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

这项拟议的研究计划旨在利用最先进的质谱学技术，确定基于阳离子脂质的纳米颗粒在细胞组织培养中的命运。阳离子脂质纳米粒作为基因递送系统显示出巨大的潜力。然而，一旦基因被传递到目标组织/细胞，传递系统会发生什么还不完全清楚。我的研究计划可以解决知识上的这一根本差距。不同的阳离子脂类在细胞培养中具有不同的毒理学特征，因为阳离子脂类的化学结构的变化改变了暴露时细胞的活性特征(即毒性)。在这个项目中，我正在评估两个结构相关的阳离子类脂基团的命运，即双季铵盐双子表面活性剂(包括两个不同的结构亚家族)和新型双子吡啶表面活性剂。之所以选择这些化合物，是因为它们在培养细胞中显示出作为基因传递系统的前景，并显示出不同的毒性特征。基于化学修饰的毒性也在每组中观察到了变化。这项拟议的研究将监测测试的阳离子脂类的命运，包括亚细胞定位和代谢物形成。它们在细胞内的行为可能解释了不同阳离子脂类之间毒性分布的差异。我的研究计划的长期目标是加强我们对阳离子脂类化学结构和生物系统(即组织培养)之间相互作用的了解。所产生的知识将用于设计无毒和高效的基因传递的新的脂类材料。

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.