【摘要】：超順磁性氧化鐵納米粒(SPION)因具有良好的生物相容性、生物可降解性、在外磁場作用下能實現(xiàn)靶向治療等優(yōu)點,近年來備受研究者關(guān)注。作為腫瘤治療的三大手段之一,化學(xué)治療廣泛用于各類腫瘤的治療,如肺癌、肝癌、胃癌、子宮癌等。但化療藥物大多數(shù)都是細(xì)胞毒性藥物,對腫瘤細(xì)胞和正常細(xì)胞都有強(qiáng)大的細(xì)胞毒性作用,往往導(dǎo)致正常細(xì)胞和組織也受到傷害。因此,開發(fā)出特異性針對腫瘤細(xì)胞起抑制作用的靶向藥物傳遞系統(tǒng)是解決化療藥物全身毒性的一條主要途徑。超順磁性氧化鐵納米粒是目前靶向藥物傳遞系統(tǒng)中常用的材料之一,其高通透性和滯留效應(yīng)(Enhanced Permeability and Retention,EPR)以及超順磁性有助于其在腫瘤靶部位大量聚集,實現(xiàn)靶向給藥,從而減少化療藥物的全身毒性。超順磁性氧化鐵納米粒合成工藝很多,如水相共沉淀法、微乳液法、水熱/溶劑熱法、熱分解法、溶膠-凝膠法、超聲法、多元醇法和電化學(xué)法等。如何找到一條能有效控制納米粒的形貌、粒徑大小與分布,同時使其具有超順磁性并且能應(yīng)用于靶向藥物傳遞體系的合成方法,是當(dāng)前研究的熱點。在前期對大量相關(guān)文獻(xiàn)的調(diào)研和預(yù)實驗的基礎(chǔ)上,本課題的研究思路確定為在借鑒前人研究成果的基礎(chǔ)上,首先以超聲輔助水相共沉淀法制備表面修飾檸檬酸的磁性四氧化三鐵納米粒,在控制其形貌、粒徑尺寸與分布及磁性能的基礎(chǔ)上,構(gòu)建以四氧化三鐵納米粒為磁核的靶向藥物傳遞系統(tǒng),并開展載藥與體外釋放研究。水相共沉淀法是合成四氧化三鐵納米粒的主要方法之一,相關(guān)報道很多,但普遍存在產(chǎn)物粒徑大、分布寬、團(tuán)聚嚴(yán)重的問題。本課題嘗試(1)用超聲輔助水相共沉淀方法通過調(diào)整反應(yīng)參數(shù)來控制產(chǎn)品形貌、粒徑大小與分布,同時兼顧其磁性能;(2)以檸檬酸修飾四氧化三鐵納米粒表面,使其呈單分散狀態(tài),減少團(tuán)聚。另外,從文獻(xiàn)調(diào)研中發(fā)現(xiàn)現(xiàn)有的磁靶向藥物傳遞系統(tǒng)存在一些問題,如載藥率低、藥物釋放存在明顯突釋現(xiàn)象等。β-環(huán)糊精作為一種常用的包合材料,是由7個D-葡萄糖分子以1,4-糖苷鍵連接的環(huán)狀低聚糖化合物,具有能容納疏水性藥物的空穴結(jié)構(gòu),其自身毒性很低,適用于提高疏水性藥物的水溶性或者延緩藥物釋放,是一種比較理想的制劑輔料。目前有很多藥物如5-氟尿嘧啶、紫杉醇都有包合物制劑已經(jīng)上市。據(jù)此,本課題設(shè)計了一條以四氧化三鐵@β-環(huán)糊精納米微球包合模型藥物多柔比星來提高載藥量和實現(xiàn)藥物緩釋的研究路線。本文的主要工作如下:1.采用超聲輔助水相共沉淀法合成了平均粒徑84 nm的檸檬酸修飾的Fe3O4納米粒(Fe3O4@CA),通過查閱文獻(xiàn)及預(yù)實驗,確定了反應(yīng)條件,即Fe3+∶Fe2+摩爾比為2∶1,反應(yīng)時間15 min,陳化時間30 min,陳化溫度90℃。X射線粉末衍射證明其組成為純Fe3O4,晶型為反尖晶石;傅里葉變換紅外光譜顯示其含有檸檬酸;透射電鏡下Fe3O4@CA納米粒外觀呈球形,略有團(tuán)聚;熱重分析表明檸檬酸在Fe3O4@CA中的含量為12.1%;磁性能檢測顯示其具有順磁性,飽和磁化強(qiáng)度Ms為17.5emu/g,適合用于構(gòu)建磁靶向藥物傳遞體系。2.利用上一步合成的表面修飾檸檬酸的磁性四氧化三鐵納米粒與β-環(huán)糊精偶聯(lián),獲得了Fe3O4@β-環(huán)糊精納米微球。紅外光譜證明β-環(huán)糊精與Fe3O4@CA納米粒偶聯(lián)成功。透射電鏡下,Fe3O4@β-環(huán)糊精呈球形或類球型,有部分團(tuán)聚。粒徑分析表明,Fe3O4@β-環(huán)糊精納米微球平均粒徑104nm,比Fe3O4@CA平均粒徑增大了20nm。以Fe3O4@β-環(huán)糊精微球為藥物載體,多柔比星為模型藥物,借助β-環(huán)糊精的分子空穴成功制備了Fe3O4@β-環(huán)糊精-多柔比星磁靶向藥物傳遞體系,研究了該藥物傳遞體系在體外的釋藥過程。建立了多柔比星的濃度-紫外吸收標(biāo)準(zhǔn)曲線,并就Fe3O4@β-環(huán)糊精微球?qū)Χ嗳岜刃堑妮d藥量和藥物包封率進(jìn)行了研究。Fe3O4@β-環(huán)糊精對多柔比星的載藥量可達(dá)12%,在超聲作用下僅30min就能達(dá)到最大載藥量,藥物包封率30%。Fe3O4@β-環(huán)糊精-多柔比星藥物傳遞系統(tǒng)在p H 7.4的磷酸鹽緩沖液中釋放緩慢,釋放時間長達(dá)12h,具有緩釋效果。
[Abstract]:The superparamagnetic iron oxide nanoparticle (SPION) has the advantages of good biocompatibility, biodegradability and targeted therapy under the action of external magnetic field, and has attracted much attention in recent years. Chemotherapy is widely used in the treatment of various tumors, such as lung cancer, liver cancer, gastric cancer, cancer, etc. But most chemotherapeutic agents are cytotoxic drugs that have strong cytotoxic effects on tumor cells and normal cells, which often result in normal cells and tissues being damaged. Therefore, targeting drug delivery system that specifically targets tumor cells is one of the main ways to solve systemic toxicity of chemotherapeutic drugs. Superparamagnetic iron oxide nanoparticles are one of the most commonly used materials in drug delivery systems. The high permeability and retention effect (EPR) and