Identification and Analysis of Lipid-Like Materials for Nucleic Acid Delivery

描述（由申请人提供）：本项目旨在推进核酸治疗领域，通过改变问题基因靶点的表达，可能对人类疾病的治疗和预防产生变革性影响。具体来说，本研究将试图通过研究类脂质递送载体（我们称之为“类脂质”）来解决与DNA和siRNA的无毒递送相关的挑战。本建议的总体目标包括：1。开发高质量的候选物，用于使用脂质递送纳米颗粒安全有效地递送核酸。2. 探索基于类脂质的输送的潜在机制，以便能够有洞察力地设计未来几代类脂输送剂。这些总体目标将首先通过高通量化学合成大量新的和多样化的类脂纳米粒子库来实现。这些脂质将被筛选它们以无毒的方式将核酸输送到HeLa细胞的能力。主要候选药物将在动物身上进一步研究治疗潜力。最后，为了改进未来脂质输送载体库的设计，我们将尝试深入了解脂质输送机制。这将通过使用荧光粒子跟踪的运输研究以及旨在确定脂质结构-功能关系的分子建模研究来完成。我们期望这样的实验将导致令人兴奋的新材料能够特定的基因操作，以及更好地理解类脂质的功能。一旦克服了与分娩相关的挑战，核酸疗法有可能彻底改变疾病治疗和预防领域。本研究将研究由类脂质材料制成的纳米颗粒安全有效地递送siRNA和DNA的能力，同时深入了解递送作用的机制。

DESCRIPTION (provided by applicant): This project sets out to advance the field of nucleic acid therapeutics, which is likely to have a transformative effect on the treatment and prevention of human disease through the altered expression of problematic gene targets. Specifically, this study will attempt to address the challenges associated with the non-toxic delivery of DNA and siRNA through the investigation of lipid-like delivery vehicles (which we term 'lipidoids'). The general objectives of this proposal include: 1. Development of high-quality candidates for the safe and effective delivery of nucleic acids using lipidoid delivery nanoparticles. 2. Exploration of the underlying mechanisms of lipidoid-based delivery in order to enable the insightful design of future generations of lipidoid delivery agents. These general objectives will be accomplished first through the high throughput chemical synthesis of a large library of new and diverse lipidoid nanoparticles. These lipidoids will be screened for their ability to deliver nucleic acids to HeLa cells in a non-toxic fashion. Leading candidates will be further examined for therapeutic potential in animals. Finally, in order to enable the improved design of future libraries of lipidoid delivery vehicles, we will attempt to gain insight into lipidoid delivery mechanisms. This will be accomplished through transport studies using fluorescent particle tracking as well as molecular modeling studies intended to identify structure-function relationships for lipidoids. We expect that such experiments will lead to exciting new materials capable of specific gene manipulation as well as a better understanding of lipidoid function. Nucleic acid therapeutics has the potential to revolutionize the field of disease treatment and prevention once the challenges associated with delivery are overcome. This study will investigate the ability of nanoparticles made from lipid-like materials to safely and effectively deliver siRNA and DNA while gaining insight into the mechanisms of delivery action.