响应性聚合物组装体的纳米结构调控与功能构筑

发布时间：2018-01-11 16:40

  本文关键词：响应性聚合物组装体的纳米结构调控与功能构筑　出处：《中国科学技术大学》2017年博士论文　论文类型：学位论文

  更多相关文章： 刺激响应性聚合物 嵌段聚合物 自降解连接基 自组装 交联诊疗

【摘要】：刺激响应性聚合物能够对外界刺激进行智能响应,产生可逆或不可逆的物化性质和(或)化学结构的改变,进而引起其组装体的溶胀与塌缩、解离与聚集、交联与解交联以及形貌转变等。另外,与正常器官、组织及细胞相比,病变器官、组织及细胞的生理参数会发生变化;利用这些特异性的生理变化来发展响应性聚合物组装体可以实现治疗和成像试剂的选择性传输。本论文集中研究了对肿瘤及炎症微环境具有响应性的聚合物组装体,重点是氧化还原响应性聚合物囊泡和胶束体系的设计、纳米结构的调控及多功能构筑与集成。具体来说,本论文的工作包括以下三个方面:1.很多生理和病理过程与活性氧物质和氧化压力直接相关,这就为设计治疗和诊断功能的纳米材料提供了非常重要的生化基础。由两亲性聚合物自组装制备的氧化响应性聚合物胶束或者囊泡已经进行了大量的研究。然而,在以前的氧化响应性体系研究中,包括H2O2在内的活性氧物质都会导致聚合物组装体微结构的破坏。以氧化性聚合物囊泡为例,微结构的破坏会使囊泡内包覆的亲水性药物和活性分子快速释放,在某些特定情况下,限制了聚合物囊泡作为缓释药物载体和长效活体内纳米反应器的应用。另外,传统聚合物囊泡由于其双层膜较厚、膜渗透性差,因而不能作为有效的药物载体和纳米反应器。这里,我们设计制备了一种多功能的氧化响应性聚合物囊泡,可以在细胞内被氧化微环境刺激触发后发生囊泡双层膜的交联,同时双层膜渗透性提高,表现出成像能力增强和药物释放性能提高的性质。通过自组装疏水嵌段含有芳基硼酸酯保护的具有自降解侧基的两亲性嵌段聚合物制备聚合物囊泡,在其表面进一步用多肽进行修饰从而得到具有线粒体靶向的H2O2响应性聚合物囊泡。内吞进入细胞后,胞内H2O2触发引发连续的脱保护反应产生伯胺,由于新产生的伯胺在疏水的双层膜中会发生酰胺化反应,导致囊泡双层膜发生同步的交联和疏水到亲水的转变过程。这一过程可以用于实现药物可控释放、组合化疗,同时化疗效果可以通过磁共振成像和荧光成像能力的增强进行实时监测,进一步构筑了检测细胞质中的含巯基的生物活性分子的荧光产生型纳米反应器。2.开发不同生化信号响应的具有治疗和诊断功能的纳米医药用于实现药物、多肽、蛋白质以及成像试剂的选择性和时空分辨传输已被广泛地研究。其中,利用细胞外的氧化性微环境和细胞内的还原性微环境间的氧化还原电势梯度开发氧化还原响应性两亲性嵌段共聚物胶束纳米粒子在生物医药方面的应用已经被大量地报道。此外,许多方法被采用来进一步增强胶束的稳定性,例如利用可逆连接基团进行化学交联,以避免不期望的解离和药物提前释放。值得注意的是,在所有这些情况下,可逆连接基团的断裂都会引起胶束纳米粒子解交联和不稳定化,从而导致胶束纳米粒子在目标位置快速被清除进而降低富集效果。因此,对于材料设计者来说,发展新策略以实现选择性的响应肿瘤和细胞内微环境,更重要的是如何增强诊疗功能的聚合物胶束在活体内目标位置的定位和富集仍是重大的挑战。特别地,对于大部分二硫键可逆交联的聚合物胶束纳米粒子,二硫键断裂仅仅导致解交联而没有显著的疏水到亲水转变,阻碍了包覆物质完全有效的释放。这里,我们设计合成了氧化还原响应性核自交联的胶束纳米粒子,其具有长的血液循环半衰期、细胞内还原性微环境触发的交联方式转换和胶束核从疏水到亲水的转变以及增强的诊断成像和药物释放特性。从疏水嵌段含有二硫键的具有自降解性质的两亲性嵌段共聚物出发,自组装制备胶束,进而表面修饰整合素靶向肽,最后通过紫外光引发二硫键交换反应进行交联,从而得到了肿瘤细胞靶向的还原性微环境响应的二硫键交联(DCL)胶束。通过整合素介导的内吞作用进入细胞后,细胞质还原性微环境触发胶束核内发生级联的消除反应产生伯胺;新生成的伯胺在疏水的胶束核中会进一步发生酰胺化反应,导致交联方式转换与胶束核疏水到亲水转变同时发生。该过程还被进一步用来实现荧光和磁共振成像指导的化学治疗。3.免疫细胞主要作用就是保护机体免受感染。但是当它们被不正常激活时,就会引发很多炎症反应,例如风湿性关节炎、动脉粥样硬化以及糖尿病并发症等。在这些疾病的发展过程中,包括巨噬细胞在内的免疫细胞会产生多种细胞因子,例如白细胞介素(IL-1和IL-6)、肿瘤坏死因子(TNF-α）、消化酶(胶原酶等)、前列腺素以及活性氧物质,这些细胞因子可以加重加速对正常组织的破坏。非甾体抗炎症药物(NSAIDs)被广泛用来治疗疼痛、发热以及炎症。但是,长期使用非甾体抗炎症药物会产生一些副作用,例如肠胃损伤和中风风险增加,因而限制了它们的使用以及其他适用症状的研究。这里,我们设计合成了炎症组织相关的氧化性和还原性微环境响应的聚前药两亲性分子,其中疏水嵌段含有吲哚美辛前药,进一步通过自组装制备了抗炎症的聚合物囊泡。以此为基础,评价了聚合物囊泡体系氧化和还原微环境触发的药物可控释放和对于巨噬细胞的抗炎症效果。
[Abstract]:Stimuli responsive polymer to outside stimulation intelligent response, physicochemical and properties of reversible or irreversible (or) chemical structure changes, which caused the collapse of the body assembly of swelling and shrinkage, dissociation and aggregation, crosslinking and crosslinking and morphology transition. In addition, compared with normal tissues and organs, cells of diseased organs, tissues and cell physiological parameters will change; to develop selective transmission responsive polymer assembly can achieve treatment and imaging agents using these specific physiological changes. This paper focuses on the tumor and inflammatory microenvironment responsive polymer assembly, especially redox response design polymer vesicles and micelles, nanoparticles structure and multi functional architecture and integration. Specifically, the work of this paper includes the following three aspects: 1. a lot of physiological and pathological. The process of reactive oxygen species and oxidative stress are directly related, which provides an important biochemical