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Star polymers for gene delivery

用于基因传递的星形聚合物

基本信息

批准号：
2275313
负责人：
金额：
--
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2275313
关键词：
Star polymers gene delivery

项目摘要

Gene delivery is an important challenge for the realisation of any genetic therapy. One of the main problems is that the charge of genetic material, be it DNA or RNA, is the same as the surface of the cell. Hence, shuttling these polymers inside the cell to do their job requires to overcome a large energetic barrier due to electrostatic repulsion. One of the ideas to solve this issue is to form a complex between the genetic material and a poly-cation so as to neutralise the overall effective charge. However, care must be taken with using this simple concept because the strength of the interaction must still be tuned: If the complex is too stable, once inside the cell it will not allow DNA or RNA to be released and interact with the cellular machinery required for the therapy to be effective. If not stable enough, the genetic material will not be shuttled inside the cell in the first place. In this project, we aim to use coarse-grained modelling and molecular dynamics to study the stability of complexes between positively charged star polymers and small DNA sequences representative of what are usually employed in genetic therapy. Our goal is to determine how synthetically tuneable parameters of the poly-cation affect the overall binding free-energy, and hence the complex stability. Results from simulation will be able to provide rational guidelines to our experimental collaborators.

基因传递对于实现任何基因治疗都是一个重要的挑战。其中一个主要问题是，遗传物质的电荷，无论是DNA还是RNA，都与细胞表面相同。因此，在细胞内穿梭这些聚合物来完成它们的工作需要克服由于静电排斥而产生的巨大的能量障碍。解决这一问题的想法之一是在遗传物质和聚阳离子之间形成络合物，从而中和整体有效电荷。然而，使用这个简单的概念必须小心，因为相互作用的强度仍然必须调整：如果复合体太稳定，一旦进入细胞，它就不会允许DNA或RNA释放，并与治疗有效所需的细胞机制相互作用。如果不够稳定，遗传物质一开始就不会在细胞内穿梭。在这个项目中，我们的目标是使用粗粒度建模和分子动力学来研究正电荷星形聚合物与小DNA序列之间的络合物的稳定性，这些小DNA序列通常用于遗传治疗。我们的目标是确定聚阳离子的可综合可调参数如何影响总的结合自由能，从而影响络合物的稳定性。模拟结果将能够为我们的实验合作者提供合理的指导。