抗肿瘤药物维生素E琥珀酸磷脂的研究

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摘 要

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抗肿瘤药物维生素E琥珀酸磷脂的研究

摘要

维生素E琥珀酸酯（Vitamin E Succinate，α-VES）是人体必需的脂溶性抗氧化物维生素E（Vitamin E，VE）的一种主要酯化衍生物，具有选择性抑制肿瘤细胞增殖活力并诱导肿瘤细胞自主凋亡的特性。然而，α-VES存在较明显的疏水性，其在水相体系的溶解度非常低，难以直接将其应用于临床治疗中。为了提高α-VES的溶解度，探究其自组装药物传递系统（Self-Assembly Drug Delivery System，SADDS）的性质，本论文提出借助磷脂的生物学特性设计一种两亲性VES偶联物，并对其合成路线、理化性质进行探究。主要研究内容如下：

（1）以维生素E琥珀酸酯（Vitamin E Succinate，α-VES）和甘油磷脂酰胆碱（L-α-Glycerophosphorylcholine，GPC）为反应原料，通过一步反应得到维生素E琥珀酸酯-甘油磷脂酰胆碱偶联物（Dual Vitamin E Succinate-tailed Glycerylphosphorylcholine Conjugate，Di-VES-GC），以MS、HPLC和¹H NMR和¹³C NMR检测化合物的纯度和结构信息；

（2） 通过薄膜分散法制备Di-VES-GC纳米微球，以DLS和TEM确定其粒径分布和微观形貌。结果显示，Di-VES-GC的纯度为95%，结构信息与理论相符；所得微球的平均水合直径为183 nm；Di-VES-GC脂质体的微观形貌为具有双分子层结构的微球结构，符合一般脂质体的结构特征。

综上，以α-VES作为疏水药物模型构建出的α-VES磷脂偶联物具有组装形成脂质体纳米微球的能力。该脂质体剂型具有较为理想的载药量，并且可在保持原药的抗肿瘤活性的基础上实现对α-VES的控制释放，因而具有潜在的应用价值以及深入研究的意义。

关键词： 抗肿瘤药物，脂质体，磷脂，维生素E琥珀酸酯，Di-VES-GC

STUDY OF VITAMIN E SUCCINATE PHOSPHOLIPID CONJUGATE THROUGH SELF-ASSEMBLY DRUG-DRUG SYSTEM FOR CANCER THERAPY

Abstract

Vitamin E Succinate (α-VES) refers to a major esterified derivative of Vitamin E which is an essential lipid-soluble antioxidant of our human body. As one of the most biologically active forms of the Vitamin E group, α-VES can also perform its functions as a kind of anti-tumor drug by selectively inhibiting the proliferation of tumor cells and inducing the apoptosis of tumor cells. Due to the hydrophobic characteristic of α-VES which leads to its poor solubility in pharmaceutically acceptable excipients, there is still a large quantity of work to carry on before we can safely use it as an application in clinical treatment. In order to improve the solubility of α-VES as well as to acknowledge the properties of its self-assembly drug delivery system (SADDS), this thesis mainly demonstrate a strategy of preparing self-assemble nanoparticles from amphiphilic Di-VES-GPC conjugate with the investigations of the synthesis scheme, physical and chemical properties and self-assembly behavior. The main content and results are listed as follows:

(1) Dual Vitamin E Succinate-tailed Glycerylphosphorylcholine Conjugate (Di-VES-GC) is synthesized by vitamin E succinate (α-VES) and L-α-glycerophosphorylcholine (GPC) with one-step reaction. MS, HPLC, ¹H NMR and ¹³C NMR are applied to characterize the properties of target product Di-VES-GC. The results show that the purity of Di-VES-GC is 95%.

(2) The Di-VES-GC liposomes are prepared by applying conventional thin film dispersion method. The properties of conjugate liposomes are further evaluated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The DLS result shows that the average size of Di-VES-GC liposomes is accorded with normal distribution with the hydrodynamic diameter about 183 nm. The TEM image demonstrates the sphere structure with a lipid bilayer, which accords with the characteristic of the general liposomes.

In conclusion, Di-VES-GC conjugates possess the ability of self-assembling into liposome-like nanoparticles. This novel dosage form performs high drug-loading content, which may have profound potential for future clinical application after a series of extensive evaluation.

Keywords: anti-tumor drugs, liposomes, phospholipid, Vitamin E Succinate, Di-VES-GC

主要缩略词注释表

目录

摘要 I

Abstract II

主要缩略词注释表 III

目录 IV

第一章 绪论 1

1.1 抗肿瘤药物 1

1.1.1 现阶段临床抗肿瘤药物概述 1

1.1.2 抗肿瘤药物的现存问题与研究展望 3

1.2 维生素E琥珀酸酯在肿瘤治疗中的应用 4

1.2.1 维生素E琥珀酸脂的基本性质 5

1.2.2 维生素E琥珀酸脂的抗肿瘤作用及治疗应用 5

1.3 抗肿瘤药物纳米给药系统 6

1.3.1 纳米乳 6

1.3.2 聚合物胶束 7

1.3.3 纳米混悬剂 7

1.3.4 纳米脂质体 7

1.3.5 自组装药物输送系统 8

1.4 本课题的立题依据和主要研究内容 9

1.4.1 立题依据和意义 9

1.4.2 主要研究内容 9

第二章 维生素E琥珀酸磷脂的合成 10

2.1 前言 10

2.2 实验部分 11

2.2.1 实验试剂与仪器 11

2.2.2 维生素E琥珀酸磷酯的合成 12

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