基于纳米羟基磷灰石的新型药物载体系统的研究
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摘要
随着现代医学技术与材料科学的发展,特别是无机纳米粒子对生物分子载药的多样性和潜在的应用已成为材料科学的前沿领域。一些新型的无机无机纳米粒子如金纳米粒子、二氧化硅纳米粒子、磷酸钙纳米粒子等用作基因药物载体成为研究热点。其中,磷酸钙纳米粒子特有的生物相容性、生物可吸收性、生物降解、较低毒性性和化学稳定性使其可有效地导入细胞,同时磷酸钙粒子能粘附和传递生物活性大分子药物(如蛋白质、抗体、核酸、造影剂等)作为药物载体可以进入到人体组织受损或病变部位,使磷酸钙作为药物载体成为可能。磷酸钙载体以钙离子和反义核酸结构中的磷酸骨架基团形成化学键来实现对核酸的保护和转染,通过药物载体负载反义核酸能够将药物选择性将其浓集在癌变部位以减少药物降解及损失,降低细胞毒性药物对正常细胞组织的伤害,同时提高药物利用度。
本文利用微乳法制备反义寡聚核苷酸-磷酸钙纳米粒子的基因载药系统,将反义寡聚核苷酸掺杂到磷酸钙晶格中导入HeLa细胞以实现有效转染,为构建抗肿瘤新型药物载体系统和提高反义核酸药物利用效率作为研究主要方向。进一步将磁性造影剂复合到羟基磷灰石中制备出具有荧光标记且具有造影功能的多功纳米粒子,为多功能药物造影剂的发展提供研究基础。本论文包括三部分,其主要研究内容如下:
1.第一部分主要探讨利用水相合成法制备纳米级的羟基磷灰石的研究。利用水相合成法具有纳米级球形的羟基磷灰石,并通过在HeLa细胞中的细胞学作用效果研究,再通过MTT法来检测该纳米级球形羟基磷灰石的细胞毒性,实验表明在一定浓度范围内羟基磷灰石对细胞具有良好的生物安全性。
2.第二部分反义核酸-羟基磷灰石纳米粒子载药体系的研究。以羟基磷灰石作为抗癌药物ASODNs的药物载体,即利用钙离子能与ASODNs上的磷酸基团反应作用以共掺杂的方法成功地制备复合型的ASODNs-羟基磷灰石纳米粒子,用紫外可见光谱、荧光光谱、TEM、MTT法、流式细胞仪等检测方法来证实药物载体的成功构建,其具有较高的转染率并能有效地提高抗癌药物的抗癌效率。用激光共聚焦显微镜、生物电镜等证实复合药物载体导入细胞后能真正有效促进肿瘤细胞凋亡。
3.第三部分初步探索了复合型锰造影剂-ASODNs-羟基磷灰石的制备及表征,用透射电镜、振动样品磁强计和激光扫描共聚焦显微镜等方法来检测,结果显示较成功地制备的具有多功能的磁共振成像靶向造影剂具有抗癌药效的复合型的分散性的纳米粒子,其有较高的弛豫率荧光效应,该探索研究也为新型多功能基因药物的发展提供了新方法和新思路。
With the development of modern medical technology and materials science development, especially, the emerging area of inorganic nanoparticles entrapping biomolecules has already exhibited its diversity and potential applications in many frontiers of modern material science. Some of the novel inorganic carriers for gene drug delivery have been a hot spot in the field of medicine transportation in recent years such as gold nanoparticles, silica nanoparticles, calcium phosphate nanoparticles, manganous phosphate nanoparticles and other inorganic phosphate nanoparticles. The calcium phosphate nanoparticles could translocated into cells because it had good biocompatibility, bioabsorbability and biodegradability, lack toxicity and stable chemical properties, on the other hand, it also could be exploited to deliver a broad range of therapeutics including proteins, antibodies, oligonucleotides, imaging agents and liposomes in a variety of situations and biological systems. Calcium ions of calcium phosphate carrier can form chemical bond with phosphate backbone groups of antisense oligonucleotides (ASODNs), it’s one of the efficient methods for protecting ASODNs transfer into cell lines, drug carrier loaded antisense drugs can be selectively concentrated in cancerous site to reduce drug degradation and losses, reduce drug cytotoxicity to normal cells or tissue and improve drug availability.
