Interfacially Engineered Pyridinium Pseudogemini Surfactants as Versatile and Efficient Supramolecular Delivery Systems for DNA, siRNA, and mRNA

Satyal, Uttam; Draghici, Bogdan; Dragic, Lisa; Norris, Kyle W.; Madesh, Muniswamy; Brǎiloiu, Eugen; Ilies, Marc A.

doi:10.1021/acsami.7b07066

Cited by 13 publications

(16 citation statements)

References 69 publications

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“…This compound, referred to as C 3 (C 16 His) 2 , consists of two N ( τ ), N ( π )-bis(methyl)-histidine hexyl amides linked through a bridge of three –CH 2 – groups (Scheme 1). The palmitoyl fatty chain (C 16 ) has been selected based on the structure–activity results relationship reported in the literature, which suggests that surfactants with C 16 –C 18 alkyl chains exhibit superior transfection properties [58,59].…”

Section: Resultsmentioning

confidence: 99%

A Gemini Cationic Lipid with Histidine Residues as a Novel Lipid-Based Gene Nanocarrier: A Biophysical and Biochemical Study

et al. 2018

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This work reports the synthesis of a novel gemini cationic lipid that incorporates two histidine-type head groups (C3(C16His)2). Mixed with a helper lipid 1,2-dioleoyl-sn-glycero-3-phosphatidyl ethanol amine (DOPE), it was used to transfect three different types of plasmid DNA: one encoding the green fluorescence protein (pEGFP-C3), one encoding a luciferase (pCMV-Luc), and a therapeutic anti-tumoral agent encoding interleukin-12 (pCMV-IL12). Complementary biophysical experiments (zeta potential, gel electrophoresis, small-angle X-ray scattering (SAXS), and fluorescence anisotropy) and biological studies (FACS, luminometry, and cytotoxicity) of these C3(C16His)2/DOPE-pDNA lipoplexes provided vast insight into their outcomes as gene carriers. They were found to efficiently compact and protect pDNA against DNase I degradation by forming nanoaggregates of 120–290 nm in size, which were further characterized as very fluidic lamellar structures based in a sandwich-type phase, with alternating layers of mixed lipids and an aqueous monolayer where the pDNA and counterions are located. The optimum formulations of these nanoaggregates were able to transfect the pDNAs into COS-7 and HeLa cells with high cell viability, comparable or superior to that of the standard Lipo2000*. The vast amount of information collected from the in vitro studies points to this histidine-based lipid nanocarrier as a potentially interesting candidate for future in vivo studies investigating specific gene therapies.

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Section: Resultsmentioning

confidence: 99%

A Gemini Cationic Lipid with Histidine Residues as a Novel Lipid-Based Gene Nanocarrier: A Biophysical and Biochemical Study

et al. 2018

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“…Recently, pyridinium amphiphiles were shown to generate promising transfection systems for gene therapy [29,30,31,32]. Several supramolecular pyridinium containing complexes proved to be extremely efficient nucleic acid delivery systems, displaying excellent serum stability and tissue penetration [30,32].…”

Section: Introductionmentioning

confidence: 99%

“…Besides, pyridinium containing compounds are used as herbicides [38,39], drugs [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32], and as intermediates in the synthesis of many heterocyclic compounds [1,2,3,4,5,6,7,11] and are considered as possible exogenous neurotoxins [40,41,42]. However, several lines of evidence suggest that pyridinium derivatives may be formed under endogenous conditions [43], for example during the Maillard reaction between proteins and carbonyl compounds [43,44,45].…”

Section: Introductionmentioning

confidence: 99%

Novel Synthesis of Substituted 2-Trifluoromethyl and 2-Perfluoroalkyl N-Arylpyridinium Compounds—Mechanistic Insights

et al. 2019

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We report a new one-pot synthesis of 2-trifluoromethylated/2-perfluoroalkylated N-aryl-substituted pyridiniums, 5,6,7,8-tetrahydroquinoliniums and 6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridinium compounds starting from an activated β-dicarbonyl analogue (here a perfluoro-alkylated gem-iodoacetoxy derivative), an aromatic amine and a (cyclic or acyclic) ketone. The key step of this multicomponent reaction, involves the formation of a 3-perfluoroalkyl-N,N’-diaryl-1,5-diazapentadiene intermediate, various examples of which were isolated and characterized for the first time, together with investigation of their reactivity. We propose a mechanism involving a concurrent inverse electron demand Diels-Alder or Aza-Robinson cascade cyclisation, followed by a bis-de-anilino-elimination. Noteworthy, a meta-methoxy substituent on the aniline directs the reaction towards a 2-perfluoroalkyl-7-methoxyquinoline, resulting from the direct cyclization of the diazapentadiene intermediate, instead of pyridinium formation. This is the first evidence of synthesis of pyridinium derivatives from activated β-dicarbonyls, ketones, and an aromatic amine, the structures of which (both reactants and products) being analogous to species involved in biological systems, especially upon neurodegenerative diseases such as Parkinson’s. Beyond suggesting chemical/biochemical analogies, we thus hope to outline new research directions for understanding the mechanism of in vivo formation of pyridiniums, hence possible pharmaceutical strategies to better monitor, control or prevent it.

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“…With N/P = 2 and DOPE (α = 0.5), these compounds gave transfection of NCI-H23 cells equivalent to that of Lipofectamine; the optimum alkyl chain length was the intermediate one (b) in both cases. 170 The observed lower (virtually absent) cytotoxicity of the ester 69 compared to the amide 70 was tentatively ascribed to the different products expected to be formed by enzymic hydrolysis. For the pseudogemini analogue 71 in which the amide bond is reversed HO-Chol was a better helper lipid than DOPE, and the transfection activity at N/P = 2 decreased in the order 71c > 71a > 71b, with much reduced toxicity compared to 70.…”

Section: Geminis With Delocalized Chargesmentioning

confidence: 96%

Transfection by cationic gemini lipids and surfactants

Damen¹,

Groenen²,

Dongen³

et al. 2018

Med. Chem. Commun.

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Interfacially Engineered Pyridinium Pseudogemini Surfactants as Versatile and Efficient Supramolecular Delivery Systems for DNA, siRNA, and mRNA

Cited by 13 publications

References 69 publications

A Gemini Cationic Lipid with Histidine Residues as a Novel Lipid-Based Gene Nanocarrier: A Biophysical and Biochemical Study

A Gemini Cationic Lipid with Histidine Residues as a Novel Lipid-Based Gene Nanocarrier: A Biophysical and Biochemical Study

Novel Synthesis of Substituted 2-Trifluoromethyl and 2-Perfluoroalkyl N-Arylpyridinium Compounds—Mechanistic Insights

Transfection by cationic gemini lipids and surfactants

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