提供了新视野，为癌症综合治疗带来希望。
3.以天然糖胺为基元构建应用于基因治疗的多功能超支化含糖缀合物
较好的癌症治疗是多种因素共同作用的结果。因此，具有高转染、低毒、抗菌和抗肿瘤特性的基因载体是临床所急需的。利用简单的迈克尔加成，可以制备符合上述要求的超支化含糖缀合物作为多功能基因载体。采用红外、核磁、分子排阻色谱、ζ-电位和酸碱滴定技术表征了聚合物的物理化学特性。实验结果表明，该材料具有较低的细胞毒性。由于存在大量的伯胺、仲胺和叔胺，该聚合物显示较好的质子缓冲能力、DNA压缩能力和转染效率。同时，由于分子结构中存在糖胺基团，聚合物可以有效地抑制肿瘤及细菌的生长。这些结果表明，以天然糖胺为基元构建的多功能载体，不仅可以有效地抑制肿瘤生长，同时可以降低病人遭受细菌感染的风险，促进病人康复。
4.利用超支化缀合物构建药物顺序释放体系实现癌症治疗与免疫增强
在化学治疗过程中，癌症患者常因化学药物的副作用导致白细胞低下，进而导致免疫力受损，影响病人的康复。因此，临床上迫切需要构建能协同治疗癌症，又能促进免疫的药物释放系统。采用阳离子开环聚合制备了超支化聚缩水甘油（HPG），然后将中药去甲斑蝥素（NCTD）成功地接枝到HPG表面，获得了中药缀合的超支化聚合物HPG-NCTD。借助电子显微镜及动态光散射研究了HPG-NCTD与顺铂（CDDP）组装成纳米颗粒的形貌、尺寸及分布。在不同pH值条件下考察了两种药物的释放行为。以传统的MTT法测定了HPG-NCTD/CDDP复合物的抗肿瘤效果，考察了体内白细胞提升行为。实验结果表明，HPG-NCTD/CDDP为分布较均匀的纳米颗粒，CDDP和NCTD能够按照顺序从HPG-NCTD/CDDP纳米颗粒上依次释放出来，可以有效地抑制癌细胞。体内实验发现，在CDDP存在的条件下，HPG-NCTD/CDDP纳米颗粒能够有效地提升白细胞。这些结果表明，基于可降解共价键及配位键构建起来的药物顺序释放体系，可以克服癌症治疗过程中白细胞低下的难题，达到协同治疗的效果。
Gene and drug carriers are one of important research fields in nanomedicine. Hyperbranched polymer is widely used to overcome many deficiencies of the conventional carriers in this field due to its unique physical and chemical properties, such as low viscosity, many functional terminals, large internal cavity and high solubility. However, there are still a lot of issues, such as the contradiction between cytotoxicity and transfection efficiency, unsatisfied efficacy of individual gene therapy, and bacterial infection from low immunity. In this thesis, various functional hyperbranched conjugates have been constructed for improvement of treatment efficacy. The details and main conclusions are given as follows:
1. Hyperbranched Glycoconjugated Polymer from Natural Small Molecule Kanamycin as a Safe and Efficient Gene Vector
The exploration of safe and efficient polycationic gene vectors from natural small molecules such as kanamycin is proposed. Cationic hyperbranched glycoconjugated polymer is synthesized by the Michael-addition polymerization of kanamycin and N',N'-methylenebisacrylamide, and the resultant product is well characterized by Fourier transform infrared (FTIR),1H nuclear magnetic resonance (1H NMR),13C NMR, size exclusion chromatography-multiangle laser light scattering (SEC-MALLS) and ξ-potential analyses. The nitrogen content (7.3%) of this kanamycin-based hyperbranched glycoconjugated polymer is much lower than that (32.6%) of polyethylenimine (PEI) control. Moreover, this resultant polymer could be degraded in acidic conditions. Therefore, the hyperbranched glycoconjugated polymer shows low cytotoxicity, even lower than that of natural biomacromolecule chitosan. Due to the existence of various primary, secondary and tertiary amines in the polymer backbone, hyperbranched glycoconjugated polymer exhibits high buffering capacity and strong pDNA condensation ability. In vitro transfection shows that the luciferase expression of hyperbranched glycoconjugated polymer is about4.4×108RLU per mg protein, approximately33-fold greater than that of chitosan transfection. These results demonstrate that the construction of highly branched polycations from natural small molecules provides a new opportunity for developing safe and efficient gene vectors.
