聚合物修饰多功能纳米探针在医学成像和肿瘤治疗中的应用

发布时间：2018-05-10 12:10

  本文选题：纳米探针 + 分子成像　； 参考：《长春工业大学》2017年硕士论文

【摘要】：纳米材料在生物医学应用领域具有独特的优势,如可控合成、易于表面功能化修饰、长的体内循环时间、可以负载多功能物质于一身等,因此,纳米材料已广泛应用于生物成像、临床诊断和治疗等领域。本论文面向恶性肿瘤早期诊断的重大需求,从肿瘤的同时诊断和治疗角度出发,设计制备了两种新型的多功能纳米探针,探索了其在T1/T2-MR/CT多模式成像和成像介导的肿瘤光热治疗中的应用。研究内容为以下两部分:1、设计制备了封装Gd和Dy离子的牛血清白蛋白(BSA)纳米粒子,利用多巴胺的自聚合特性在粒子表面原位聚合生长聚多巴胺层(PDA),然后通过化学键将叶酸(FA)修饰到粒子表面,成功获得了具有肿瘤靶向性的诊疗探针BSA:Gd,Dy@PDA-FA。该探针的设计基于以下几点:稀土元素Gd具有顺磁性,Dy具有较强的X-射线吸收能力,可以作为MRI/CT成像探针的基质。聚多巴胺在近红外区有强的吸收,在808 nm激光器照射下能把光能转换成热能进行光热治疗。叶酸受体在肿瘤表面是过表达的,所以利用叶酸对叶酸受体的高度亲和性,可将探针靶向至肿瘤。研究结果表明,BSA:Gd,Dy@PDA-FA诊疗探针具有优异的稳定性,通过细胞毒性和组织切片分析证实此探针毒性相对较低。此探针水溶液在NIR激光照射5min后能升高温度到60℃,这种高的光热转换效率说明我们制备的探针能够进行肿瘤的光热治疗。经此探针培育后,肿瘤细胞在激光照射后存活率下降到8%。此外,BSA:Gd,Dy@PDA-FA诊疗探针具有较高的r1值(9.47mM-1 s-1)、r2值(18.42 mM-1 s-1)和X-射线吸收系数(51.8 HU g-1),可以进行T1/T2-MR/CT多模式成像。2、稀土氟化物纳米粒子由于具有良好的光稳定性、低的生物毒性、易于调控的粒子尺寸和形貌,通常被用作多模式成像探针的载体材料。我们通过热解法制备了超小的、粒径可控的Dy掺杂NaGd F_4纳米粒子,通过配体交换法将两亲性聚乙烯吡咯烷酮(PVP)修饰到粒子表面,获得了水溶性的T1/T2-MR/CT多模式成像探针PVP-NaGdF_4:Dy。从细胞、组织器官到整体生物水平上的系统研究证实了此成像探针具有良好的生物相容性。体内分布代谢研究显示此探针进入小鼠体内之后主要累积在肝和脾中,注射30天后基本能全部排出体外,避免了在体内的长期毒性。该成像探针的r1值(6.15mM-1 s-1)、r2值(13.82mM-1 s-1)和X-射线吸收能力(48.5HU g-1)明显高于临床上常用的成像探针Gd-DTPA和碘比醇。小鼠体内MR和CT成像结果表明此成像探针在肝和脾有明显的对比增强效果。重要的是,此成像探针实现了肿瘤成像。
[Abstract]:Nanomaterials have unique advantages in biomedical applications, such as controllable synthesis, easy surface functionalization, long internal circulation time, and the ability to load multifunctional substances in one body. Nanomaterials have been widely used in biological imaging, clinical diagnosis and treatment. In order to meet the great need of early diagnosis of malignant tumors, two novel multifunctional nanoprobes were designed and prepared from the point of view of simultaneous diagnosis and treatment of malignant tumors. Its application in T1/T2-MR/CT multi-mode imaging and imaging-mediated photothermal therapy was explored. The BSA nanoparticles encapsulated in Gd and Dy ions were designed and prepared in the following two parts: 1. The dopamine layer PDA-PDA-FAA was prepared by in-situ polymerization of dopamine on the surface of particles by self-polymerization of dopamine, and then modified to the surface of the particles by chemical bonds. A tumor targeting diagnostic probe, BSA: GdCy DyPDA-FA-FA-FA-FA-FA-PDA-FA-PDA-FA-Dy was successfully obtained. The design of the probe is based on the following points: the rare earth element Gd has the strong X- ray absorption ability of paramagnetic Dy and can be used as the substrate of the MRI/CT imaging probe. Poly (dopamine) has strong absorption in near infrared region and can convert light energy into heat energy for photothermal therapy under 808 nm laser irradiation. Folic acid receptor is overexpressed on the surface of tumor, so the high affinity of folic acid to folate receptor can target the tumor. The results showed that BSA: GdDy @ PDA-FA probe had excellent stability, and was proved to be relatively low by cytotoxicity and histological analysis. This probe solution can raise the temperature to 60 鈩，

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