水滑石插层材料在生物成像和癌症治疗领域的研究

发布时间：2018-08-27 06:07

【摘要】：水滑石(LDHs)作为一类典型的二维层状材料,由于其具有层板元素可调性、层间阴离子可交换性、层板可剥层等特点,近年来被广泛应用于药物缓释、基因运输以及生物成像等领域,成为生物医学材料研究极具发展潜力的药物载体之一。本论文以LDHs为主体,通过改变LDHs主体层板元素、调控主客体之间的相互作用,制备了一系列新型生物医学诊疗材料。采用实验方法与理论计算相结合的手段,深入探索与揭示了此类功能材料的结构与性能之间的构效关系,实现了生物成像和肿瘤治疗一体化的LDHs基复合材料的可控制备及性能调控；并且进一步研究了此类层状材料的协同效应及性能强化的关键科学问题。本论文具体的研究内容如下：1.LDHs插层材料在荧光成像与化学治疗方面的研究采用插层组装方法,将抗癌药物阿霉素(DOX)和靶向分子叶酸(FA)共同插层到LDHs层间,制备得到超分子层状材料DOX-FA/LDHs。XRD、IR证明客体分子DOX与FA共存于LDHs层间；该材料呈现规则的片状形貌,颗粒尺寸为～171 nm。采用癌症细胞HepG2以及正常肝细胞L02进行体外实验,实验结果显示DOX-FA/LDHs复合物具有良好的荧光成像性质,并且具有较高的细胞摄取量。由于HepG2细胞具有过度表达的FA受体,因此DOX-FA/LDHs对HepG2细胞显示了靶向识别能力,而对正常细胞不响应。DOX-FA/LDHs对癌细胞HepG2具有很强的抑制作用(IC50=7.14 μg/mL),而对正常细胞L02的细胞毒性较小(IC50=22.81 μg/mL),表现了良好的生物相容性和较高的药效。2. LDHs插层材料在双模成像与化学治疗方面的研究采用共插层的方法将抗癌药物DOX与叶酸靶向分子FA共同插层到了Gd3+掺杂的LDHs层间,然后在层板上通过化学吸附负载FITC荧光探针,成功制备了FITC/FA-DOX/Gd-LDHs层状材料。该材料表现出均一的形貌、良好的稳定性,颗粒尺寸为～178 nm。此外,层板掺杂的Gd3+元素以及层板吸附的FITC分子,使得复合材料同时具备优异的荧光成像与核磁共振成像的性质；该材料的弛豫效率(r1=6.23 mM-1s-1),高于目前商用临床造影剂的弛豫效率(r1=4.1 mM-1s-1),具有潜在的应用前景。体外实验证明FITC/FA-DOX/Gd-LDHs样品具有良好的细胞成像效果以及显著提高的靶向摄取能力,对癌细胞KB产生很强的抑制作用。3. LDHs插层材料在双模成像与光热光动力协同治疗方面的研究采用共插层方法将光敏剂酞菁锌(ZnPc)、光热试剂吲哚菁绿(ICG)与叶酸FA共插层进入Gd3+掺杂的LDHs层间,成功制备了ZnPc-ICG-FA/Gd-LDHs层状复合材料,实现了双模成像与靶向协同治疗。制备的复合材料ZnPc-ICG-FA/Gd-LDHs不仅具有优异的荧光成像能力,其层板掺杂的Gd3+元素具有核磁成像能力,因此实现了双模成像。该复合材料的弛豫效率(r1=9.13 mM-1s-1)显著高于临床成像剂的弛豫效率(r1=4.1mM-1s-1),具有潜在的应用价值。更为重要的是,基于上转换能量机理,在近红外光(808 nm)的照射下,ICG被激发后将光能转化为热能,起到了光热治疗的效果；ICG被激发后产生的能量部分传递给ZnPc,造成ZnPc的间接激发和产生单线态氧’02,达到了光动力治疗的效果,因此实现了协同治疗。综上所述,本论文通过插层组装方法构筑了基于LDHs的新型层状材料,在生物成像与癌症治疗一体化研究领域具有潜在的应用价值。
[Abstract]:Hydrotalcite (LDHs), as a typical two-dimensional layered material, has been widely used in the fields of drug release, gene transport and bioimaging in recent years because of its adjustable elements, anion exchange between layers and strippable layers. LDHs have become one of the most promising drug carriers in the research of biomedical materials. In this paper, a series of new biomedical diagnostic materials were prepared by changing LDHs'main lamellar elements and regulating the interaction between host and guest. The structure-activity relationship between the structure and properties of these functional materials was explored and revealed by means of combining experimental method with theoretical calculation. Controllable preparation and performance regulation of LDHs-based composites integrated with tumor therapy were studied. The synergistic effects and key scientific problems of performance enhancement of these layered materials were further studied. The specific research contents of this paper are as follows: 1. LDHs-based intercalated materials used intercalation assembly method in fluorescence imaging and chemotherapy research. Supramolecular layered material DOX-FA/LDHs.XRD was prepared by intercalating doxorubicin (DOX) and folic acid (FA) into LDHs layers. IR showed that DOX and FA coexisted in LDHs layers. The material exhibited regular patchy morphology with particle size ranging from 171 nm. HepG2 cells and L02 cells were used as carriers. In vitro experiments, the results showed that DOX-FA/LDHs complex had good fluorescence imaging properties and high cell uptake. Owing to the over-expression of FA receptors in HepG2 cells, DOX-FA/LDHs showed target recognition ability to HepG2 cells, but did not respond to normal cells. Fabrication (IC50 = 7.14 ug/mL), but less cytotoxic to normal L02 cells (IC50 = 22.81 ug/mL), showing good biocompatibility and high efficacy. 2. LDHs intercalation materials in bimodal imaging and chemotherapy research using co-intercalation method DOX and folic acid targeted molecule FA intercalation to Gd3 + doping. FITC/FA-DOX/Gd-LDHs layered materials were successfully prepared by chemisorption-loaded FITC fluorescent probes between the layers of LDHs. The materials exhibited homogeneous morphology, good stability and particle size ranging from 178 nm. In addition, Gd3+ elements doped by the laminates and FITC molecules adsorbed by the laminates made the composites possess excellent properties at the same time. The relaxation efficiency of this material (r1 = 6.23 mM-1s-1) is higher than that of commercial clinical contrast media (r1 = 4.1 mM-1s-1) and has potential application prospect. LDHs intercalation materials were intercalated with zinc phthalocyanine (ZnPc), indocyanine green (ICG) and folic acid FA into the interlayer of Gd3 + doped LDHs by co-intercalation method. ZnPc-ICG-FA/Gd-LDHs laminated composite was successfully prepared. The composite material ZnPc-ICG-FA/Gd-LDHs not only has excellent fluorescence imaging ability, but also has the ability of NMR imaging with the doped Gd3+ elements in the laminate, thus achieving dual-mode imaging. The relaxation efficiency of the composite material (r1 = 9.13 mM-1s-1) is significantly higher than that of the clinical imaging agent (r 1 = 9.13 mM-1s-1). 1 = 4.1mM-1s-1), which has potential application value. More importantly, based on the upconversion energy mechanism, ICG is excited to convert the light energy into heat energy under near-infrared (808 nm) irradiation, which has the effect of photothermal therapy; the energy generated by the excitation of ICG is partly transferred to ZnPc, resulting in the indirect excitation of ZnPc and the production of singlet oxygen'02'. In summary, a novel layered material based on LDHs was constructed by intercalation assembly method, which has potential application value in the field of integration of bioimaging and cancer therapy.
【学位授予单位】：北京化工大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R318.08

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