2. A Controlled Drug Delivery System with Promotion of Gene Transfection and Anticancer Efficacy
As an efficient method to improve the polycationic gene delivery, hydrophobic modification has received more and more attention. However, it is rarely reported that hydrophobic drugs are used to promote gene transfection. Considering that the target of hydrophobic chlorambucil is DNA strands, the hyperbranched polycations are modified with chlorambucil for both gene transfection and drug delivery. The hyperbranched glycoconjugated polymers are modified with chlorambucil, and its chemical structure is well analyzed by FTIR,1H NMR, Size Exclusion Chromatography (SEC) and biophysical properties. Since the polycations can transport drugs into the nucleus efficiently, the anticancer efficacy of drug conjugates is much better than that of free chlorambucil. The results from confocal laser scanning microscope and flow cytometry have verified the efficient cell internalization of polymeric carriers. Owning to the hydrophobic modification and the controlled release of chlorambucil from polycations, the hyperbranched glycoconjugated polymers with chlorambucil show high transfection efficiency than pure polymers.
3. Multi-functional Hyperbranched Glycoconjugated Polymers Based on Natural Aminoglycosides
The multi-functional gene vectors with high transfection, low cytotoxicity, and good anti-tumor and anti-bacterial activities are prepared from natural aminoglycosides. Through the Michael-addition polymerization of gentamycin and N',N'-methylenebisacrylamide, cationic hyperbranched glycoconjugated polymers are synthesized and their physical and chemical properties are well analyzed by FTIR,1H NMR,13C NMR, SEC, ξ-potential, and acid-base titration techniques. The cytotoxicity of these hyperbranched glycoconjugated polycations is low because of the hydrolysis of degradable glycosidic and amide linkages in acid conditions. Owing to the presence of various primary, secondary and tertiary amines in the polymers, hyperbranched glycoconjugated polymers show high buffering capacity and strong DNA condensation ability, resulting in the high transfection efficiency. In the meantime, due to the introduction of natural aminoglycosides into the polymeric backbone, the resultant hyperbranched glycoconjugated polymers inhibit the growth of cancer cells and bacteria efficiently. Combining the gene transfection, anti-tumor and anti-bacterial abilities together, the multi-functional hyperbranched glycoconjugated polymers based on natural aminoglycosides may play an important role in protecting cancer patients from bacterial infections.
4. Sequential Drug Release for Synergistic Cancer Treatment and Immunity Promotion
Effective drug sequential release can enhance the efficacy, so sequential delivery system is one of most important goals in cancer therapy. In this work, a sequential drug release for synergistic cancer treatment and immunity promotion has been constructed. Firstly, the hyperbranched glycidol (HPG) is synthesized by cationic ring-opening polymerization. Benefiting from the existence of many hydroxyl end-groups in HPG, the traditional Chinese medicine norcantharidin (NCTD) with anhydride can be readily conjugated onto polyols via ester linkages, forming the HPG-NCTD conjugates. Owing to the coordination between cisplatin (CDDP) and carboxyls in HPG-NCTD conjugates, the HPG-NCTD/CDDP complexes with nano scale are obtained. Both in vitro and in vivo evaluations show that the sequential release of CDDP and NCTD is achieved by combination of coordination connections and hydrolysable ester bonds. Correspondingly, a synergistic efficiency of cancer treatment and immunity promotion is realized. These experimental results confirm that the sequential release carriers based on coordination connections and degradable covalent bonds can be used to overcome the problems of leukopenia in cancer therapy, giving us a perspective in cancer treatment.
