兰州大学机构库 >化学化工学院
刺激响应型稀土基智能纳米诊疗探针的合成与应用研究
Alternative TitleThe Synthesis and Application of Stimuli-Responsive Intelligent Diagnosis and Treatments Nanoprobes based on Rare Earth
张彤
Subtype博士
Thesis Advisor唐瑜
2023-05-30
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name理学博士
Degree Discipline化学
Keyword稀土纳米探针 Rare earth nanoprobes 诊疗一体化 integrated diagnosis and treatment 荧光成像 fluorescence imaging 光疗 phototherapy 声动力治疗 sonodynamic therapy
Abstract

每年有数百万人饱受癌症的折磨而死亡,因此精准高效的癌症诊疗对人类健康和发展具有重要意义。成像作为一种可视化手段,对于癌症的早期诊断和治疗具有重要的作用。单一的治疗手段很难取得理想的治疗效果,如光热治疗效果往往受到光功率不足或者过热效应的限制,而基于活性氧的治疗方式,如光动力治疗,声动力治疗,化学动力学治疗方法,其治疗效果受到肿瘤微环境如乏氧,高谷胱甘肽分泌等的严重限制。设计对肿瘤微环境进行响应的智能纳米材料,能够改善肿瘤微环境,并且通过结合外源刺激如光照,超声等实现多种治疗方式的联合应用,增强疾病诊疗效果。刺激响应型纳米材料的设计构筑为成像指导下的联合治疗纳米平台的设计提供了新思路。

稀土基纳米材料由于具有稀土元素固有的发光优势,类酶催化等性质且能方便的与其它材料进行结合,近些年来在生物医学方面有较为广泛的应用。本论文的研究内容为刺激响应型稀土纳米探针的设计构筑及其在癌症诊治方面的应用探索。本文的研究重点如下:

1.癌症监测和精确治疗对于减少其治疗的副作用具有重要意义。我们制备了核壳材料金纳米棒@铽金属有机框架(AuNRs@Tb-MOF),并通过后配位双光子配体TMP-DPA及负载化疗药物DOX构筑了智能纳米探针A@M-T@DOX,该探针在近红外光照射下具有高效的光热转换能力和药物释放效率,可用于实时荧光成像引导的多模式治疗。纳米探针不仅可以实现显著的光热治疗和可控药物释放,而且作为荧光温度计,有望通过不同温度下铽的光致发光强度和寿命变化来实现温度的实时反馈。同时,双光子配体设计显著提高了纳米探针的组织穿透能力。该工作有望为肿瘤的精确治疗和实时监测提供参考,同时为制定个性化治疗方案提供新思路。

2.基于活性氧的癌症治疗方式往往受到肿瘤微环境的限制,通过类酶催化可调节肿瘤微环境,进而联合多种治疗方式可以提升其治疗效果。在该工作中我们构筑了一个混合价Ce-MOF/Au@ICG(CeMAI)的纳米材料,并将其用于肿瘤微环境响应的级联催化提升的光动力,光热及化学动力学联合治疗。在该纳米材料中,混合价Ce-MOF可以催化内源性过氧化氢产生氧气以缓解肿瘤乏氧,在负载ICG的同时提升ICG的PDT活性,而且它还可以作为类芬顿试剂产生•OH进一步增加ROS产量。Au NPs可以催化葡萄糖产生H2O2,Ce-MOF实现级联催化产生羟基自由基。Ce-MOF负载的ICG还具有优异的光热治疗效果,从而使Ce-MOF/Au@ICG纳米材料最终具有优异的“三合一”功能,达到诱导肿瘤细胞凋亡的效果。本章工作通过合理设计具有多酶活性的无机纳米酶Ce-MOF材料,实现了高疗效和出色的生物安全性,为多合一功能化纳米催化肿瘤治疗材料的设计构筑提供了新的思路。

