【作者】 王杨云；

【导师】 马建标；

【作者基本信息】 南开大学 ， 高分子化学与物理， 2013， 博士

【摘要】 环境响应性聚合物是一类能够感知外界并对外界环境的细小变化做出响应,产生相应的物理结构和化学性质变化甚至突变的高分子。研究者根据病灶部位微环境的特征,设计出具有不同环境响应性聚合物作为药物载体实现病灶部位的定点放药。在早期的研究中,大多数以单一刺激响应性的聚合物为研究对象。但是在实际应用中,外界环境的变化是多样化的,因此多重刺激响应性的聚合物受到越来越多的关注。聚氨酯具有较好的生物、血液相容性,在生物医学领域具有广泛应用前景,但是到目前为止环境响应性的聚氨酯特别是多重响应性的聚氨酯作为药物载体的研究还不是很充分。本文综述了环境响应性聚合物的发展或生物可降解聚氨酯作为药物载体的研究进展,在此基础上设计了一种简单的路线,合成了多种具有单一或者多重刺激响应性的聚醚氨酯。聚合物的刺激响应性行为通过透光率、动态光散射以及透射电镜表征。并以憎水的抗癌药物阿霉素为模型,研究了聚醚氨酯载药纳米粒子在体外和肿瘤细胞内的释放行为及抑制肿瘤细胞的能力。(1)用简单的一锅法合成了温度响应性的聚醚氨酯。以聚乙二醇二异氰酸酯和脂肪族的二醇为原料,以二月桂酸二丁基锡为催化剂合成了具有亲疏水链段交替结构的温度响应性聚醚氨酯。通过调节聚合物中亲水链段或者疏水链段的长度,可以精确地控制聚氨酯的相转变温度。新型聚氨酯具有优异的生物相容性和生物可降解性,用这种聚醚氨酯作为药物载体可以包封疏水药物,且通过控制环境的温度,可以实现药物的可控释放。(2)用简单的一锅法合成了具有温度、pH双重响应性的聚醚氨酯。以聚乙二醇二异氰酸酯和N-甲基二乙醇胺为原料,以二月桂酸二丁基锡为催化剂合成了具有交替结构的聚醚氨酯。通过调节聚合物中亲水链段聚乙二醇的长度,可以调控聚氨酯的相转变温度。这种两亲性的聚醚氨酯可以在水溶液中自组装形成纳米粒子,并可以作为药物载体包封疏水的抗癌药物。通过控制环境的刺激或者选择具有不同相转变温度的聚醚氨酯作为药物载体,可以精确地控制药物的释放量以及抑制肿瘤的能力。(3)用简单的一锅法合成了温度、还原双重响应性的聚醚氨酯。以聚乙二醇二异氰酸酯和二硫代二乙二醇为原料或者以聚乙二醇、六亚甲基二异氰酸酯和二硫代二乙二醇为原料,以二月桂酸二丁基锡为催化剂合成了具有不同结构的聚醚氨酯,且温度响应性控制着还原响应性的发生。通过调节聚合物中亲水链段长度或者亲疏水链段的比例,可以精确地控制聚氨酯的相转变温度。新型的聚氨酯具有优异的生物相容性,并且在还原条件下,聚合物链段中的二硫键可以立即被切断,导致聚醚氨酯纳米粒子解离,快速完全地释放出包封的抗癌药物。(4)用简单的一锅法合成了温度、pH和还原多重响应性的聚醚氨酯。以聚乙府管醇二异氰酸酯、N-甲基二乙醇胺和二硫代二乙二醇为原料或者以聚乙二醇、六亚甲基二异氰酸酯、N-甲基二乙醇胺和二硫代二乙二醇为原料,以二月桂酸二丁基锡为催化剂合成了具有不同结构的聚醚氨酯。聚合物的相转变温度可以通过调节聚合物中亲水链段长度或者亲疏水链段的比例来精确调控。通过研究聚醚氨酯载药纳米粒子在不同条件下的释药行为,发现通过调协外界的多重刺激,可以有效地调节药物的释放速率。同时,模拟肿瘤部位的微环境,通过调节外界环境的温度,有可能实现肿瘤部位的按需给药。更多还原

