三种纳米载体在口服吸收细胞模型及动物模型中吸收机理的比较性研究

After years of development, nanotechnology has become more mature than before and is now being used in various areas. In medical area, using nanotechnology can help us build nanocarriers, which are capable of delivering therapeutic drugs specifically to the disease focus.As orally administered drug delivery systems, nanocarriers can also increase the bioavailabilities of its loaded drugs. In the research of oral administration, intestinal epithelium cells has built a physiological barrier for drug absorption.In order to obtain a satisfying delivery result, nanocarriers must overcome this barrier.Currently there are a large variety of nanocarriers and evaluation methods both in vivo and in vitro.In this project, we intend to choose three types of commonly used nanocarriers, including nanoparticles, liposomes and micelles; and evaluate the delivery efficiency of them in three different cell models and animal models. The interaction between nanocarriers and intestinal epithelium cells will be studied here, including the contact of nanocarriers at cell membrane, the uptake of nanocarriers, their intracellular distribution and transport across different cell monolayers.The pharmacodynamic and pharmacokinetic characteristics will be investigated on animal models. Different methods will be employed to clarify the unclear points that people eager to know in the cell-nanocarrier interaction. The aim of this project is to find out the characteristics of these three types of nanocarriers when they are being transported throught different cell models and to understand there are similaritis and differences during the uptake and intracellular distribution of nanocarriers; and the correalation between in vivo and in vitro data.These results will provide useful information for the afterwards study of nanocarrier designs.

纳米载体的应用极为广泛，采用纳米技术构建的纳米载体可以向人体的多处病灶有效地输送药物；同时，其作为口服药物输送系统也有效发挥着提高药物生物利用度的作用。在口服给药研究中，小肠上皮细胞为药物的吸收构建了一道生理屏障，纳米载体需要跨过这层屏障才能实现药物的成功递送。目前口服研究中应用的纳米载体种类繁多，体内外评价方式也多种多样。本项目拟选用最常用的三种纳米载体：纳米粒、脂质体和胶束，在三种常用口服吸收细胞模型和动物模型中评价它们的递送效果，同时对纳米载体与小肠上皮细胞之间的相互作用，包括细胞膜层面相互接触、摄取入胞、胞内定位和跨膜机理；以及药动学和药效学特征进行深入研究，采用多种评价方式进行考察分析。通过此研究，可以阐明常用载体在口服给药时的转运特点，明确不同纳米载体被细胞摄取及跨膜时所表现的异同点及体内外研究的相关性，并对后续纳米载体的研究提供参考信息。

在医药学领域中，采用纳米技术构建的纳米载体可以向人体的多处病灶，如肿瘤、胃肠道、骨组织、炎症组织等输送药物，一方面能够增加药物在病灶部位的蓄积，另一方面则可以减少毒副作用等。在口服给药的研究中，小肠上皮细胞为药物的吸收构建了一道生理屏障，而纳米载体可以通过包载或偶联药物来改变药物的溶解度等，有效的促进药物的口服吸收。纳米载体在肿瘤的治疗中应用也十分广泛，大多是借助实体瘤的高通透性和滞留效应被动靶向于肿瘤组织来提高肿瘤部位药物的蓄积。此外，在上述研究的基础上还发现，对纳米载体表面进行靶向修饰可以进一步提高细胞对纳米载体及药物的摄取，从而达到更好的治疗效果。尽管目前看来靶向纳米载体的研究越来越热，而且在口服给药系统中和肿瘤靶向治疗中都展现出良好的药效，但关于纳米载体与肠道上皮细胞及肿瘤细胞相互作用的机理性研究却较少。.针对这种现状，本课题以经靶向配体修饰的胶束和未修饰的胶束作为研究对象，分别建立肠道上皮细胞单层模型和肿瘤细胞模型，评价和分析了胶束体系在细胞的摄取、内吞机理、胞内转运、体内外靶向性等方面的机理。通过此研究，可以为后续胶束设计和靶向纳米载体的机理研究提供参考信息。