Mass spectrometric approaches to assess the biodistribution and fate of cationic surfactants used as drug delivery nanoparticles

质谱方法评估用作药物递送纳米粒子的阳离子表面活性剂的生物分布和归宿

• 批准号: RGPIN-2015-03715
• 负责人: ElAneed, Anas
• 金额: $ 1.46万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=612521
• 关键词: Mass; spectrometric; approaches; assess; biodistribution

In the pharmaceutical industry, the fastest growing area is drug delivery, accounting currently for more than $80 billion of total value, including gene delivery. The latter has gained momentum with the recent first approval in the European Union of the gene therapy, Glybera® for the treatment of genetic lipid disorders. In fact, there are 5000 genetic diseases that do not have a cure. Therefore, it is not surprising that over 2000 clinical trials (i.e. human testing) have been conducted, evaluating various gene therapy strategies. Among the various gene delivery systems, cationic-lipid nanoparticles have demonstrated a great potential as chemical vectors. However, it has been shown that different cationic lipids have varying toxicological profiles in cells as toxicity is dependent on the chemical structure. It is not fully understood what happens to the delivery system once the gene is transferred to the targeted tissue/cell. Such basic knowledge is lacking and is critical for understanding the relationship between structure and toxicity, leading to the development of efficient and safe lipid-based nanoparticles. My research program aims at addressing this essential gap in knowledge. I am evaluating the fate of two structurally related cationic lipid groups belonging to the subfamily gemini surfactants. These compounds can assemble to form nanoparticles when complexed with genetic materials. The main short-term goal of my research program is to determine the fate of gemini surfactant-based nanoparticles within cells, utilizing state-of-the-art mass spectrometric techniques. The proposed research will monitor the subcellular localization and degradation profile of gemini surfactants. Their behavior within cells may explain the variation in the toxic profiles among different compounds. We will develop methods to determine the cellular fate of gemini surfactants including cellular localization and metabolic byproduct formation. My research program will contribute to the basic understanding of such behavior. The knowledge produced will be used in engineering new gemini surfactants that are non-toxic and efficient in drug delivery. In the long term, my research program can impact the development of safe and efficient therapeutic products. It should be noted that gemini surfactants have many other industrial applications such as detergents, cosmetics and solubilization agents. The proposed work can allow for the assessment of the safety of gemini surfactants regardless of the application.

在制药行业，增长最快的领域是药物递送，目前占总价值的800多亿美元，包括基因递送。随着欧盟最近首次批准Glybera®基因疗法治疗遗传性血脂紊乱，后者获得了发展势头。事实上，有5000种遗传病是无法治愈的。因此，进行了2000多项临床试验(即人体试验)，评估各种基因治疗策略也就不足为奇了。 在众多的基因传递系统中，阳离子脂质纳米粒作为化学载体显示出巨大的潜力。然而，已有研究表明，不同的阳离子脂类在细胞中具有不同的毒理学特征，因为毒性取决于化学结构。一旦基因被转移到目标组织/细胞，传递系统会发生什么，目前还不完全清楚。这些基础知识是缺乏的，对于理解结构和毒性之间的关系，导致高效和安全的脂基纳米粒的开发至关重要。我的研究计划旨在解决知识上的这一根本差距。 我正在评估属于双子家族表面活性剂的两个结构相关的阳离子脂质基团的命运。当这些化合物与遗传物质络合时，可以组装成纳米颗粒。我的研究计划的主要短期目标是利用最先进的质谱学技术，确定基于双子表面活性剂的纳米颗粒在细胞内的命运。这项拟议的研究将监测双子表面活性剂的亚细胞定位和降解情况。它们在细胞内的行为可能解释了不同化合物之间毒性分布的差异。 我们将开发方法来确定双子表面活性剂的细胞命运，包括细胞定位和代谢副产物的形成。我的研究计划将有助于对这种行为的基本理解。所产生的知识将被用于设计无毒和高效的药物输送的新型双子表面活性剂。从长远来看，我的研究计划可以影响安全有效的治疗产品的开发。应该指出的是，双子表面活性剂还有许多其他工业应用，如洗涤剂、化妆品和增溶剂。建议的工作可以对双子表面活性剂的安全性进行评估，而不考虑其应用。