基于Cu₃BiS₃的多功能纳米材料在生物成像和光热治疗上的应用

【作者】 杨艳；

【导师】 吴惠霞；

【作者基本信息】 上海师范大学 ， 无机化学， 2015， 硕士

【摘要】 在全球范围内,癌症已经成为导致死亡的主要原因之一。现有的临床治疗手段,包括放射治疗、化疗(药物治疗)、激素治疗,免疫治疗等,经常会引起一些副作用。基于这些原因,发展新的治疗方法成为当务之急。光热治疗(PTT)是近年来发展起来的一种治疗癌症的新方法,具有较高的选择性和较小的侵害性。通过给予光热转换剂一定时间的近红外光照射,PTT治疗方法可以特异性的消融肿瘤组织,并且不会对周围正常组织产生明显伤害。本文主要以廉价易得的原材料,采用简单易操作的方法制备集诊断与治疗于一体的Cu3Bi S3三元硫属纳米材料,随后对其体外、体内毒性、CT成像效果和PTT效果进行了探讨。接着将Cu3Bi S3功能化,使其具有多模式的成像功能和PTT功能。全文共分四章。第一章首先介绍了一些含有较高原子序数的含金属元素的纳米材料作为CT造影剂在CT成像中的应用。随后介绍了无机纳米材料,主要包括不同结构的金纳米材料、碳纳米材料、钯纳米片、硫化铜纳米材料和其它新型纳米材料,作为光热剂在PTT中的应用。最后提出本文的研究设想。第二章首先探讨了在不同条件,主要包括溶剂体系、反应温度和时间对Cu3Bi S3粒径和形貌的影响,得到制备Cu3Bi S3的最优条件。随后将疏水性Cu3Bi S3纳米粒子的表面进行改性改善其水溶性,成为亲水性Cu3Bi S3/PVP纳米材料。采用MTT法测试其体外细胞毒性,发现该材料的毒性较小。接着,用Cu3Bi S3/PVP纳米材料进行了体内和体外光热实验。体外光热实验表明,Cu3Bi S3/PVP的光热效应可以将大部分He La细胞杀死,细胞存活率能将至20%左右;体内光热治疗效果也比较显著,通过尾静脉注射的材料能够有效地抑制肿瘤的生长。Bi元素的存在使Cu3Bi S3/PVP具有CT成像效果。与商用CT造影剂碘海醇相比,同等条件下,Cu3Bi S3/PVP具有增强的体外CT效果,并且体内CT效果也比较显著。因此,Cu3Bi S3/PVP集CT成像和光热治疗于一体,为癌症的治疗和诊断提供了一个新的平台。第三章主要是在第二章的基础上,将Cu3Bi S3进一步功能化。现在集多种成像模式和治疗手段为一体的纳米材料已经成为研究的热点,因此将具有CT成像和PTT功能的Cu3Bi S3三元硫属纳米粒子功能化后,使其同时具备CT成像、MRI成像和荧光成像的多模式成像功能。用带有双氨基的PEG使疏水性Cu3Bi S3转变成为亲水性Cu3Bi S3–PEG–NH2,接着利用裸露在外面的氨基先后共价连接FITC和Gd–DTPA。对所制备的Cu3Bi S3–PEG–(FITC&Gd–DTPA)最终材料进行了体外光热测试,并对体外荧光成像功能和MRI功能进行了初步探究。结果表明,Cu3Bi S3–PEG–(FITC&Gd–DTPA)是一种集多模式成像和PTT于一体的纳米材料,在生物医学领域具有良好应用前景。第四章对本文的重要结果进行了总结,并提出了无机纳米材料作为光热剂还面临的问题和应该着重研究的方向。更多还原

【Abstract】 Over the past decade, cancers have become one of the major causes of mortality in the world. Current clinical therapy methods, including radiation therapy, chemotherapy, hormone therapy and immunotherapy, are often associated with severe side effects. For this reason, there is an urgent need to develop new approaches for cancer treatment. Photothermal therapy(PTT), which emerges in recent years, is considered as a new technique for cancer treatment. PTT specifically ablates the tumor tissues without harming normal tissues. In this paper, Cu3 Bi S3 ternary chalcogenide nanomaterials, which combine diagnosis and therapy functions into one system, were synthesized by using cheap raw materials and simple synthesis method, then the toxicity in vitro and in vivo, CT imaging and PTT effects of the obtained nanomaterials were studied. Then Cu3 Bi S3 nanomaterials were functionalized for multi-mode imaging and PTT functions. The full text is divided into four chapters.In the first chapter, we first introduce some nanomaterials containing metal elements with high atomic number as CT contrast agents for CT imaging. And then the inorganic nanomaterials used as photothermal agents for PTT are summarized, including different structures of gold materials, carbon based nanomaterials, palladium nanosheets, copper sulfide nanomaterials and other new nanomaterials. Finally, the research ideas of this paper were proposed.In the second chapter, we first discuss the influence of different conditions on the size and morphology of the resulting Cu3 Bi S3 nanoparticles, mainly including solvent system, reaction temperature and time, and finally, the optimal conditions for preparing Cu3 Bi S3 were obtained. Then the surface of hydrophobic Cu3 Bi S3 nanoparticles was modified with polyvinyl pyrrolidone(PVP) to produce hydrophilic Cu3 Bi S3/PVP. The methyl thiazolyl tetrazolium(MTT) assay was performed to evaluate the toxicity of Cu3 Bi S3/PVP in vitro, making sure the toxicity of the material is low enough to be used for biological application. In vitro experiments showed that the majority of He La cells can be killed, with cell viability at around 20%. The effect of photothermal therapy in vivo is also remarkable, which indicate that the photothermal effect of Cu3 Bi S3/PVP can effectively inhibit tumor growth. Due to the existence of Bi elements, Cu3 Bi S3/PVP has enhanced X-ray computed tomography imaging(CT imaging) compared with iohexol, a commercial CT imaging contrast agent under the same conditions. Cu3 Bi S3/PVP also has notable CT imaging effect in vivo. Therefore, Cu3 Bi S3/PVP provides a potential platform for the treatment and diagnosis of cancer therapy.The third chapter is based on the second chapter. The Cu3 Bi S3 nanoparticles were further functionalized. Nowdays, nanoparticles having integrated imaging and therapy functions have become a research hotspot, so Cu3 Bi S3 nanoparticles were functionalized for CT imaging, fluorescence imaging and magnetic resonance imaging(MRI). Firstly, Hydrophilic Cu3 Bi S3-PEG-NH2 was obtained by ligand exchange using polyethylene glycol with two amino, then FITC and Gd-DTPA were conjugated through covalent interaction between amino and carboxyl. Preliminary experimental results of in vitro photothermal test, fluorescence imaging and MRI measurement reveal that Cu3 Bi S3-PEG-(FITC&Gd-DTPA) is a multi-functionalized nanomaterial of multi-mode imaging and PTT, having potential applications in biomedicine.Chapter IV mainly summerizes important results of this thesis, and then presents the remaining issues and future research directions of inorganic nanoparticles as photothermal agents.更多还原