【Abstract】 Stimuli-responsive polymers are able to undergo relatively large and abrupt, physical or chemical changes in response to small external changes in the environmental conditions. They are of fundamental importance in biomedical areas and have been extensively developed for drug delivery systems considering the special microenvironment in many pathological sites. During the past two decades, there have been numerous reports on stimuli-sensitive polymeric systems. But a majority of them deal with response to single stimulus. In nature, however, the change in behavior of a macromolecule (proteins and nucleic acids) is often a result of its response to a combination of environmental changes other than a single factor. To mimic this feature, formulation of materials which can sense specific changes and respond to multiple stimuli in a predictable manner would be of great interest. Polyurethanes are one of the most widely used biomaterials in medical applications due to their excellent biocompatibility, biodegradation, mechanical and processing properties. In the recent years, some kinds of biodegradable polyurethanes have been developed for drug delivery systems. Nevertheless, very little attention has been paid to the stimuli-responsive polyurethane especially multi-responsive polyurethane nanoparticles as drug delivery systems. In this thesis, we summarize the recent advances in design and development of stimuli-responsive polymers and polyurethanes as drug delivery systems. Based on previous studies, several kinds of single stimuli or multi-stimuli responsive polyurethanes were designed and synthesized using a facile one-pot method. The whole process for the responsive behaviours of the poly(ether urethane) nanoparticles is confirmed by light transmission, dynamic light scattering, nuclear magnetic resonance and transmission electron microscopy. The potential use of these polymers for flexible control of drug release in vivo and vitro is also explored, using doxorubicin (DOX) as the model drug. (1) A series of temperature-responsive poly(ether urethane)s with alternative hydrophilic/hydrophobic segments was synthesized using a facile one-pot approach, from PEG-diisocyanates and aliphatic diols. Nanoparticles prepared by self-assembly of the resulting copolymers showed sharp temperature-responsive phase transition. The phase transition temperature could be easily modulated by the length of hydrophilic or hydrophobic segments of the polymer. In the presence of these obtained poly(ether-urethane)s, doxorubicin (DOX) could be dispersed into aqueous solution. The ratio of DOX release from the polymeric particles increased sharply above the phase transition temperature, while the release was suppressed below the phase transition temperature. A controlled drug release can be achieved by changing the environmental temperature. The easy-prepared polymeric nanoparticles, with features of biocompatibility, biodegradability, and tail-made temperature responsiveness, are a kind of promising carriers for temperature-controllable drug release.(2) A series of linear temperature-and pH-responsive poly(ether urethane)s was synthesized using a facile one-pot method from PEG-diisocyanates of different molecular weight and N-methyldiethanolamine containing ternary amino moieties. In aqueous solution, the amphiphilic copolymers could be self-assembled into nanoparticles, which showed temperature and pH dually responsive characters. The phase transition temperature (Tp) of the nanoparticles could be modulated by changing the molecular weight of PEG segments. The encapsulation and release of doxorubicine (DOX) were investigated using the obtained polymeric nanoparticles as carriers. The system showed a temperature-triggered pH-dependent drug release. The viability of liver hepatocellular cells (HepG2cells) treated with the DOX-loaded polymeric nanoparticles was observed using microscopy. The results demonstrated that the therapeutic activity and the DOX distribution could be precisely controlled by the novel dually responsive system.(3) A series of temperature-and redox-responsive poly(ether urethane)s have been achieved using a facile one-pot approach. The amphiphilic poly(ether urethane)s were comprised of2,2’-dithiodiethanol, hydrophobic hexamethylene diisocyanate and hydrophilic Poly(ethylene glycol)(PEG) segments. In aqueous solution, the amphiphilic copolymers could be self-assembled into their nanoparticles, which showed temperature and redox dually responsive characters. The phase transition temperature (Tp) of the prepared poly(ether urethane)s in aqueous solution could be easily controlled by changing the length of PEG segment or the ratio of PEG to2,2’-dithiodiethanol and Tp could be used to trigger the redox-degradable behavior. The Doxorubicin (DOX)-loaded poly(ether urethane) nanoparticles were prepared in order to investigate their stimuli-responsive release. Drug release profiles showed that a transient or slow release was obtained when a temperature or redox stimulus was applied by itself. A long-term accelerated drug release could be obtained through the redox-responsive degradation at a higher temperature above Tp. This polymeric carrier system provides an opportunity to fine-tune release kinetics resulting in a desired release profile through the synergistic effect of these two stimuli.(4) A series of multi-responsive degradable poly(ether urethane)s have been achieved using a facile one-pot method. The multi-segmented poly(ether urethane)s were synthesized through a simple one-pot condensation polymerization of poly (ethylene glycol),2,2’-dithiodiethanol, N-methyldiethanolamine and hexamethylene diisocyanate. The obtained amphiphilic copolymers could be self-assembled into their nanoparticles in aqueous solution, which were responsive respectively to temperature, pH and redox potential with tailored phase transition temperature. The nanoparticles possessed the encapsulation of hydrophobic drugs and showed a temperature-triggered accelerated and complete drug release profile. These results presented the polymeric nanoparticles as effective multi-responsive degradable nanocarriers to achieve on-off drug release.更多还原