3.声动力治疗是一种新型且有效的癌症治疗方式,探索更多的无机声敏剂对发展新型纳米精准诊疗药物具有重要的意义。我们成功地构筑了一系列不同锰含量的CeOx@MnOx异质结(CM-1~CM-4),首次研究了该异质结的形成对CeOx声敏活性提升的效果及机制。我们研究发现这种异质结构通过降低半导体带隙,减少电子和空穴的复合从而大大提升了CeOx的声敏活性,可将其用于声动力治疗。其中CM-3具有最小的带隙,从而具有最优异的声动力活性。此外,CM-3还具有化学动力学活性,可以催化H2O2产生羟基自由基和氧气,缓解肿瘤乏氧,从而增强声动力活性以及消耗GSH,实现了肿瘤抑制效率的提升。这项工作提供了一种独特的CeOx异质结半导体纳米结构的设计范例,用于改进基于CeOx的超声纳米治疗并实现高效肿瘤治疗,进一步扩展了CeOx在疾病治疗方面的应用。

4.探索更多的高效声敏剂对声动力治疗具有重要的意义。我们开发了一个pH/GSH双响应的Cu-LDH/Nd-CD异质结用于提升肿瘤声动力治疗效果。Cu-LDH在pH/GSH双刺激作用下产生缺陷,降低了Cu-LDH的能带带隙,使其具有了良好的SDT活性。Cu-LDH/Nd-CD异质结的构筑进一步降低了材料的带隙,提升了SDT活性,且Nd-CD的引入使Cu-LDH/Nd-CD异质具有红光及近红外二区荧光发射,有望使其实现近红外二区成像指导下的癌症声动力治疗。这项工作构筑了Cu-LDH/Nd-CD异质结并研究了其在pH/GSH双刺激下的带隙变化及SDT活性,为构筑具有增强声敏活性的纳米治疗材料提供了一种新的策略。

Other Abstract

Millions of people suffer from cancer and die every year, so accurate and efficient diagnosis and treatment of cancer are really significant for human health and development. As a visualized method, imaging plays an important role in the early diagnosis and guided treatment of cancer. It is difficult to achieve the ideal therapeutic effect with a single treatment method. For example, the effect of photothermal therapy is limited by insufficient light power or overheating effect, while the therapeutic effect of ROS-based treatment methods, such as photodynamic therapy, sonodynamic therapy, chemodynamic therapy, severely limited by the tumor microenvironment such as hypoxia, high GSH, etc. Designing smart nanomaterials that can respond to the intrinsic stimuli of the tumor microenvironment, and further change the tumor microenvironment and then combining with external stimuli, such as light, ultrasound, etc, which can achieve a combination of multiple treatment methods and enhance the therapeutic effect. The design and construction of stimuli-responsive nanomaterials provides a new idea for the design of synergistic therapeutic nanoplatforms with guiding of imaging.

Rare earth-based nanomaterials have been extensively studied in biomedical applications in recent years, due to their inherent advantages of luminescence, enzyme-like catalytic properties and the ability to be easily combined with other materials. Therefore, in this thesis, we are mainly devoted to the design and construction of stimuli-responsive rare earth nanomaterials and to study their application in cancer diagnosis and treatment. The research provides a new idea for the design and construction of stimuli-responsive nanoprobes based on rare earth, which can be applied in cancer diagnosis and treatment. The research content of this paper is as follows:

1. Real-time monitoring and accurate treatments are of great significance for reducing the side effects during the cancer therapy. Gold nanorods hybridized with terbium metal-organic framework (AuNRs@Tb-MOF) was prepared as core-shell materials, and smart nanoprobes, i.e., A@M-T@DOX, were constructed by postsynthetical functionalization of TMP-DPA and encapsulation of DOX. This material had highly effective photothermal conversion capacity and drug release efficiency under near-infrared light irradiation for real-time fluorescence imaging-guided multimodal therapy. The nanoprobe could achieve prominent photothermal therapy and controllable drug release, acting as a fluorescence thermometer. Thus, the real-time feedback of temperature was also expected to be achieved. At the same time, the design of two-photon ligand significantly improved the tissue penetration. This work is expected to provide a reference for precise treatment and real-time monitoring of tumors and new ideas for the formulation of individualized treatment plans.

