聚合物杂化纳米载药系统的构建及在肿瘤诊疗中的应用

发布时间：2018-06-24 12:41

  本文选题：纳米诊疗剂 + 可降解聚合物纳米粒子　； 参考：《华中科技大学》2016年博士论文

【摘要】：近年来,纳米技术在生物医药领域的快速发展为肿瘤诊疗一体化带来了新机遇。新型纳米诊疗剂具有高灵敏成像能力和靶向治疗的特性,可实现癌症诊断和治疗效率最大化,并有效地克服传统治疗的毒副作用及耐药性等棘手问题。因此,设计和制备新型纳米诊疗剂逐渐成为肿瘤有效治疗的理想途径之一。而在一系列新型纳米诊疗剂中,多功能杂化纳米材料由于结合了有机纳米材料和无机纳米材料各自的特性,具有设计性强、治疗效率高和生物相容性好等显著优势,因此在肿瘤诊疗领域中具有良好的应用前景。然而,如何设计和制备简单高效的多功能杂化纳米载药系统作为纳米诊疗剂,仍然面临着诸多挑战。本论文分别设计和构建了三种新型多功能聚合物杂化纳米材料：尺寸均一、可控的可降解聚合物杂化纳米粒子、脂质体包覆的多功能金纳米笼和聚合物/金纳米粒子杂化组装体,并研究了这些新型多功能杂化纳米材料在肿瘤诊疗中的应用,为新型纳米诊疗剂的设计与制备提供了实验依据。本论文的主要研究内容如下：1.尺寸均一、可控的可降解聚合物杂化纳米粒子的构建及在肿瘤诊疗中的应用。分别采用手动膜挤出乳化法和自组织沉淀法成功地制备了尺寸均一的可降解聚合物纳米粒子。通过改变实验参数对纳米粒子的尺寸及其分布进行了有效的调控。量子点、磁性纳米粒子和抗肿瘤药物等能同时包覆在聚合物纳米粒子中,从而制备出多功能可降解杂化纳米粒子,实现了荧光成像、磁共振成像、磁场诱导定向聚集以及抗肿瘤治疗。负载抗肿瘤药物的纳米粒子具有较高的药物包封率和负载量、优良的药物缓释性能以及比裸药更强的肿瘤细胞杀伤能力。另外,与乳化法制备的纳米粒子相比,经自组织沉淀法制备的无表面活性剂包覆的聚合物纳米粒子具有更高的细胞吞噬率和更好的生物相容性。本研究提供了简单、快速地制备尺寸均一可降解聚合物载药纳米粒子的方法,为纳米诊疗剂的制备提供了一定的实验依据。2.脂质体包覆的多功能金纳米笼的构建及在肿瘤诊疗中的应用。采用多元醇还原法和电流置换法制备了中空多孔的金纳米笼。将脂质体包覆在金纳米笼的表面,不仅有效地增加了金纳米笼的生物相容性、防止药物泄露,还能将靶向树突状细胞的抗体通过化学键连接在脂质体表面,或将磷脂类免疫佐剂嵌入脂质体层中,有效地增强了免疫刺激响应。还通过溶剂扩散和真空干燥法有效地将免疫抗原多肽和近红外光敏剂负载到金纳米笼内腔或脂质体层中。这类多功能杂化金纳米笼集药物载体、热疗剂和荧光成像剂为一体,实现了荧光成像介导的光热/免疫联合治疗或光热/光动力/免疫多重联合治疗,可望在肿瘤诊疗中发挥重要作用。3.聚合物/金纳米粒子杂化组装体的构建及在肿瘤诊疗中的应用。分别采用超分子诱导和二维受限自组装的方法构建了棒状的聚合物/金纳米粒子杂化组装体。提出了通过改变金纳米粒子表面化学性质来准确调控金纳米粒子在棒状聚合物胶束中分布的途径；研究了金纳米粒子的体积分数、尺寸和超分子微区尺寸等因素对金纳米粒子空间分布和杂化胶束形貌的影响。此外,基于聚合物修饰的金纳米粒子在二维纳米孔道中受限组装,制备出了在本体中难以得到的、具有新颖有序结构的棒状杂化组装体。受限效应对金纳米粒子的粒间距、组装体的结构及其光学性能起到了主要调节作用,使组装体具有良好的细胞暗场成像能力和光热转换性能。本研究为功能性复合材料的设计和制备提供了实验依据,在肿瘤诊疗剂的制备和应用中有重要的潜在应用价值。以上工作提供了三种多功能杂化纳米载药系统的制备方法,并初步研究了它们在肿瘤诊疗中的应用,为高效纳米诊疗剂的设计与制备提供了一定的实验依据和技术支撑。
[Abstract]:In recent years, the rapid development of nanotechnology in the field of biological medicine has brought new opportunities for the integration of tumor diagnosis and treatment. The new nano diagnostic and therapeutic agents have high sensitivity imaging ability and target treatment characteristics, can realize the cancer diagnosis and treatment efficiency maximization, and effectively overcome the traditional treatment and drug resistance and drug resistance and other thorny problems. The design and preparation of new nano diagnostic and therapeutic agents have gradually become one of the ideal approaches for effective treatment of tumors. In a series of new nano diagnostic and therapeutic agents, multi-functional hybrid nanomaterials have strong design, high therapeutic efficiency and good biocompatibility because of their respective characteristics of organic nanomaterials and inorganic nanomaterials. Therefore, how to design and prepare a simple and efficient multifunction hybrid nano drug delivery system is still facing many challenges. Three new multi-functional polymer hybrid nanomaterials are designed and constructed in this paper: the size homogenization and controllable biodegradability Polymer hybrid nanoparticles, multi-functional gold nanometers coated with liposomes and polymer / gold nanoparticles hybrid assembly, and the application of these new multifunctional hybrid nanomaterials in the diagnosis and treatment of tumor, which provide experimental basis for the design and preparation of new nano diagnostic and therapeutic agents. The main contents of this paper are as follows: 1. feet The construction of a homogeneous and controllable biodegradable polymer hybrid nanoparticle and its application in the diagnosis and treatment of tumor. The size homogeneous biodegradable polymer nanoparticles were successfully prepared by manual membrane extrusion emulsification and self organizing precipitation. The size and distribution of the nanoparticles were effectively adjusted by changing the experimental parameters. Control. Quantum dots, magnetic nanoparticles and antitumor drugs can be encapsulated in the polymer nanoparticles at the same time, thus