1.利用天然小分子构建含糖缀合物作为低毒高效基因载体
糖类分子既可与细胞相互作用，同时也具有较低的细胞毒性。因此，从天然糖基小分子开发低毒高效的基因载体，是克服该类载体毒性与转染效率矛盾的一个很有希望的方向。通过迈克尔加成聚合，制备了阳离子超支化糖缀合聚合物（HPKM）。采用红外、核磁、分子排阻色谱-多角度激光光散射联用和ζ-电位技术等常规表征手段对合成产物进行了化学结构表征。表征结果发现，HPKM的含氮量为7.3%，远低于超支化聚乙烯亚胺的32.6%，且HPKM可以在酸性环境中降解，因此HPKM具有很低的细胞毒性，甚至低于壳聚糖。由于分子结构中存在伯胺、仲胺和叔胺，HPKM呈现良好的质子缓冲能力和DNA压缩能力。体外转染实验表明HPKM介导的转染效率较高，大约是壳聚糖的33倍。这些结果说明，以天然小分子为基础，可以制备低毒高效的超支化糖缀合物基因载体。
2.利用疏水药物分子缀合的阳离子超支化缀合物同时促进基因转染与药效
作为促进基因转染的一种有效方式，阳离子聚合物的疏水修饰受到越来越多的关注。然而，利用疏水药物修饰阳离子聚合物促进基因转染的工作尚未见报道。考虑到疏水药物苯丁酸氮芥的靶标是DNA链，经苯丁酸氮芥修饰的阳离子聚合物既有利于基因转染，又可以增强药效。苯丁酸氮芥缀合的超支化聚合物的各种物理化学表征表明，该缀合物可以有效地将DNA压缩成纳米颗粒。激光共聚焦显微镜技术及流式细胞仪研究发现，该缀合物能快速进入细胞核，因此药效明显强于相同浓度的单药。相对于未经修饰的阳离子聚合物，疏水药物缀合的聚合物的转染性能有较大提高。该工作构建的可控释放载体能够同时促进药效与基因转染，给药物与基因共传递纳米体系提供了新视野，为癌症综合治疗带来希望。
3.以天然糖胺为基元构建应用于基因治疗的多功能超支化含糖缀合物
较好的癌症治疗是多种因素共同作用的结果。因此，具有高转染、低毒、抗菌和抗肿瘤特性的基因载体是临床所急需的。利用简单的迈克尔加成，可以制备符合上述要求的超支化含糖缀合物作为多功能基因载体。采用红外、核磁、分子排阻色谱、ζ-电位和酸碱滴定技术表征了聚合物的物理化学特性。实验结果表明，该材料具有较低的细胞毒性。由于存在大量的伯胺、仲胺和叔胺，该聚合物显示较好的质子缓冲能力、DNA压缩能力和转染效率。同时，由于分子结构中存在糖胺基团，聚合物可以有效地抑制肿瘤及细菌的生长。这些结果表明，以天然糖胺为基元构建的多功能载体，不仅可以有效地抑制肿瘤生长，同时可以降低病人遭受细菌感染的风险，促进病人康复。
4.利用超支化缀合物构建药物顺序释放体系实现癌症治疗与免疫增强
在化学治疗过程中，癌症患者常因化学药物的副作用导致白细胞低下，进而导致免疫力受损，影响病人的康复。因此，临床上迫切需要构建能协同治疗癌症，又能促进免疫的药物释放系统。采用阳离子开环聚合制备了超支化聚缩水甘油（HPG），然后将中药去甲斑蝥素（NCTD）成功地接枝到HPG表面，获得了中药缀合的超支化聚合物HPG-NCTD。借助电子显微镜及动态光散射研究了HPG-NCTD与顺铂（CDDP）组装成纳米颗粒的形貌、尺寸及分布。在不同pH值条件下考察了两种药物的释放行为。以传统的MTT法测定了HPG-NCTD/CDDP复合物的抗肿瘤效果，考察了体内白细胞提升行为。实验结果表明，HPG-NCTD/CDDP为分布较均匀的纳米颗粒，CDDP和NCTD能够按照顺序从HPG-NCTD/CDDP纳米颗粒上依次释放出来，可以有效地抑制癌细胞。体内实验发现，在CDDP存在的条件下，HPG-NCTD/CDDP纳米颗粒能够有效地提升白细胞。这些结果表明，基于可降解共价键及配位键构建起来的药物顺序释放体系，可以克服癌症治疗过程中白细胞低下的难题，达到协同治疗的效果。
Gene and drug carriers are one of important research fields in nanomedicine. Hyperbranched polymer is widely used to overcome many deficiencies of the conventional carriers in this field due to its unique physical and chemical properties, such as low viscosity, many functional terminals, large internal cavity and high solubility. However, there are still a lot of issues, such as the contradiction between cytotoxicity and transfection efficiency, unsatisfied efficacy of individual gene therapy, and bacterial infection from low immunity. In this thesis, various functional hyperbranched conjugates have been constructed for improvement of treatment efficacy. The details and main conclusions are given as follows:
1. Hyperbranched Glycoconjugated Polymer from Natural Small Molecule Kanamycin as a Safe and Efficient Gene Vector
The exploration of safe and efficient polycationic gene vectors from natural small molecules such as kanamycin is proposed. Cationic hyperbranched glycoconjugated polymer is synthesized by the Michael-addition polymerization of kanamycin and N',N'-methylenebisacrylamide, and the resultant product is well characterized by Fourier transform infrared (FTIR),1H nuclear magnetic resonance (1H NMR),13C NMR, size exclusion chromatography-multiangle laser light scattering (SEC-MALLS) and ξ-potential analyses. The nitrogen content (7.3%) of this kanamycin-based hyperbranched glycoconjugated polymer is much lower than that (32.6%) of polyethylenimine (PEI) control. Moreover, this resultant polymer could be degraded in acidic conditions. Therefore, the hyperbranched glycoconjugated polymer shows low cytotoxicity, even lower than that of natural biomacromolecule chitosan. Due to the existence of various primary, secondary and tertiary amines in the polymer backbone, hyperbranched glycoconjugated polymer exhibits high buffering capacity and strong pDNA condensation ability. In vitro transfection shows that the luciferase expression of hyperbranched glycoconjugated polymer is about4.4×108RLU per mg protein, approximately33-fold greater than that of chitosan transfection. These results demonstrate that the construction of highly branched polycations from natural small molecules provides a new opportunity for developing safe and efficient gene vectors.