In this study, we used the double reverse emulsion approach to prepare the ASODNs loaded into calcium phosphate nanoparticles as gene delivery system for achieving high efficiency transfection in HeLa cell lines. it provided a main research direction for structure new antitumor drug carriers and improved the efficiency of drug utilization. For further study, it considered magnetic contrast agent composite with hydroxyapatite to prepare fluorescent marker and magnetic imaging function of multifunctional nanoparticles, this provides a research direction for the developmentof multifunctional drug nanoparticles. This paper includes three part contents as follows:
1. The first part content mainly discusses preparation of nanometer hydroxyapatite with aqueous phase method. The results show that it has succeed for preparing nanoscale spherical hydroxyapatite nanoparticles. In vitro cytotoxicity studies of hydroxyapatite nanoparticles using the MTT assay with HeLa cells to cytotoxicity, the results show hydroxyapatite have a good biological safety in a certain concentration range of concentration.
2. The second part content mainly discusses calcium phosphate nanoparticles as carriers for efficient cellular delivery of antisense oligodeoxynuclecotides. In this study, we used the double reverse emulsion approach to prepare the ASODNs loaded into calcium phosphate nanoparticles as gene delivery system. Calcium phosphate coprecipitation is one of the most common methods for successful preparation of ASODNs-CP nanoparticles, because divalent metal cation Ca2+ can bind phosphate backbone groups of antisense oligodeoxynucleotide. We successfully preparation ASODNs-CP nanoparticles and this drug carrier system have a high loading efficiency and improve transfection and anti-cancer efficiency by the characterizations of uv-vis spectra, fluorescence spectrum, TEM, MTT method and flow cytometry. ASODNs-CP nanoparticles can be truly effective promote HeLa cells apoptosis by using laser confocal microscopy, biological microscope.
3. The third part preliminary exploration of researching the manganese contrast agent- ASODNs-hydroxyapatite composites preparation and characterization, it was charactered by TEM, LSCM and vibrating sample magnetometer, the results showed that we successfully prepared dispersible multifunction contrast magnetic agent imaging nanoparticles which have a certain relaxation rate and fluorescence effect. This study for the development of new-type multifunctional magnetic agent imaging provides a new method and idea.
本文利用微乳法制备反义寡聚核苷酸-磷酸钙纳米粒子的基因载药系统,将反义寡聚核苷酸掺杂到磷酸钙晶格中导入HeLa细胞以实现有效转染,为构建抗肿瘤新型药物载体系统和提高反义核酸药物利用效率作为研究主要方向。进一步将磁性造影剂复合到羟基磷灰石中制备出具有荧光标记且具有造影功能的多功纳米粒子,为多功能药物造影剂的发展提供研究基础。本论文包括三部分,其主要研究内容如下:
1.第一部分主要探讨利用水相合成法制备纳米级的羟基磷灰石的研究。利用水相合成法具有纳米级球形的羟基磷灰石,并通过在HeLa细胞中的细胞学作用效果研究,再通过MTT法来检测该纳米级球形羟基磷灰石的细胞毒性,实验表明在一定浓度范围内羟基磷灰石对细胞具有良好的生物安全性。
2.第二部分反义核酸-羟基磷灰石纳米粒子载药体系的研究。以羟基磷灰石作为抗癌药物ASODNs的药物载体,即利用钙离子能与ASODNs上的磷酸基团反应作用以共掺杂的方法成功地制备复合型的ASODNs-羟基磷灰石纳米粒子,用紫外可见光谱、荧光光谱、TEM、MTT法、流式细胞仪等检测方法来证实药物载体的成功构建,其具有较高的转染率并能有效地提高抗癌药物的抗癌效率。用激光共聚焦显微镜、生物电镜等证实复合药物载体导入细胞后能真正有效促进肿瘤细胞凋亡。
3.第三部分初步探索了复合型锰造影剂-ASODNs-羟基磷灰石的制备及表征,用透射电镜、振动样品磁强计和激光扫描共聚焦显微镜等方法来检测,结果显示较成功地制备的具有多功能的磁共振成像靶向造影剂具有抗癌药效的复合型的分散性的纳米粒子,其有较高的弛豫率荧光效应,该探索研究也为新型多功能基因药物的发展提供了新方法和新思路。
