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物中基于阳离子脂质的纳米颗粒的命运。 阳离子脂质纳米粒作为基因传递系统具有很大的潜力。 然而，还没有完全理解一旦基因被递送到靶组织/细胞，递送系统会发生什么。 我的研究计划可以解决知识的这一重要差距。 不同的阳离子脂质在细胞培养物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，我正在评估两种结构相关的阳离子脂质基团的命运，即双季铵双子表面活性剂（包括2种不同的结构亚族）和新型双子吡啶表面活性剂。选择这些化合物是因为它们显示出作为基因递送系统的前景，并且在培养的细胞内表现出不同的毒性特征。在每组中也观察到基于化学修饰的毒性变化。 拟议的研究将监测测试的阳离子脂质的命运，包括亚细胞定位和代谢产物的形成。 它们在细胞内的行为可以解释不同阳离子脂质之间毒性特征的变化。我的研究计划的长期目标是提高我们对阳离子脂质的化学结构和生物系统（即组织培养物）之间的相互作用的理解。 所产生的知识将用于设计新的脂质材料，这些材料无毒且在基因传递中有效。

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.