2. A Controlled Drug Delivery System with Promotion of Gene Transfection and Anticancer Efficacy
As an efficient method to improve the polycationic gene delivery, hydrophobic modification has received more and more attention. However, it is rarely reported that hydrophobic drugs are used to promote gene transfection. Considering that the target of hydrophobic chlorambucil is DNA strands, the hyperbranched polycations are modified with chlorambucil for both gene transfection and drug delivery. The hyperbranched glycoconjugated polymers are modified with chlorambucil, and its chemical structure is well analyzed by FTIR,1H NMR, Size Exclusion Chromatography (SEC) and biophysical properties. Since the polycations can transport drugs into the nucleus efficiently, the anticancer efficacy of drug conjugates is much better than that of free chlorambucil. The results from confocal laser scanning microscope and flow cytometry have verified the efficient cell internalization of polymeric carriers. Owning to the hydrophobic modification and the controlled release of chlorambucil from polycations, the hyperbranched glycoconjugated polymers with chlorambucil show high transfection efficiency than pure polymers.
3. Multi-functional Hyperbranched Glycoconjugated Polymers Based on Natural Aminoglycosides
The multi-functional gene vectors with high transfection, low cytotoxicity, and good anti-tumor and anti-bacterial activities are prepared from natural aminoglycosides. Through the Michael-addition polymerization of gentamycin and N',N'-methylenebisacrylamide, cationic hyperbranched glycoconjugated polymers are synthesized and their physical and chemical properties are well analyzed by FTIR,1H NMR,13C NMR, SEC, ξ-potential, and acid-base titration techniques. The cytotoxicity of these hyperbranched glycoconjugated polycations is low because of the hydrolysis of degradable glycosidic and amide linkages in acid conditions. Owing to the presence of various primary, secondary and tertiary amines in the polymers, hyperbranched glycoconjugated polymers show high buffering capacity and strong DNA condensation ability, resulting in the high transfection efficiency. In the meantime, due to the introduction of natural aminoglycosides into the polymeric backbone, the resultant hyperbranched glycoconjugated polymers inhibit the growth of cancer cells and bacteria efficiently. Combining the gene transfection, anti-tumor and anti-bacterial abilities together, the multi-functional hyperbranched glycoconjugated polymers based on natural aminoglycosides may play an important role in protecting cancer patients from bacterial infections.
4. Sequential Drug Release for Synergistic Cancer Treatment and Immunity Promotion
Effective drug sequential release can enhance the efficacy, so sequential delivery system is one of most important goals in cancer therapy. In this work, a sequential drug release for synergistic cancer treatment and immunity promotion has been constructed. Firstly, the hyperbranched glycidol (HPG) is synthesized by cationic ring-opening polymerization. Benefiting from the existence of many hydroxyl end-groups in HPG, the traditional Chinese medicine norcantharidin (NCTD) with anhydride can be readily conjugated onto polyols via ester linkages, forming the HPG-NCTD conjugates. Owing to the coordination between cisplatin (CDDP) and carboxyls in HPG-NCTD conjugates, the HPG-NCTD/CDDP complexes with nano scale are obtained. Both in vitro and in vivo evaluations show that the sequential release of CDDP and NCTD is achieved by combination of coordination connections and hydrolysable ester bonds. Correspondingly, a synergistic efficiency of cancer treatment and immunity promotion is realized. These experimental results confirm that the sequential release carriers based on coordination connections and degradable covalent bonds can be used to overcome the problems of leukopenia in cancer therapy, giving us a perspective in cancer treatment.
引文
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