论文总字数：20503字

摘 要

目的：黄斑区视网膜慢性疾病又称为年龄相关性黄斑变性（Age-Related Macular Degeneration，AMD）,是一种老年性进行性眼部疾病，是老年人视力下降的主要原因。人口统计结果显示 ，我国逐渐成为老龄化国家，老龄人口数量增多，比重增加，并且糖尿病也会诱发黄斑区视网膜疾病的发生，而我国又是糖尿病人口大国，截止至2008年我国糖尿病患者人数高达2千多万，占总糖尿病人数的12%，预估至2030年这一数字会突破4 千万，相对应的AMD患者也会增多[1, 2]。现有的治疗黄斑区视网膜慢性病的方法主要有注射抗氧化剂、消炎剂以及手术治疗。其中丹酚酸A（SAA）因具有抗氧化作用及抗炎作用成为潜在的AMD治疗药物。但目前的研究表明，丹酚酸A具有组织选择性差、生物相容性低等缺点。因此，本课题拟开发出丹酚酸A的新剂型，以解决其存在的问题，加速其应用于临床、造福千万百姓的速度。

方法：本论文将增生及变厚的异常黄斑区视网膜作为靶点，制备治疗黄斑区视网膜慢性疾病的药物。首先采用化学合成法制备¹²⁵I标记的功能化聚乙烯亚胺树状大分子微粒，负载丹酚酸A。¹²⁵I作为示踪剂，用于监测药物的体内代谢途径，精氨酸-甘氨酸-天冬氨酸（RGD）作为靶向物质。

结果： 本实验结果表明，通过化学合成法所制得的¹²⁵I标记的功能化聚乙烯亚胺树状大分子微粒的合成较为成功。其次用聚乙二醇（PEG）修饰所得功能化聚乙烯亚胺树状大分子微粒，表面改性后用精氨酸-甘氨酸-天冬氨酸（RGD）三肽修饰，改善了制剂的生物相容性及靶向性，借助¹²⁵I，对药物在病灶部位的成像及富集程度做了表征。

结论：¹²⁵I标记的功能化聚乙烯亚胺树状大分子微粒作为药物载体应用于黄斑区视网膜慢性疾病的治疗有望推动实现抗炎纳米药物的智能型诊疗一体化，提高药物疗效和使用安全性。

关键词：黄斑区视网膜慢性疾病;抗炎;抗氧化;功能化聚乙烯亚胺;碘125

¹²⁵I labeled functional polyethyleneimine loaded salvianolic acid A for the treatment of chronic retinal diseases in the macular region

Abstract

Objectives: The chronic diseases of macular retina, also known as age-related macular degeneration(AMD), is a progressive eye disease in the elderly, which is the main cause of vision decline in the elderly. The results of population statistics show that China has gradually become an aging country, the number and proportion of the aging population are increasing, and diabetes can also induce the occurrence of retinal diseases in the macular region, and China is also a large population of diabetes. By 2008, the number of diabetes patients in China has reached more than 20 million, accounting for 12% of the total number of diabetes. It is estimated that by 2030, the number will exceed 4 Tens of millions, corresponding amd patients will also increase. The current treatment methods for chronic macular diseases are mainly injection of antioxidants, anti-inflammatory agents and surgical treatment. Among them, salvianolic acid A (SAA) has become a potential therapeutic drug for AMD due to its antioxidant and anti-inflammatory effects. However, the current research shows that salvianolic acid A has the disadvantages of poor tissue selectivity and low biocompatibility. Therefore, we plan to develop a new formulation of salvianolic acid A in order to solve its problems and accelerate its clinical application and benefit millions of people.

Methods: In this paper, the proliferative and thickened abnormal macular retina was used as the target to prepare drugs for the treatment of chronic diseases of macular retina. Firstly, ¹²⁵I labeled functionalized polyethyleneimine dendrimer particles were prepared by chemical synthesis method and loaded with salvianolic acid a. ¹²⁵I is used as a tracer to monitor the metabolic pathway in vivo. The synthesized particles were characterized by NMR.

Results: The results showed that the ¹²⁵I labeled polyethyleneimine dendrimer particles were synthesized successfully by chemical synthesis method. Secondly, polyethylene glycol (PEG) was used to modify the functionalized polyethylenimine dendrimer particles. After surface modification, arginine glycine aspartic acid (RGD) tripeptide was used to improve the biocompatibility and targeting of the preparation. With the aid of ¹²⁵I, the imaging and enrichment of the drug in the focus were characterized.

Conclusions: ¹²⁵I labeled functionalized polyethyleneimine dendrimers as drug carriers are expected to promote the integration of intelligent diagnosis and treatment of anti-inflammatory nanodrugs and improve the efficacy and safety of drugs.

Key Words: Chronic diseases of retina in macular region; anti inflammation; antioxidation; functionalized polyethyleneimine; iodine 125

目录

摘要 1

Abstract 2

第一章 文献综述 5

1.1黄斑区视网膜慢性疾病及现阶段诊疗方式 5

1.1.1黄斑区视网膜慢性疾病 5

1.1.2诊疗方式 5

1.2 纳米药物载体的发展 6

1.2.1 用于 AMD治疗的纳米药物载体 6

1.2.2 纳米药物载体的特点 6

1.3 ¹²⁵I标记的功能化聚乙烯亚胺的制备与应用 7

1.3.1 聚乙烯亚胺的性质 7

1.3.2 聚乙烯亚胺的表面功能化 7

1.3.3 精氨酸-甘氨酸-天冬氨酸（RGD）肽修饰用作靶向系统 7

1.3.4 FI荧光和¹²⁵I放射诊断系统 8

1.3.5 核医学成像体系 8

1.4 新丹酚酸A剂型的研究意义 8

第二章 实验方法 9

2.1 实验仪器 9

2.2 实验试剂 9

2.3 实验方法 10

2.4 RGD-PEG-COOH的制备、纯化与表征 10

2.4.1 RGD-PEG-COOH的合成 10

2.4.2 RGD-PEG-COOH的纯化 11

2.4.3 RGD-PEG-COOH的1H NMR表征 11

2.5 PEI的修饰 12

2.5.1 RGD-PEG-COOH修饰PEI 12

2.5.2 HPAO修饰PEI 12

2.5.3 FI修饰PEI 13

2.5.4 对比材料的合成 13

第三章 结果与讨论 15

3.1 功能化聚乙烯亚胺以及中间产物的表征 15

3.1.1 对RGD-PEG-COOH的表征 15

3.1.2 对PEI.NH₂-(PEG-RGD)的表征 15

3.1.3 对PEI.NH₂-HPAO-(PEG-RGD)的表征 15

3.1.4 对PEI.NH₂-FI-HPAO-(PEG-RGD)以及PEI.NH₂-FI-HPAO-(mPEG)的表征 15

第四章 结论与展望 17

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