basis of nanometer materials for the design of therapeutic and diagnostic function. By two amphiphilic polymer self-assembly prepared by oxidation responsive polymer micelles or vesicles have been studied extensively. However, in the previous oxidation response system study, reactive oxygen species including H2O2 will cause the polymer assembly micro structural damage. The oxidative polymer vesicles as an example, the micro structural damage will make vesicles coated with hydrophilic drugs and active molecules fast release, in certain circumstances, limiting the application of polymersomes as drug carrier and long-term in vivo nano reactor. In addition, the traditional polymer vesicles due to its double thick film, membrane permeability, and thus cannot be used as a drug carrier and nano reactor effectively. This , we designed and fabricated a multifunctional oxidation responsive polymer vesicles can be oxidized in the cell microenvironment after stimulation triggers cross-linking vesicle bilayers, and double membrane permeability increased, showed improvement in the quality of imaging capability enhancement and drug release properties. Through the self-assembly of hydrophobic blocks containing aryl boric acid ester protection with self degradation side group two amphiphilic block copolymers, preparation of polymer vesicles on the surface by a further modified polypeptide resulting in a mitochondrial targeting H2O2 responsive polymer vesicles. Endocytosis into cells, intracellular H2O2 trigger caused continuous amine the deprotection reaction, because the new primary amine produced by amidation reaction occurs in the bilayer hydrophobic, resulting in vesicle bilayer cross-linking and hydrophobic to hydrophilic synchronous transformation process. This process can be used for medicine Controlled release material, combination chemotherapy, and chemotherapy effect can be monitored by contrast-enhanced magnetic resonance imaging and fluorescence imaging capabilities, further build a fluorescent thiol containing biologically active molecules in the cytoplasm of the detection of producing nano reactor.2. developed different biochemical signal response with the diagnosis and treatment of functional nano medicine for drug peptides, proteins and reagents, imaging selectivity and spatial resolution transmission has been widely studied. The micro aerobic environment between the reduction potential of the redox gradient development response application of two amphiphilic block copolymer micelle nanoparticles in biomedicine have been extensively reported by reductive oxidation of the extracellular microenvironment and within the cell. In addition, many methods are used to further enhance the stability of the micelle, such as the use of chemical linkers are reversible Crosslinking, dissociation and drug release in advance to avoid undesirable. It is worth noting that, in all these cases, the fracture spacer will cause reversible crosslinking and unstable micelle nanoparticles, leading to micellar nanoparticles in the target location quickly cleared and reduce the concentration effect. Therefore, the materials for the designers. The new development strategy to achieve the selective response of tumor microenvironment