The Interaction of Polycationic Organic Polymers with Biological Membranes

描述（由申请人提供）：纳米技术在药物运输中的应用需要理解纳米级材料如何与细胞膜相互作用和穿越细胞膜。文献中讨论的纳米级材料内化到细胞中的主要机制包括能量依赖性内吞作用、能量依赖性膜移位和能量依赖性纳米级膜孔的形成。该研究项目将测试这三种机制假设，这些假设适用于一类重要的纳米级材料：树状大分子、氨基端聚阳离子聚合物和细胞穿透肽，它们与药物传递和细胞转染有关。除了评估这三种内化机制的相对重要性外，该研究项目还将探索纳米材料与膜之间导致细胞膜通透性的关键物理相互作用。无论内化机制如何，这一点都很重要，因为诱导通透性可能导致药物递送应用的选择性差和/或毒性。了解导致细胞膜通透性的物理参数，并探索可能形成纳米级膜孔作为通透性的微观机制，对于合理利用纳米技术在药物运输中的应用具有重要意义。本研究的具体目的是：1)评估树状大分子和聚阳离子聚合物等一类纳米材料的膜相互作用和传输机制；2)定量表征脂质双分子层中形成孔与纳米材料的尺寸、表面化学和电荷之间的关系；3)确定纳米材料诱导活细胞膜形成纳米孔的程度和性质。这项工作与公共卫生相关，因为它将为设计药物或基因治疗的输送平台提供所需的基本理解。适当设计的系统将导致治疗显著减少副作用。

DESCRIPTION (provided by applicant): The application of nanotechnology to drug transport requires an understanding of how nanoscale materials interact with and cross cellular membranes. The principle mechanisms debated in the literature for internalization of nanoscale materials into cells include energy-dependent endocytosis, energy-independent membrane translocation, and energy-dependent formation of nanoscale membrane holes. This research program will test these three mechanistic hypotheses for an important class of nanoscale materials, dendrimers, amine-terminated polycationic polymers, and cell-penetrating peptides, that have relevance to drug delivery and cell transfection. In addition to assessing the relative significance of these three internalization mechanisms, the research program will also explore the key physical interactions between the nanoscale materials and the membrane that cause cell membrane permeability. This is important regardless of the mechanism used for internalization since induction of permeability could lead to poor selectivity in drug delivery applications and/or toxicity. Developing an understanding of the physical parameters that lead to cell membrane permeability, and exploring the possible formation of nanoscale membrane holes as a microscopic mechanism of permeabiliy, is important for the rational use of nanotechnology for the application of drug transport. The specific aims of this research are: 1) assessment of the membrane interaction and transport mechanism of a class of nanoscale materials including dendrimers and polycationic polymers 2) quantification of the relationship between hole formation in lipid bilayers and the size, surface chemistry, and charge of the nanoscale materials 3) determination of the extent and nature of nanoscale hole formation in living cell membranes induced by the nanoscale materials. This work is relevant to public health because it will provide the basic understanding needed to design delivery platforms for drug or gene therapy. Properly designed systems will lead to therapeutics with signficantly reduced side effects.