【作者】 吴战宇；

【导师】 王静媛；

【作者基本信息】 吉林大学 ， 高分子化学与物理， 2010， 博士

【摘要】 功能性高分子材料与纳米技术相结合在生物医学领域具有十分重要的意义和应用价值。功能性两亲梳状聚合物形貌规整可控,既具有高度的两亲性同时能够包覆药物及纳米粒子,是良好的多功能纳米载药体系载体。荧光纳米量子点及氧化铁纳米粒子在生物医学领域应用广泛,具有良好光学性能的荧光纳米量子点及具有良好磁性能的氧化铁纳米粒子在医学成像方面具有独特的优势。本论文主要合成了多羧基聚合物及功能性两亲梳状共聚物,对聚合物的性质和结构进行了研究。利用这些聚合物制备水溶性纳米粒子,并考察这些纳米粒子的特性。最终,制备了具有成像、靶向、药物缓释的多功能纳米粒子载药体系,具体工作如下:首先,利用溶液聚合法合成生物可降解的多羧基聚合物,聚衣康酸甲基丙烯酸(PIA-MAA)。利用配体交换反应制备水溶性荧光纳米量子点PIA-MAA-QDs,该量子点水溶性好,性能稳定。其次,利用溶液聚合法合成两亲性聚合物,聚(甲基丙烯酸十八酯-co-甲基丙烯酸)(PSM)。通过相转移作用,制成水溶性好、性能稳定的量子点(PSM-QDs)。第三,利用酰胺化反应用乙醇胺及氨基聚乙二醇2000修饰PSM,合成了两亲性梳状聚合物聚(甲基丙烯酸十八酯-co-甲基丙烯酸)-乙醇胺(PSM-EtA)以及聚(甲基丙烯酸十八酯-co-甲基丙烯酸)-聚乙二醇胺(PSM-PEG)。利用PSM-EtA包埋叶酸(FA),通过相转移的方法制备聚合物载药体系PSM-EtA@FA,并利用PSM-PEG包埋盐酸阿霉素(DOX),制备聚合物载药体系PSM-PEG@DOX。两种载药体系的包埋率高,载药量大,缓释作用明显。最后,利用酰胺化反应将靶向分子尿激酶(uk)连接到两亲梳状共聚物PSM-PEG上,合成了具有靶向功能的聚(甲基丙烯酸十八酯-co-甲基丙烯酸)-聚乙二醇胺-尿激酶(PSM-PEG-uk)。利用PSM-PEG及PSM-PEG-uk作为相转移试剂,制得水溶性PSM-PEG-uk@IO纳米粒子,及PSM-PEG-uk@IO-DOX复合载药纳米粒子体系。该纳米粒子体系具有良好的超顺磁性、载药率大、包埋率高。由于荧光纳米粒子出色的光学特性及医学成像优势,进一步制得PSM-PEG@QDs,PSM-PEG-uk1@QDs,PSM-PEG-uk2@QDs及PSM-PEG-uk2@ QDs-DOX四种荧光纳米粒子。这些荧光纳米粒子的光学性能稳定并具有良好的药物包埋特性。总之,具有成像、靶向、药物缓释的多功能纳米粒子载药体系功能独特,优势突出,必将在生物医学领域得到广泛应用。更多还原

