兰州大学机构库 >化学化工学院
基于金属-卟啉客体柱[5]芳烃手性囊泡的构建及在协同治疗肿瘤和降低肿瘤顺铂耐药性中的研究
Alternative TitleConstruction of pillar[5]arene-based chiral vesicles with metal-porphyrin guests for synergistic treatment of tumors and reduction of tumor cisplatin resistance
张泽帆
Subtype硕士
Thesis Advisor汪宝堆
2023-05-31
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name理学硕士
Degree Discipline化学
Keyword手性囊泡 Chiral vesicles, 柱芳烃 Pillar[5]aren 协同治疗 synergistic treatment 手性葡萄糖 Chiral glucose
Abstract

作为威胁人类生命最主要的疾病之一,恶性肿瘤的诊断与治疗一直是科学家关注的重要问题。化疗作为最常用的一线治疗方法,其治疗效果常受限于水溶性差,靶向能力低和稳定性有限等因素。此外,化疗药物的毒副作用和肿瘤耐药性也会限制治疗的效果。

针对传统药物治疗的固有缺陷,利用肿瘤具有的特殊微环境,科学家们又研究出多种治疗方法,如光动力疗法(PDT)、化学动力疗法(CDT)和声动力疗法。四苯基卟啉(TPP)及其衍生物是一种常见的光敏剂,在具有显著的近红外PDT效率的同时,内部空腔可携带不同金属元素,从而达到协同治疗的效果。只可惜TPP的靶向能力限制了它进一步的发展和应用。

柱芳烃作为一种新兴的超分子大环,已被广泛的研究和应用于肿瘤治疗领域。其中羧基化柱[5]芳烃具有良好的主客体识别性能和较高的合成效率,易与客体识别后自组装为囊泡,从而作为一种良好的药物递送载体。但这种囊泡对肿瘤细胞只具备酸响应性能,如何使得这种囊泡具有更强的生物膜响应特征并同时增强对肿瘤的靶向能力成为了我们研究的重点之一。

基于PDT治疗、CDT治疗和传统药物治疗以及水溶性柱[5]芳烃药物递送体系的研究,本文主要研究工作分为以下三个部分:

①手性葡萄糖修饰的柱[5]芳烃与烷基Fe卟啉衍生物的主客体识别作用及其自组装手性囊泡的构建

利用柱芳烃易修饰的特性,可以构建出多种环境刺激响应的主客体络合物。羧基化柱[5]芳烃具有良好的酸响应性能,在经过D-/L-葡萄糖修饰后可形成手性柱芳烃(DCP5/LCP5)。通过对四苯基卟啉(TPP)进行烷基长链的修饰(FeTPPNHC),使得TPP对手性柱[5]芳烃具有了主客体识别作用,随后通过核磁验证了其相互作用方式,用紫外滴定和荧光滴定分别验证客体为FeTPPNHC而主体为手性柱芳烃。在用job’s滴定确定最佳主客体识别比例后,用芘荧光探针确定临界胶束浓度。最后,在大于临界胶束浓度的情况下,用透射电子显微表征了LOX@LCP5⊃FeTPPNHC囊泡的形态,证实了这种囊泡的成功构建并进一步对药物包封率和酸响应性能进行了探究。

②LOX@LCP5⊃FeTPPNHC在靶向递送LOX和协同治疗肿瘤并抑制肿瘤转移中的应用

由于肿瘤微环境具有乳酸堆积、H2O2和GSH增多等特点,PDT和CDT治疗受到了极大的动力学限制。乳酸氧化酶(LOX)具有消耗乳酸进而抑制肿瘤转移的作用。Fe3+不仅具备在细胞质中催化H2O2产氧进而促进PDT的性能,还能消耗GSH得到Fe2+进而增强CDT性能。基于上一章所构建的用于递送LOX的手性囊泡(LOX@LCP5⊃FeTPPNHC),我们分别验证了超分子消耗GSH的能力、催化H2O2产O2的能力和超分子囊泡催化乳酸产H2O2的能力,最后通过探针表征了光动力性能和化学动力性能。在生物实验中,我们首次验证了L型葡萄糖修饰后的柱[5]芳烃所形成的囊泡以手性识别的方式靶向肿瘤组织,并在细胞实验和活体实验中得到了印证。

③DDP@LCP5⊃CuTPPBr的构建及在降低肿瘤顺铂耐药性中的应用

肿瘤细胞和正常细胞一样,会受到在肿瘤产生、增殖、转移和免疫应激过程中形成的肿瘤微环境的应激,在不断给药的过程中逐渐产生耐药性。顺铂(DDP)是一种常见的无机化疗药物,因其具有的药物副作用和在治疗过程中产生的耐药性,其应用受到了限制。科学家们研究发现谷胱甘肽(GSH)的增多直接影响着其耐药性的产生。我们以上述的方式,合成了一种卤代烷基卟啉作客体,协助运输Cu离子并通过化学动力的方式协同消耗GSH,达到降低肿瘤顺铂耐药性的效果。

Other Abstract

As one of the most important diseases threatening human life, the diagnosis and treatment of malignant tumors has always been an important issue for scientists. As the most commonly used first-line treatment, the therapeutic effect of chemotherapy is often limited by factors such as poor water solubility, low targeting ability, and limited stability. In addition, the toxic side effects of chemotherapy drugs and tumor resistance can also limit the effectiveness of treatment..

