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

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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, Glyberar 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.******