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Title:
纳米药物在穿透血管壁输运中的力学问题
Alternative Title: The Mechanical Problems of Transvascular Transport of Nanodrug
Author: 张路姚
Abstract:

纳米药物是一种以纳米颗粒为载体的药物,自上世纪60年代被提出以来,其经历了半个多世纪的发展,在癌症治疗、基因输运以及肿瘤成像等方面发挥了巨大的作用。目前批准上市的纳米药物已经达到几十种。

提高纳米药物的输运效率,增加纳米药物进入病灶点的比例,降低纳米药物对正常器官的毒副作用一直以来是纳米药物研发工作者追求的目标。而达到这一目标,需要人们充分的认识纳米药物在人体内的输运过程。纳米药物在人体中的运输过程大致可以分为四个阶段,在血管中的输运、穿透血管壁进入组织间隙、在组织间隙中的输运以及进入病变细胞。其中穿透血管壁的输运在整个输运过程中扮演着重要的角色,然而研究人员却很少进行这方面的实验或者理论研究,人们对于纳米药物的透壁过程以及纳米药物的物理化学性质对其穿透血管壁效率的影响仍然缺乏一个清晰的认识。

纳米药物穿透血管壁一共有两种方式。第一种方式:通过转胞吞作用进入组织间隙。纳米药物首先被内皮细胞吞入胞内,然后再由内皮细胞排出。这种情况下由于血管内皮细胞通常覆盖着一层厚度超过0.5 μm的糖萼,纳米药物很难到达细胞表面,因此输运效率较低。第二种方式:细胞旁路输运,即纳米药物从细胞与细胞之间的间隙穿过进入组织间隙。其又可以根据纳米药物是否与内皮细胞发生相互作用分为两类,一类是细胞与细胞之间的间隙尺寸远大于纳米药物的尺寸,纳米药物可以自由的从间隙中通过,这类情况通常发生在血管壁上有孔洞的器官或组织,如肝脏、脾脏等网状内皮系统或者肿瘤组织。另一类则是纳米药物与细胞间隙的尺寸相当,纳米药物通过细胞间隙的时候会与内皮细胞以及细胞与细胞之间的连接分子,如钙黏素,发生相互作用。这种情况下纳米药物的尺寸、表面性质以及细胞之间连接的强弱都会影响纳米药物的透壁效率。

本文从理论方面出发,建立了定量化的模型,分析了不同大小和不同表面性质的纳米药物分别以转胞吞和细胞旁路输运的方式穿透血管壁的效率,以及在这个过程中血管内皮细胞表面糖萼的性质和内皮细胞之间黏附连接的性质对输运效率的影响。此模型对开展纳米药物穿透血管壁的实验以及新型纳米药物的研发具有指导意义。

English Abstract:

Nanodrug is a kind of drugs which is based on the carrier of nanoparticles. It was first proposed in 1960s since then nanodrug has been widely used for many fields, including cancer therapy, transport of genes and tumor angioimaging. Now, there are dozens of nanodrugs in market.

The goal of studying nanodrug is to improve the transport efficiency, enhance the proportion of nanodrug to the diseased tissues and reduce side effect for healthy organ. To achieve this, fully understanding the transport process of nanodrug in body is very important. There are four important pharmacokinetic steps governing drug delivery, including vascular transport, transvascular transport, interstitial transport, and transport in cells. Among these transport steps, transvascular transport plays an important role. Nevertheless, there were few experimental or theoretical researches and scientists were lack of clear understanding of the transvascular transport of nanodrug and how the physical and chemical properties influence the process.

There are two possible ways for nanodrug transporting across the vascular membrane. One is transcellular transport by transcytosis of nanodrug. In this way nanodrug is first captured in vesicles on one side of the cell, then drawn across the cell, and finally ejected on the other side. Because of the barrier of the glycocalyx on cell surface, nanodrug is difficult to target the endothelial cell. The other way is traversing across the vascular by paracellular route. This way can be generally divided into two categories according to whether nanodrug interacts with cells. For the first one, the size of the cellular gap is much larger than that of nanodrug, which always happens in tissues with leaking vessel, such as liver, spleen and tumor tissue. For the other one, the cellular gap has a similar size with nanodrug so the nanodrug will interact with the cells and the junction molecular, such as VE-cadherin, at the cellular gap. And the efficiency of transvascular transport is dependent on the size of nanodrug, surface properties and the properties of the cellular junction.

In this work, we present a theoretical model to predict the efficiency of transvascular transport for nanodrug with different sizes and surface properties. Also, we discuss the role of the glycocalyx layer and the junctions of VE-cadherins in transvascular transport of nanodrug. We believe that our model could be helpful for the experiments of transvascular transport of nanodrugs and designing of new nanodrugs.

Degree Level: 硕士
Issued Date: 2018-05-30
Degree Grantor: 中国科学院大学
Place of Degree Grantor: 北京
Major: 固体力学
Language: 中文
Other responsible: 中国科学院力学研究所
Content Type: 学位论文
URI: http://dspace.imech.ac.cn/handle/311007/73187
Appears in Collections:非线性力学国家重点实验室_学位论文

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Recommended Citation:
张路姚. 纳米药物在穿透血管壁输运中的力学问题[D]. 北京. 中国科学院大学. 2018-05-30.
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