【Abstract】 The integration of nanotechnology with molecular biology and medicine has resulted in active developments of a new emerging research area, nanobiotechnology,1 which offers exciting opportunities for discovering new materials, processes, and phenomena. Semiconductor quantum dots (QDs) are emerging as a new class of fluorescent labels for molecular, cellular, and in-vivo imaging applications, due to their narrow and size-tunable emission spectra, broad absorption profiles, and superior photostability.Nanoscale magnetic materials have their own advantages that provide many exciting opportunities in biomedical applications. First, they deliver controllable sizes ranging from a few up to tens of nanometers, so their optimization of sizes and properties easily matches with the interest of study. Second, the nanoparticles can be manipulated by an external magnetic force. Third, magnetic nanoparticles play an important role as MRI contrast enhancement agents because the signal of magnetic moment of a proton around magnetic nanoparticles can be captured by resonant absorption. Recently, the active explorations of the applications of nanoparticles have advanced considerably, including biomedicine.The development of multifunctional nanoparticles that have dual capabilities of tumor imaging and delivering therapeutic agents into tumor cells holds great promises for novel approaches for tumor imaging and therapy. In this paper, the multi-carboxyl copolymers and the multifunctional comb amphiphilic copolymers are synthesized, the properties and structure of the copolymers are studied. Using these copolymers, water soluble nanoparticles are prepared by different methods, at the same time, the properties of the nanoparticles are studies. In addition, we prepared the nanoparticles drug loading vehicles with multifunction of imaging, targeting and drug delivery, and their properties and the application in tumor imaging and therapy were studied.In Chapter 1, we firstly described the research progress and the synthesis of the amphiphilic copolymer. Next, we expounded the properties, synthesis and application of the luminescent nanoparticles and the magnetic nanoparticles. At last, we introduced the preparation, properties and application of the multifunctional nanoparticles drug loading vehicles.In Chapter 2, the itaonic Acid/methylacrylate copolymer, PIA-MAA, obtaining multi-carboxyl was synthesized using solution copolymerization, and we studied the influence of different reaction conditions on the viscosity-average molecular weight. The control of the copolymer’s molecular weight was realized by detecting the influence of reaction conditions on Mη, including monomer molar ratio, reaction time, tempature and initiator dosage. The PIA-MAA was used to replace the organic alkylamine ligands coated on CdSe/CdS core-shell nanocrystals. The PIA-MAA-QDs were characterized by TEM, DLS, PL and UV-vis measurements, further studies are carried out to determine the chemical, thermal and photochemical stability of the water-soluble QDs.In Chapter 3, the amphiphilic copolymer, poly (stearyl methacrylate-co- methylacrylic acid) (PSM) was synthesized using solution copolymerization. PSMs with different hydrophobic ratio were synthesized by controlling monomer molar ratio, and the PSMs with appropriate molecular weight were determined, which could be used to coat QDs. Base on the investigation of hydrophobic ratios of PSMs, PSM/QDs mass/volume ratios and reaction time, a simple but effective phase transfer method is developed to make the CdSe/ZnS QDs water-soluble completely. We characterize the optical properties and sizes of our QDs samples using multiple tools, we also examine the stability against chemical, photochemical, and thermal treatments of these QDs. In Chapter 4, the amphiphilic comb coplymers, poly (stearyl methacrylate-co- methylacrylic acid)-ethanolamine (PSM-EtA) and poly (stearyl methacrylate-co- methylacrylic acid)-polyethylene glycol amine (PSM-PEG), were synthesized by amidation reaction using EtA and amino- polyethylene glycol 2000 (NH2PEG2000). Next, FA was embedded by PSM-EtA to prepare PSM-EtA@FA drug loading. The maximum drug loading of the vehicle was 520 mg/g, and the embedding ratio was 90%. Adriamycin hydrochloride (DOX) was embedded by PSM-PEG to prepare PSM-PEG@DOX drug loading. The maximum drug loading of the vehicle was 460 mg/g, and the embedding ratio was 80%. The delivery properties of the two vehicles were detected with different pH and tempature conditions. The results showed that PSM-EtA and PSM-PEG were favourable drug carriers to realize sustained release, which could be applied in biomedicine.In Chapter 5, the amphiphilic comb targeting coplymers, poly (stearyl methacrylate-co- methylacrylic acid)-polyethylene glycol amine-urokinase (PSM- PEG-uk), were synthesized by amidation reaction. Next, water soluble PSM-PEG- uk@IO and PSM-PEG-uk@IO-DOX nanoparticles were prepared using PSM-PEG and PSM-PEG-uk as phase transfer agents. The diameter distribution, paramagnetism and embedding ratio were studied. The two nanoparticles were uniform and kept the similar superparamagnetism as the original IO nanoparticles. The maximum drug loading of PSM-PEG-uk@IO-DOX was 200 mg/g, and the embedding ratio was 80%. Furthermore, four fluorescent nanoparticles were prepared, that is, PSM-PEG@QDs, PSM-PEG-uk1@QDs, PSM-PEG-uk2@QDs and PSM-PEG-uk2@QDs-DOX. The four nanoparticles were uniform and kept the similar optical properties as the original QDs. The maximum drug loading of PSM-PEG-uk@QDs-DOX was 210 mg/g, and the embedding ratio was 83%. The nanoparticle drug loading vehicle was hoped to be applied in biomedicine field.更多还原