preparing multi-functional and biodegradable hybrid nanoparticles, realizing fluorescence imaging, magnetic resonance imaging, magnetic field induced orientation aggregation and antitumor therapy. Nanoparticles with anti swelling drugs have high drug encapsulation efficiency. In addition, the polymer nanoparticles, prepared by the self-organized precipitation method, have higher cell phagocytosis rate and better biocompatibility compared with the nanoparticles prepared by the emulsification method. This study provides a simple study. The method of preparing the homogeneous biodegradable polymer carrier nanoparticles is quickly prepared, which provides a certain experimental basis for the preparation of multi-functional gold nanoscale coated with.2. liposome and its application in the diagnosis and treatment of the tumor. The plastids coated on the surface of the gold nanoscale not only effectively increase the biocompatibility of the gold nanoscale, prevent the drug leakage, but also connect the antibody against the dendritic cells to the liposome surface through the chemical bonds, or the phospholipid immune adjuvant is embedded in the liposome layer, effectively enhancing the response of the immune stimulation. The immune antigen peptides and near infrared photosensitizers are effectively loaded into the inner cavity of the gold nanoscale or the liposome layer by the vacuum drying method. This kind of multifunctional hybrid gold nanoscale integrates the drug carrier, the thermotherapy agent and the fluorescent imager as a whole, and realizes the combined treatment of photothermal / immuno immunization mediated by fluorescence imaging, or the multiple combined treatment of photothermal / photodynamic / immunity. Therapy, which is expected to play an important role in the diagnosis and treatment of tumor, the construction of.3. polymer / gold nanoparticle hybrid assembly and its application in the diagnosis and treatment of tumor. The polymer / gold nanoparticle hybrid assembly has been constructed by using supramolecular induction and two-dimensional limited self assembly. The chemical properties of gold nanoparticles are proposed by changing the surface chemistry of gold nanoparticles. The distribution of gold nanoparticles in rod polymer micelles is accurately regulated and the influence of the volume fraction of gold nanoparticles, size and size of supramolecular microsphere on the spatial distribution of gold nanoparticles and the morphology of hybrid micelles are studied. In addition, the limited group of gold nanoparticles based on polymer modification in the two-dimensional nanopore channel. It has prepared a rod like hybrid assembly with novel and ordered structure which is difficult to obtain in the body. The limited effect has the main regulating effect on the particle space of gold nanoparticles, the structure of the assembly and the optical properties of the assembly, which makes the assembly have good imaging ability and photothermal conversion performance. This study is functional complex. The design and preparation of the composite materials provide an experimental basis and have an important potential application value in the preparation and application of the tumor diagnosis and treatment agents. The above work provides the preparation methods of three kinds of multi-functional hybrid nano drug delivery systems, and preliminary studies their application in the diagnosis and treatment of tumor, and provides the design and preparation of the efficient nano diagnosis and treatment agents. Certain experimental basis and technical support.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：TB383.1;R943;R730.4
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本文编号：2061560