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

用于核酸递送的类脂材料的鉴定和分析

• 批准号: 8115078
• 负责人: Kathryn A. Whitehead
• 金额: $ 5.3万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115078
• 关键词: Address; Animals; Blood Coagulation Factor VII; C57BL/6 Mouse; Cells; Chemicals; Clinical Trials; DNA; DNA delivery; Data; Development; Disease; Drug Delivery Systems; Future; Future Generations; Gene Delivery; Gene Targeting; Generations; Genes; Genetic Materials; Goals; Hela Cells; Hepatocyte; Human; Immune System Diseases; In Vitro; Investigation; Lead; Libraries; Life; Lipids; Liposomes; Liver; Malignant Neoplasms; Mediating; Methods; Mind; Modeling; Molecular Models; Mus; Nuclear; Nucleic Acids; Organ; Pharmaceutical Preparations; Prevention; Property; RNA Interference; Research; Research Design; Safety; Screening procedure; Small Interfering RNA; Staging; Structure-Activity Relationship; System; Techniques; Technology; Therapeutic; Transfection; Virus Diseases; advanced system; base; biological systems; chemical synthesis; design; disorder prevention; human disease; improved; insight; molecular modeling; nanoparticle; novel; particle; research study; small molecule; success; therapeutic gene; tool

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.

描述（由申请人提供）：该项目旨在推进核酸治疗领域，这可能通过改变有问题的基因靶点的表达对治疗和预防人类疾病产生变革性影响。具体而言，本研究将试图通过研究脂质样递送载体（我们称之为“类脂质体”）来解决与DNA和siRNA的无毒递送相关的挑战。本提案的总体目标包括：1。开发高质量的候选物，用于使用类胡萝卜素递送纳米颗粒安全有效地递送核酸。 2.探索基于阿糖胞苷的递送的潜在机制，以便能够有见地地设计未来几代阿糖胞苷递送剂。 这些总体目标将首先通过高通量化学合成新的和不同的类胡萝卜素纳米颗粒的大型库来实现。将筛选这些类胡萝卜素以无毒方式将核酸递送至HeLa细胞的能力。将进一步检查主要候选药物在动物中的治疗潜力。最后，为了改进未来类脂质递送载体库的设计，我们将尝试深入了解类脂质递送机制。这将通过使用荧光粒子跟踪的运输研究以及旨在确定类胡萝卜素结构-功能关系的分子建模研究来实现。我们希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，以及更好地了解类胡萝卜素的功能。一旦克服了与递送相关的挑战，核酸疗法有可能彻底改变疾病治疗和预防领域。这项研究将研究由脂质样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。

项目成果

In vitro-in vivo translation of lipid nanoparticles for hepatocellular siRNA delivery.

• DOI: 10.1021/nn301922x
• 发表时间: 2012-08-28
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Whitehead, Kathryn A.;Matthews, Jonathan;Chang, Philip H.;Niroui, Farnaz;Dorkin, J. Robert;Severgnini, Mariano;Anderson, Daniel G.
• 通讯作者: Anderson, Daniel G.