and cell, more important is how to enhance the in vivo localization of target position is still the major challenge and enrichment of diagnosis and treatment of functional polymeric micelles. Especially, for most of the two disulfide polymer micelle nanoparticles reversibly crosslinked, two disulfide cross-linking solution only leads to fracture no significant change of hydrophobic to hydrophilic, hindered the coating material completely effective release. Here, we designed and synthesized redox responsive nuclear inbred lines The micellar nanoparticles, it has a long half-life of blood circulation, reducing intracellular crosslinking mode conversion trigger microenvironment and the micelles from hydrophobic to hydrophilic transformation and enhanced diagnostic imaging and drug release properties. The hydrophobic block contains two disulfide bonds with self degradation properties of two amphiphilic copolymers of the self-assembled micelles, and surface modification of integrin targeting peptide, finally by UV induced two disulfide exchange reaction was crosslinked to obtain two disulfide cross-linking reducing tumor cell targeting micro environment response (DCL) micelles. Enter cells via endocytosis mediated by integrin cytoplasmic. The reduction of micro environment triggered cascade within the micelle core elimination reaction to produce primary amines; amines generated further amidation reaction occurs in the micelle core hydrophobic, and cause the conversion of micelle crosslinking method The nuclear changes to happen at the same time. The hydrophilic hydrophobic chemical treatment of.3. cells of the immune system main function of the process can be further used to achieve fluorescence and magnetic resonance imaging guidance is to protect the body from infection. But when they are not properly activated, will cause a lot of inflammation, such as rheumatoid arthritis, atherosclerosis and diabetic complications in the development. These disease processes, including macrophages, immune cells to produce cytokines, such as interleukin (IL-6 and IL-1), tumor necrosis factor alpha (TNF- alpha), digestive enzyme (collagenase), prostaglandin and reactive oxygen species, these cytokines can aggravate the accelerated the destruction of normal tissue. The non steroid the body of anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain, fever and inflammation. However, long-term use of non steroidal anti-inflammatory drugs will produce some side effects, patients Such as gastrointestinal injury and increased risk of stroke, thus limiting their use of other suitable symptoms. Here, we designed and synthesized the inflammatory tissue oxidizing and reducing related micro environment response of poly prodrugs of two amphiphilic molecules, the hydrophobic block containing indomethacin prodrug, further through self-assembly process preparation of polymer capsule anti-inflammatory bubble. On this basis, the evaluation of polymer vesicle system of oxidation and reduction of controlled drug release and the microenvironment triggers macrophage anti-inflammatory effect.

【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O631.1;TB383.1
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本文编号：1410373