Diaminododecane-based cationic bolaamphiphile as a non-viral gene delivery carrier

To obtain efficient non-viral vectors, a series of Gemini cationic lipids with carbamate linkers between headgroups and hydrophobic tails were synthesized. They have the hydrocarbon chains of 12, 14, 16 and 18 carbon atoms as tails, designated as G12, G14, G16 and G18, respectively. These Gemini cationic lipids were prepared into cationic liposomes for the study of the physicochemical properties and gene delivery. The DNA-bonding ability of these Gemini cationic liposomes was much better than their mono-head counterparts (designated as M12, M14, M16 and M18, respectively). In the same series of liposomes, bonding ability declined with an increase in tail length. They were tested for their gene-transferring capabilities in Hep-2 and A549 cells. They showed higher transfection efficiency than their mono-head counterparts and were comparable or superior in transfection efficiency and cytotoxicity to the commercial liposomes, DOTAP and Lipofectamine 2000. Our results convincingly demonstrate that the gene-transferring capabilities of these cationic lipids depended on hydrocarbon chain length. Gene transfection efficiency was maximal at a chain length of 14, as G14 can silence about 80 % of luciferase in A549 cells. Cell uptake results indicate that Gemini lipid delivery systems could be internalised by cells very efficiently. Thus, the Gemini cationic lipids could be used as synthetic non-viral gene delivery carriers for further study.

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“…A DNA complex size of approximately 200 nm and a positively charged surface are desirable for cellular uptake. 30 …”

Section: Resultsmentioning

confidence: 99%

Novel Gemini cationic lipids with carbamate groups for gene delivery

et al. 2014

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“…By observing the absorption spectra in Figure S10, authors for classic cationic surfactants [37], gemini surfactants [35,36], and bolaamphiphiles [38,39]. This can be an advantage compared to certain cationic species which necessitate higher Z+/-values to saturate the DNA: for example, other authors reported Z+/-= 4 for poly(ethylenimine) [40], Z+/-= 10 for TTAB and Z+/-= 30 for DTAB [34], which necessitate higher amounts of typically cytotoxic compounds to reach full condensation.…”

Section: Aqueous Solution Behavior Of [12-bis-tha]cl2mentioning

confidence: 99%

Interaction between a cationic bolaamphiphile and DNA: The route towards nanovectors for oligonucleotide antimicrobials

Mamusa

Resta

Barbero³

et al. 2016

Colloids and Surfaces B: Biointerfaces

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“…The nanocomplex N/P ratio should preferably be sufficiently high to complex the anionic oligonucleotide cargo and provide a net positive charge to promote interaction with the negatively charged cells, while minimizing the complexed vesicle size and any toxicity issues. 26,54 Complexation and retention of 25-mer gapmer ASO during agarose gel electrophoresis with bolasome preparations of both compounds resulted in the complete loss of free oligonucleotide fluorescence approaching an N/P ratio of 5 ( Figure 8B). …”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24][25] In particular, cationic bolaamphiphile nanovesicles (bolasomes) have recently been used to deliver plasmid DNA into eukaryotic cells more effectively than the gold standard of cationic polymers, polyethylenimine. 26 Cationic bolaamphiphiles are amphiphilic molecules with hydrophilic charge centers separated by an internal hydrophobic chain. The supramolecular self-organization of cationic bolaamphiphiles in an aqueous environment can produce monolayer bolasomes with a high packing density.…”

Section: Introductionmentioning

confidence: 99%

Bolaamphiphile-based nanocomplex delivery of phosphorothioate gapmer antisense oligonucleotides as a treatment for <em>Clostridium difficile</em>

Hegarty

Krzeminski

Sharma

et al. 2016

IJN

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Despite being a conceptually appealing alternative to conventional antibiotics, a major challenge toward the successful implementation of antisense treatments for bacterial infections is the development of efficient oligonucleotide delivery systems. Cationic vesicles (bolasomes) composed of dequalinium chloride (“DQAsomes”) have been used to deliver plasmid DNA across the cardiolipin-rich inner membrane of mitochondria. As cardiolipin is also a component of many bacterial membranes, we investigated the application of cationic bolasomes to bacteria as an oligonucleotide delivery system. Antisense sequences designed in silico to target the expression of essential genes of the bacterial pathogen, Clostridium difficile , were synthesized as 2′- O -methyl phosphorothioate gapmer antisense oligonucleotides (ASO). These antisense gapmers were quantitatively assessed for their ability to block mRNA translation using luciferase reporter and C. difficile protein expression plasmid constructs in a coupled transcription–translation system. Cationic bolaamphiphile compounds (dequalinium derivatives) of varying alkyl chain length were synthesized and bolasomes were prepared via probe sonication of an aqueous suspension. Bolasomes were characterized by particle size distribution, zeta potential, and binding capacities for anionic oligonucleotide. Bolasomes and antisense gapmers were combined to form antisense nanocomplexes. Anaerobic C. difficile log phase cultures were treated with serial doses of gapmer nanocomplexes or equivalent amounts of empty bolasomes for 24 hours. Antisense gapmers for four gene targets achieved nanomolar minimum inhibitory concentrations for C. difficile , with the lowest values observed for oligonucleotides targeting polymerase genes rpoB and dnaE . No inhibition of bacterial growth was observed from treatments at matched dosages of scrambled gapmer nanocomplexes or plain, oligonucleotide-free bolasomes compared to untreated control cultures. We describe the novel application of cationic bolasomes to deliver ASOs into bacteria. We also report the first successful in vitro antisense treatment to inhibit the growth of C. difficile .

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Diaminododecane-based cationic bolaamphiphile as a non-viral gene delivery carrier

Cited by 46 publications

References 38 publications

Novel Gemini cationic lipids with carbamate groups for gene delivery

Novel Gemini cationic lipids with carbamate groups for gene delivery

Interaction between a cationic bolaamphiphile and DNA: The route towards nanovectors for oligonucleotide antimicrobials

Bolaamphiphile-based nanocomplex delivery of phosphorothioate gapmer antisense oligonucleotides as a treatment for <em>Clostridium difficile</em>

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