In view of the inherent defects of traditional drug treatment, scientists have developed a variety of treatments such as photodynamic therapy (PDT), chemodynamic therapy (CDT) and sonodynamic therapy by using the special microenvironment of tumors. Tetraphenylporphyrin (TPP) and its derivatives are a common photosensitizer(FeTPPNHC), which has significant near-infrared PDT efficiency while the internal cavity can carry different metal elements, so as to achieve the effect of synergistic treatment. Unfortunately, the targeting ability of TPP limits its further development and application..

As an emerging supramolecular macrocycle, pillar[n]arenes have been widely studied and applied in the therapy of tumor. Carboxylated pillar[5]arene has good host-guest recognition performance and high synthesis efficiency which is easy to self-assemble into vesicles after guest identification, thus serving as a good drug delivery vehicle. However, this vesicle only has acid response to tumor cells, and how to make this vesicle have stronger biofilm response characteristics and enhance the ability to target tumors has become one of the focuses of our research.

Based on the research of PDT, CDT and traditional drug treatment, as well as water-soluble pillar[5]arene drug delivery system, the main research work in this paper is divided into the following three parts:

(1) Host-guest recognition of chiral glucose-modified pillar[5]arene and alkyl-Fe porphyrin derivatives and their construction of self-assembled chiral vesicles

Taking advantage of the easy modification of column aromatic hydrocarbons, a variety of host-guest complexes in response to environmental stimuli can be constructed. Carboxylated pillar[n]arenes have good acid-response performance, and chiral pillar[n]arenes can be formed after D/L-glucose modification. By modifying the alkyl long chain of tetraphenylporphyrin (TPP), TPP had the host-guest recognition effect of the chiral pillar[5]arene, and then the interaction mode was verified by nuclear magnetism, and the guest was FeTPPNHC and the main body was chiral pillar[5]arene by ultraviolet titration and fluorescence titration, respectively. After determining the optimal host-guest identification ratio with job's titration, the critical micelle concentration was determined with a pyrene fluorescent probe. Finally, the morphology of LOX@LCP5⊃FeTPPNHC vesicles was characterized by transmission electron microscopy at greater than the critical micelle concentration, which confirmed the successful construction of such vesicles and further explored the encapsulation rate and acid response performance of the drug.

(2) Application of LOX@LCP5⊃FeTPPNHC in targeted delivery of LOX and synergistic treatment of tumors and inhibition of tumor metastasis

Due to the characteristics of lactic acid accumulation, H2O2 and GSH increase in the tumor microenvironment, PDT and CDT are greatly dynamically limited. Lactate oxidase (LOX) has the effect of consuming lactic acid and thereby inhibiting tumor metastasis. Fe3+ not only has the ability to catalyze H2O2 oxygen production in the cytoplasm to promote PDT, but also consumes GSH to obtain Fe2+ and enhance CDT performance. We verified the ability of supramolecular to consume GSH, the ability to catalyze the production of O2 by H2O2, and the ability of supramolecular vesicles to catalyze the production of lactic acid from H2O2, respectively, and finally characterized the photodynamic and chemical-dynamic properties by probes. In biological experiments, we verified for the first time that vesicles formed by L-type glucose-modified pillar[5]arene target tumor tissue by chiral recognition, and have been confirmed in cell experiments and in vivo experiments.

(3) Construction of DDP@LCP5⊃CuTPPBr and its application in reduction of tumor cisplatin resistance

Tumor cells, like normal cells, are stressed by the tumor microenvironment during tumor production, proliferation, metastasis and immune stress, and gradually develop drug resistance in the process of continuous administration. Cisplatin (DDP) is a common inorganic chemotherapy drug whose use is limited due to its side effects and resistance during treatment. Scientists have found that drug resistance is mainly caused by reduced intake, increased elimination, and increased GSH. In the same way, we synthesized a halogenated alkyl porphyrin as a guest to assist in the transport of Cu2+ and synergistic consumption of GSH through chemodynamic therapy means to reduce the tumor cisplatin resistance.

MOST Discipline Catalogue理学 - 化学 - 无机化学
URL查看原文
Language中文
Other Code262010_220200924081
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/539092
Collection化学化工学院
Affiliation
兰州大学化学化工学院
Recommended Citation
GB/T 7714
张泽帆. 基于金属-卟啉客体柱[5]芳烃手性囊泡的构建及在协同治疗肿瘤和降低肿瘤顺铂耐药性中的研究[D]. 兰州. 兰州大学,2023.
Files in This Item:
There are no files associated with this item.
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Altmetrics Score
Google Scholar
Similar articles in Google Scholar
[张泽帆]'s Articles
Baidu academic
Similar articles in Baidu academic
[张泽帆]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[张泽帆]'s Articles
Terms of Use
No data!
Social Bookmark/Share
No comment.
Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.