树枝状大分子跨细胞双层磷脂膜输运过程及机理的介观模拟及理论分析

Understanding the interactions of nanoparticles with biological membranes is of fundamental importance in determining their potential application as drug delivery vehicles and therapeutic agents. As a framework in multifunctional nanodevices, dendrimers are particularly useful in the development of targeted chemotherapeutic agents. To understand the dynamical process and mechanisms of the transmembrane transport of dendrimers however requires direct measurements in a single cell and is thereby very difficult and more challenging. Tailored computer simulations offer a unique approach to address these unresolved issues through identifying and separating individual contributions to the phenomenon. In this project, the dynamical process and mechanisms during the internalization of dendrimers across a lipid bilayer membrane are investigated by employing systematically mesoscopic simulations and theoretical analysis. Firstly, the self-assembly of a single dendrimer on a bilayer membrane patch with large size will be studied by dissipative particle dynamics, where the effects of dendrimer generation and electrostatic interaction on the internalization approaches, including uptake, penetration and membrane damage, of the dendrimer will be investigated. The membrane will also be stretched or compressed to examine the surface tension-mediated transmembrane transport of dendrimers. In particular, the curvature, topological and elastic energies within the systems will be calculated to gain more detailed insight into the structural formation and mechanisms of the process. Then, the effects of receptors within the cell membrane on the transmembrane transport of dendrimers will be explored by inducing coarse-grained receptor molecules into the lipid bilayer membrane. For this purpose, the receptor number and receptor-lipid interaction will be changed to explore their effects on the transmembrane transport approaches and mechanisms of dendrimers. Finally,by adding more dendrimers into the system, the transmembrane transport of these dendrimers will be simulated and theoretically analyzed, which will help us to determine the cooperation effects of multi-dendrimers in their transmembrane transport. The results of this project could help us in clarifying the dynamical process, approaches and mechanisms of the transmembrane transport and cytotoxicity of dendrimer-like supramolecules as well as other charged nanoparticles.The findings through the combination of simulation and theoretical techniques in the project might provide guidelines for the experimental design toward novel targeted drug, and might demonstrate an intuitive framework for the research of this important topic.

本项目旨在运用介观模拟方法，研究树枝状大分子（Dendrimer）跨细胞双层磷脂膜输运的动力学过程和路径，并对该过程进行相应的理论分析，以期阐明此类功能纳米粒子细胞内化过程的机理。首先采用耗散粒子动力学方法模拟不同代数的单一带电Dendrimer分子在较大尺寸的磷脂双层膜上组装所形成的结构，并对拉伸和压缩薄膜过程中该体系的曲率能、拓扑能和弹性能等进行理论计算和分析，以阐明膜结构影响下跨膜输运的过程、路径及机理。随后，将粗粒化的受体分子引入双层磷脂薄膜中，探讨受体浓度、受体-Dendrimer相互作用强度等对Dendrimer跨膜输运过程及机理的影响。在此基础上，增加体系中Dendrimer分子的数量，从而深入研究和分析该输运过程中潜在的多Dendrimer协同效应。为探索Dendrimer类型的带电超分子跨膜输运机理及其潜在的细胞毒性，开发新型靶向药物输运体系奠定理论基础，形成原创性成果。

理解功能大分子与细胞膜的相互作用对于揭示其跨膜输运动力学路径和机理，进而开发和拓展其纳米医学应用来说意义重大。该项目旨在发展和运用介尺度计算机模拟方法和理论分析模型，深入研究树状大分子等具有复杂拓扑结构的功能纳米粒子跨细胞双层磷脂膜输运的动力学行为和影响因素，以期阐明此类复杂体系细胞内化过程的机理。取得的重要结果总结如下：1）采用介尺度计算机模拟和理论分析相结合的方法，详细阐明了树状大分子、二维石墨烯纳米片等复杂拓扑大分子体系与磷脂双层膜作用的独特动力学路径和机理。2）揭示了受体-配体相互作用、静电相互作用以及膜涨落效应等因素如何影响此类大分子体系在细胞膜平面内的随机或定向扩散行为，并对该过程进行了详细而又深入的理论分析。3）研究了膜受体蛋白介导的树状大分子和石墨烯纳米片跨膜输运的动力学过程和路径，进而发现二维纳米粒子跨膜输运过程会经历独特的扁平胶束化过程，且该过程中二维纳米粒子会展现出公转和独特的自旋转行为。4）通过系统的大规模模拟计算，在介观层次上明晰了此类大分子体系的尺寸、形状、刚度、表面性能等物理因素对其与细胞膜作用状态及动力学过程的影响。5）开发了相关的理论模型，深入揭示了功能大分子体系特别是石墨烯纳米片与细胞膜作用背后的纳米力和能量变化，进而给出了不同作用状态所对应的临界条件，初步阐明了二维纳米粒子与细胞膜作用的物理原理。6）适当探索了功能纳米粒子在其他的软物质体系内的界面相互作用，以图发展出调控纳米粒子与聚合物乃至软物质体系相互作用的更多有效途径，为新型纳米医学材料的开发提供理论参考。7) 该项目在执行期间共发表与之相关的通讯作者SCI收录文章19篇,包括IF>10.0:4篇；10>IF>7.7:6篇；7.0>IF>5.0:6篇。同时应权威学术出版机构Wiley出版社的邀约主编英文学术专著一本，全书12个章节的通讯作者为来自8个国家的本领域优秀科学家。该项目的研究结果将促进相关大分子体系的纳米医学应用，并可为揭示和理解其生物安全性等问题提供理论指导。

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