Mass Spectrometric Detection and Characterization of Metabolites of Gemini Surfactants Used as Gene Delivery Vectors

Abstract

Gemini surfactants are a class of lipid molecules that have been successfully used in vitro and in vivo as nonviral gene delivery vectors. However, the biological fate of gemini surfactants has not been well investigated. In particular, the metabolism of gemini surfactants after they enter cells as gene delivery vehicles is unknown. In this work, we used a high-resolution quadrupole-Orbitrap mass spectrometry (Q-Exactive) instrument to detect the metabolites of three model gemini surfactants, namely, (a) unsubstituted (16-3-16), (b) with pyridinium head groups (16­(Py)-S-2-S-16­(Py)), and (c) substituted with a glycyl-lysine di-peptide (16-7N­(GK)-16). The metabolites were characterized, and structures were proposed, based on accurate masses and characteristic product ions. The metabolism of the three gemini surfactants was very different as 16-3-16 was not metabolized in PAM 212 cells, whereas 16­(Py)-S-2-S-16­(Py) was metabolized primarily via phase I reactions, including oxidation and dealkylation, producing metabolites that could be linked to its observed high toxicity. The third gemini surfactant 16-7N­(GK)-16 was metabolized mainly via phase II reactions, including methylation, acetylation, glucose conjugation, palmityl conjugation, and stearyl conjugation. The metabolism of gemini surfactants provides insight for future directions in the design and development of more effective gemini surfactants with lower toxicity. The reported approach can also be applied to study the metabolism of other structurally related gemini surfactants.

Peptide-Based Drug Delivery Systems

“…The 16-7N(GK)-16 was digested primarily via methylation, acetylation, glucose conjugation, palmityl and stearyl conjugation. One can conclude that the establishment of the metabolism of Gemini surfactants offers insight for future guidelines in the design and improvement of effective Gemini surfactants with better biocompatibility [141].…”

Establishment of the tandem mass spectrometric fingerprints of taxane‐based anticancer compounds

“…Subsequently, multiple reaction monitoring (MRM) MS‐based methods were successfully developed to determine gemini surfactants in biological samples 20–22 . In addition, the established MS/MS fingerprints were essential to establish their metabolic pathways 23 . Similarly, the MS/MS dissociation behavior of plant phytosterols and tocopherols was established to develop the qualitative profiling method using precursor ion scan mode 24 .…”

Experimental and Molecular Dynamics Simulation Study on the Effects of the Carbon Chain Length of Gemini Surfactants on the Inhibition of the Acid-Rock Reaction Rate

“…7 In gene transfection, gemini surfactants can act as potential vehicles for transporting bioactive molecules. 8 For enhancing oil recovery, gemini surfactants as oil-displacement agents can better adsorb on the rock surface to change its wettability. 9 T h i s c o n t e n t i s Most researchers have focused on the properties of gemini surfactants in a bulk solution.…”

“…For example, in cleaning agents and detergents, gemini surfactants can reduce the environmental impact of detergents by reducing the amount required to perform the same function . In gene transfection, gemini surfactants can act as potential vehicles for transporting bioactive molecules . For enhancing oil recovery, gemini surfactants as oil-displacement agents can better adsorb on the rock surface to change its wettability …”