With the development of modern medical technology and materials science development, especially, the emerging area of inorganic nanoparticles entrapping biomolecules has already exhibited its diversity and potential applications in many frontiers of modern material science. Some of the novel inorganic carriers for gene drug delivery have been a hot spot in the field of medicine transportation in recent years such as gold nanoparticles, silica nanoparticles, calcium phosphate nanoparticles, manganous phosphate nanoparticles and other inorganic phosphate nanoparticles. The calcium phosphate nanoparticles could translocated into cells because it had good biocompatibility, bioabsorbability and biodegradability, lack toxicity and stable chemical properties, on the other hand, it also could be exploited to deliver a broad range of therapeutics including proteins, antibodies, oligonucleotides, imaging agents and liposomes in a variety of situations and biological systems. Calcium ions of calcium phosphate carrier can form chemical bond with phosphate backbone groups of antisense oligonucleotides (ASODNs), it’s one of the efficient methods for protecting ASODNs transfer into cell lines, drug carrier loaded antisense drugs can be selectively concentrated in cancerous site to reduce drug degradation and losses, reduce drug cytotoxicity to normal cells or tissue and improve drug availability.
In this study, we used the double reverse emulsion approach to prepare the ASODNs loaded into calcium phosphate nanoparticles as gene delivery system for achieving high efficiency transfection in HeLa cell lines. it provided a main research direction for structure new antitumor drug carriers and improved the efficiency of drug utilization. For further study, it considered magnetic contrast agent composite with hydroxyapatite to prepare fluorescent marker and magnetic imaging function of multifunctional nanoparticles, this provides a research direction for the developmentof multifunctional drug nanoparticles. This paper includes three part contents as follows:
1. The first part content mainly discusses preparation of nanometer hydroxyapatite with aqueous phase method. The results show that it has succeed for preparing nanoscale spherical hydroxyapatite nanoparticles. In vitro cytotoxicity studies of hydroxyapatite nanoparticles using the MTT assay with HeLa cells to cytotoxicity, the results show hydroxyapatite have a good biological safety in a certain concentration range of concentration.
2. The second part content mainly discusses calcium phosphate nanoparticles as carriers for efficient cellular delivery of antisense oligodeoxynuclecotides. In this study, we used the double reverse emulsion approach to prepare the ASODNs loaded into calcium phosphate nanoparticles as gene delivery system. Calcium phosphate coprecipitation is one of the most common methods for successful preparation of ASODNs-CP nanoparticles, because divalent metal cation Ca2+ can bind phosphate backbone groups of antisense oligodeoxynucleotide. We successfully preparation ASODNs-CP nanoparticles and this drug carrier system have a high loading efficiency and improve transfection and anti-cancer efficiency by the characterizations of uv-vis spectra, fluorescence spectrum, TEM, MTT method and flow cytometry. ASODNs-CP nanoparticles can be truly effective promote HeLa cells apoptosis by using laser confocal microscopy, biological microscope.
3. The third part preliminary exploration of researching the manganese contrast agent- ASODNs-hydroxyapatite composites preparation and characterization, it was charactered by TEM, LSCM and vibrating sample magnetometer, the results showed that we successfully prepared dispersible multifunction contrast magnetic agent imaging nanoparticles which have a certain relaxation rate and fluorescence effect. This study for the development of new-type multifunctional magnetic agent imaging provides a new method and idea.
引文
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