The Interaction of Polycationic Organic Polymers with Biological Membranes

描述（由申请人提供）：纳米技术在药物转运中的应用需要了解纳米级材料如何与细胞膜相互作用并穿过细胞膜。在文献中讨论的纳米材料内化到细胞中的主要机制包括能量依赖性内吞作用、能量非依赖性膜易位和能量依赖性纳米级膜孔的形成。这项研究计划将测试这三个机制的假设，一类重要的纳米材料，树枝状聚合物，胺封端的聚阳离子聚合物，和细胞穿透肽，具有相关的药物输送和细胞转染。除了评估这三种内化机制的相对意义外，该研究计划还将探索纳米材料与导致细胞膜渗透性的膜之间的关键物理相互作用。无论用于内化的机制如何，这都是重要的，因为渗透性的诱导可能导致药物递送应用中的选择性差和/或毒性。了解导致细胞膜渗透性的物理参数，并探索作为渗透性微观机制的纳米级膜孔的可能形成，对于合理使用纳米技术用于药物转运的应用是重要的。这项研究的具体目标是：1）评估包括树枝状聚合物和聚阳离子聚合物的一类纳米级材料的膜相互作用和传输机制2）定量脂质双层中的空穴形成与尺寸，表面化学，和纳米材料的电荷3）确定由纳米级材料诱导的活细胞膜中纳米级孔形成的程度和性质。这项工作与公共卫生有关，因为它将提供设计药物或基因治疗输送平台所需的基本理解。适当设计的系统将导致治疗与显着减少副作用。

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.