superparamagnetism contribute to the large aggregation of the target sites of tumor and achieve targeted drug delivery, thus reducing systemic toxicity of chemotherapeutic drugs. There are many synthetic processes of superparamagnetic iron oxide nanoparticles, such as water phase coprecipitation method, microemulsion method, hydrothermal/ solvent thermal method, thermal decomposition method, sol-gel method, ultrasonic method, polyol method and electrochemical method. How to find a synthetic method which can effectively control the morphology, particle size and distribution of the nanoparticles, and also has superparamagnetism and can be applied to the target drug delivery system is the hot spot of the current research. Based on the research and pre-experiment of a large number of related literatures, the research thought of this topic is determined to be based on the previous research achievements, firstly, the magnetic ferroferric oxide nanoparticles with the surface modified citric acid are prepared by the ultrasonic auxiliary water phase coprecipitation method, and the morphology is controlled, On the basis of particle size and distribution and magnetic properties, a targeting drug delivery system with ferroferric oxide nanoparticles as a magnetic core was constructed, and drug-carrying and in vitro release studies were carried out. Water phase co-precipitation method is one of the main methods to synthesize ferroferric oxide nanoparticles. In this paper, the morphology, particle size and distribution of the product are controlled by adjusting the reaction parameters by using the ultrasonic auxiliary water phase coprecipitation method, and the magnetic properties of the product are considered as well; (2) the surface of the ferroferric oxide nanoparticles is modified with citric acid so as to be in a single dispersion state and the agglomeration is reduced. In addition, in the literature research, it is found that there are some problems in the existing magnetic target drug delivery system, such as low drug loading rate, obvious drug release and so on. Cyclodextrin as a commonly used inclusion material is a cyclic oligosaccharide compound linked by 7 D-glucose molecules with 1,4-dioxane, has a hole structure capable of containing hydrophobic drugs, and has low toxicity, It is suitable for improving water solubility of hydrophobic drug or delaying drug release, and is an ideal preparation adjuvant. At present, many drugs such as 5-dimethylaniline and paclitaxel have been marketed. In this paper, we designed a study route to increase the drug loading rate and achieve the sustained release of drug by using ferroferric oxide @ poly-cyclodextrin nanosphere inclusion model. The main work of this paper is as follows: 1. The modified Fe3O4 nanoparticles (Fe3O4 @ CA) with an average particle size of 84 nm were synthesized by ultrasonic assisted water-phase co-precipitation method. The reaction conditions, i.e. Fe3 +: Fe2 + molar ratio of 2: 1, reaction time 15 min, aging time 30 min and aging temperature 90 鈩，

本文編號：2301957