The Interaction of Polycationic Organic Polymers with Biological Membranes

描述(申请人提供)：将纳米技术应用于药物传输需要了解纳米材料如何与细胞膜相互作用以及如何跨越细胞膜。文献中讨论的纳米材料内化到细胞内的主要机制包括能量依赖的内吞作用、能量无关的膜转位和能量依赖的纳米膜孔的形成。这项研究计划将针对一类重要的纳米材料--树枝状大分子、端胺聚阳离子聚合物和细胞穿透肽--检验这三种机制假说，这些材料与药物输送和细胞转染有关。除了评估这三种内化机制的相对重要性外，该研究计划还将探索纳米材料与导致细胞膜通透性的膜之间的关键物理相互作用。无论使用何种内化机制，这一点都很重要，因为渗透性的诱导可能导致给药应用中的选择性差和/或毒性。了解导致细胞膜通透性的物理参数，并探索可能形成的纳米级膜孔作为通透性的微观机制，对于合理使用纳米技术应用于药物传输具有重要意义。本研究的具体目的是：1)评估包括树枝状大分子和聚阳离子聚合物在内的一类纳米材料的膜相互作用和传输机制；2)量化脂质双层中孔的形成与纳米材料的尺寸、表面化学和电荷的关系；3)确定纳米材料在活细胞膜上形成纳米孔的程度和性质。这项工作与公共卫生有关，因为它将提供设计药物或基因疗法给药平台所需的基本理解。设计得当的系统将带来副作用显著减少的治疗方法。

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.