The development of mass spectrometric analytical methods for the determination of the biological fate of lipid-based drug delivery nanoparticles

拟议的研究计划旨在利用最先进的质谱技术，确定细胞组织培养中阳离子脂质纳米颗粒的命运。阳离子脂质纳米颗粒作为基因传递系统已显示出巨大的潜力。然而，目前还不完全清楚一旦基因被传递到目标组织/细胞，传递系统会发生什么。我的研究项目可以弥补这一重要的知识缺口。不同的阳离子脂质在细胞培养中具有不同的毒理学特征，因为阳离子脂质化学结构的变化改变了暴露后的细胞活力特征（即毒性）。在这个项目中，我正在评估两个结构相关的阳离子脂类基团的命运，即二季铵盐gemini表面活性剂（包括2个不同的结构亚族）和新型gemini吡啶表面活性剂。选择这些化合物是因为它们有希望作为基因传递系统，并且在培养细胞中表现出不同的毒性特征。基于化学修饰的毒性变化也在每组中观察到。拟议的研究将监测测试阳离子脂质的命运，包括亚细胞定位和代谢物的形成。它们在细胞内的行为可以解释不同阳离子脂质的毒性谱的差异。我的研究计划的长期目标是加强我们对阳离子脂质化学结构与生物系统（即组织培养）之间相互作用的理解。所产生的知识将用于工程新的脂质材料是无毒的和有效的基因传递。

The proposed research program aims at determining the fate of cationic-lipid based nanoparticles within cell tissue cultures, utilizing state-of-the-art mass spectrometric techniques. Cationic lipid nanoparticles have demonstrated a great potential as gene delivery systems. However, it is not fully understood what happens to the delivery system once the gene is delivered to the targeted tissue/cell. My research program can address this essential gap in knowledge. Different cationic lipids have varying toxicological profiles in cell cultures as changes in the chemical structure of the cationic lipids has modified the cell viability profile (i.e. toxicity) upon exposure. In this program, I am evaluating the fate of two structurally related cationic lipid groups, namely diquaternary ammonium gemini surfactants (that include 2 different structural subfamilies) and novel gemini pyridinium surfactants. These compounds are chosen because they have shown promise as gene delivery systems and exhibit different toxic profiles within cultured cells. Variation in toxicity, based on chemical modifications, was also observed within each group. The proposed research will monitor the fate of the tested cationic lipids including subcellular localization and metabolite formation. Their behavior within cells may explain the variation in the toxic profiles among different cationic lipids. The long term goal of my research program is to enhance our understanding of the interactions between the chemical structure of cationic lipids and biological systems (i.e. tissue cultures). The knowledge produced will be used in engineering new lipid materials that are non-toxic and efficient in gene delivery.