The development of simple flow injection analysis tandem mass spectrometric methods for the cutaneous determination of peptide-modified cationic gemini surfactants used as gene delivery vectors

Al‐Dulaymi, Mays; Michel, Deborah; Chitanda, Jackson M.; Badea, Ildikó; El‐Aneed, Anas

doi:10.1016/j.jpba.2018.06.063

Cited by 6 publications

(7 citation statements)

References 49 publications

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“…Future studies will be conducted using various sample extraction methods to improve the coverage of possible gemini surfactant metabolites. For example, Al-Dulaymi et al 24 has reported a modified Folch method that provides high extraction recovery for gemini surfactants with more hydrophilic nature.…”

Section: Resultsmentioning

confidence: 99%

“…In fact, we have shown recently in an ex-vivo experiment that gemini surfactants localized mainly in the skin with minimal penetration of skin tissues to enter the compartment representing the circulation. 24 As such, it is of great importance to evaluate their metabolism within a cell line that represents the target organ, i.e., the skin. Our group previously evaluated the cellular uptake and distribution of these three gemini surfactants within murine keratinocytes PAM 212 cells using mass spectrometric (MS) methods.…”

Section: Introductionmentioning

confidence: 99%

“…As our main therapeutic use for gemini surfactants is topical application, particularly for the treatment of localized scleroderma, a connective tissue disease, the epidermal keratinocytes PAM 212 cells were selected for the evaluation of the biological fate of these three gemini surfactants. In fact, we have shown recently in an ex-vivo experiment that gemini surfactants localized mainly in the skin with minimal penetration of skin tissues to enter the compartment representing the circulation . As such, it is of great importance to evaluate their metabolism within a cell line that represents the target organ, i.e., the skin.…”

Section: Introductionmentioning

confidence: 99%

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

Jin

Purves

Krol

et al. 2020

J. Am. Soc. Mass Spectrom.

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Jin

Purves

Krol

et al. 2020

J. Am. Soc. Mass Spectrom.

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“…For example, CID‐MS/MS analysis of a series of diquaternary ammonium gemini surfactants, used as gene‐delivery systems, was first established 17–19 . 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 .…”

Section: Introductionmentioning

confidence: 99%

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

Khajavinia

Haddadi

El‐Aneed

2021

Rapid Comm Mass Spectrometry

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Rationale Compounds in the taxane drug family are among the most successful and effective chemotherapeutic agents used in the treatment of solid tumors, such as breast, ovarian, and prostate cancers. The tandem mass spectrometric (MS/MS) fragmentation behavior of these compounds is described in detail, and a generalized MS/MS fingerprint is established for the first time. Methods Five compounds, namely paclitaxel, docetaxel, cabazitaxel, cephalomannine, and baccatin III, were evaluated. A hybrid quadrupole orthogonal time‐of‐flight (Q‐TOF) mass spectrometer was used to obtain accurate mass measurements, whereas MS/MS and second‐generation MS/MS (MS3) analyses were performed using a triple quadrupole‐linear ion trap mass spectrometer. Both instruments were equipped with an electrospray ionization source operated in the positive ion mode. Results All taxanes showed an abundant singly charged [M + H]+ species in the single‐stage analysis with mass accuracies less than 3 ppm. The evaluated compounds exhibited common fragmentation behavior in their MS/MS analysis, which allowed for the production of a universal fragmentation pattern. MS3 experiments confirmed the genesis of the various product ions proposed in the fragmentation pathway. In addition, diagnostic product ions were originated from a cleavage in the ester bond between the core diterpene ring structure and the side chain. Conclusions Varying functional groups present in these compounds resulted in unique product ions that are specific to each structure. The established MS/MS fingerprints will be used in the near future for identification and for the development of multiple reaction monitoring liquid chromatography–MS/MS quantification methods.

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“…Furthermore, they mimic cell penetrating peptides located on viral capsids that are believed to be responsible for the viruses’ high infection capacity . Accordingly, a new series of gemini surfactants was introduced by coupling mono- and di- amino acids moieties into their spacer region. − They demonstrated a superior in vitro transfection efficiency and safety compared to the previously developed classical gemini surfactants. − In addition, topical application of lipoplexes composed of glycyl-lysine modified gemini surfactants, designated as 12-7N(G-K)-12, into rabbit vaginal cavities exhibited higher gene expression compared to the unsubstituted parent compound without evidence of visible toxicity …”

Section: Introductionmentioning

confidence: 99%

Molecular Engineering as an Approach To Modulate Gene Delivery Efficiency of Peptide-Modified Gemini Surfactants

Al‐Dulaymi¹,

Michel²,

Chitanda³

et al. 2018

Bioconjugate Chem.

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The unique molecular structure confers the diquaternary ammonium gemini surfactants with enhanced nucleic acid complexation ability, bottom-up design flexibility, and relatively low cytotoxicity. To capitalize on their potential as gene delivery vectors, novel structural modifications should be explored. In this work, 22 novel peptide-modified gemini surfactants with various alkyl tails and peptide spacer modifications were evaluated. This work represents the first report of dendrimer-like gemini surfactants and first evaluation of the impact of incorporating a hydrocarbon linker into the peptide chain. Our aim was to establish a structure activity relationship of the peptide-modified gemini surfactants and to identify the fundamental architectural requirements needed for the ultimate gene delivery systems. In vitro assessment revealed that the highest transfection efficiency and lowest cytotoxicity were associated with the glycyl-lysine modified gemini surfactants having the hexadecyl tail, 16-7N(G-K)-16. In fact, it showed an 8-fold increase in secreted protein with 20% increase in cell viability relative to the first-generation unsubstituted gemini surfactants. Further increase in the size of the attached peptides resulted in a decrease in the transfection efficiency and cell viability. Whereas the incorporation of a hydrocarbon linker into the peptide chain decreased the transfection efficiency of compounds with dipeptides, it increased the transfection efficiency of compounds with larger peptide chains. Such an increase was more prominent with the incorporation of a longer hydrocarbon linker. We conclude that a balance between the hydrophilic and hydrophobic characteristics of the compound is necessary since it results in physicochemical parameters conducive to the gene delivery process.

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The development of simple flow injection analysis tandem mass spectrometric methods for the cutaneous determination of peptide-modified cationic gemini surfactants used as gene delivery vectors

Cited by 6 publications

References 49 publications

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

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

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

Molecular Engineering as an Approach To Modulate Gene Delivery Efficiency of Peptide-Modified Gemini Surfactants

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