2. Reactive oxygen species (ROS)-based cancer treatments are limited by the sophisticated tumor microenvironment, so it is of great significance to adjust the tumor microenvironment through enzyme-like catalysis and combine multiple treatment methods to improve its therapeutic effect. We constructed a nanomaterial, i.e., mixed valence Ce-MOF/Au@ICG (CeMAI), which could be used for combined photodynamic, photothermal and chemokinetic therapy with cascade catalytic enhancement in response to the tumor microenvironment. In this nanomaterial, the mixed valence Ce-MOF coukd catalyze endogenous hydrogen peroxide to generate oxygen to alleviate tumor hypoxia and increase PDT activity of ICG after loading. Then it could be used as a Fenton-like reagent to generate •OH and further increase ROS output. Au NPs could catalyze the oxidation of glucose to generate H2O2, and realize a cascade catalytic function with Ce-MOF to generate hydroxyl radicals. Moreover, the Ce-MOF-loaded ICG also had excellent photothermal therapy effect, so that the Ce-MOF/Au@ICG nanomaterial finally had a "three-in-one" excellent effect of inducing tumor cell apoptosis. This work paves the way for nanocatalytic tumor therapy by rationally designing an inorganic nanozyme Ce-MOF system with multienzyme activities while achieving high efficacy and excellent biosafety.

3. Sonodynamic therapy is a newly-developed and effective method for treatment of cancer. It is of great significance for development of precisely tailored theranostics based on nanomaterials to explore more inorganic sonosensitizers. A series of CeOx@MnOx heterojunctions (CM-1~CM-4), with different manganese content, had been successfully designed and synthesized. In addition, the effect and mechanism of sonodynamic activity enhancement resulted by heterojunction construction of CeOx had been studied for the first time. Our research found that the construction of this heterostructure could greatly improve the sonodynamic activity of CeOx by reducing the semiconductor band gap and reducing the recombination of electrons and holes. Thus the material could be used as sonodynamic therapy. Therein, CM-3 exhibited the most excellent sonodynamic activity due to its smallest band gap. In addition, CM-3 also had chemodynamic activity which could catalyze H2O2 to generate •OH and oxygen to alleviate tumor hypoxia, further enhancing sonodynamic activity and GSH consumption, ultimately achieving high tumor suppression efficiency. This work provides a unique design paradigm to construct CeOx-related heterojunction semiconductor nanostructures, which can improve effect of ultrasound-based nanotherapy and achieve high tumor therapeutic efficacy. Thereby further extendation for the application of CeOx in therapies for disease can also be realized.

4. It is of great significance to explore more efficient sonosensitizers for sonodynamic therapy. In this work, we developed a pH/GSH dual-responsive Cu-LDH/Nd-CD heterojunction to enhance the therapeutic effect. Cu-LDH produced defects under the double stimulation of pH/GSH, which reduced the energy band gap of Cu-LDH, so that it exhibited good SDT activity. The construction of Cu-LDH/Nd-CD heterostructure further reduced the band gap of the material and improved the SDT activity. Morover, the introduction of Nd-CD maked the Cu-LDH/Nd-CD heterogeneous have red light and NIR II fluorescence emission, which was expected to achieve excellent cancer sonodynamic therapy under the guidance of NIR II imaging. In this work, a Cu-LDH/Nd-CD heterojunction has been constructed and its bandgap change and SDT activity under dual stimulation of pH/GSH has also been studied, which provides a new strategy for design of nanotheranostics with enhanced acoustic activity.

MOST Discipline Catalogue理学 - 化学 - 无机化学
URL查看原文
Language中文
Other Code262010_120190903820
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/536927
Collection化学化工学院
Affiliation
兰州大学化学化工学院
Recommended Citation
GB/T 7714
张彤. 刺激响应型稀土基智能纳米诊疗探针的合成与应用研究[D]. 兰州. 兰州大学,2023.
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