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

Mamusa, Marianna; Resta, Claudio; Barbero, Francesco; Carta, Davide; Codoni, Doroty; Hatzixanthis, Kostas; McArthur, Michael; Berti, Debora

doi:10.1016/j.colsurfb.2016.03.031

Cited by 14 publications

(15 citation statements)

References 37 publications

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“…For ON-C-Chol ( Figure 4A), absence of THA second layer led to TFD degradation ( Figure 4A These results suggest that external THA generates full TFD protection against enzymatic degradation, probably because of improved hiding and condensed state of TFD, a structural conformation which may help in making it refractory to DNase I. These observations are consistent with published circular dichroism spectroscopy data demonstrating DNA condensation by 12-bis-THA [37,38]. Representative images of SLN interaction with bacteria were obtained after 1 and 4 hours of incubation ( Figure 5 and figure S3).…”

Section: Dnase I Protection Studiessupporting

confidence: 88%

Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides

González-Paredes¹,

Sitia

Ruyra

et al. 2019

European Journal of Pharmaceutics and Biopharmaceutics

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Novel alternatives to antibiotics are urgently needed for the successful treatment of antimicrobial resistant (AMR) infections. Experimental antibacterial oligonucleotide therapeutics, such as transcription factor decoys (TFD), are a promising approach to circumvent AMR. However, the therapeutic potential of TFD is contingent upon the development of carriers that afford efficient DNA protection against nucleases and delivery of DNA to the target infection site. As a carrier for TFD, here we present three prototypes of anionic solid lipid nanoparticles that were coated with either the cationic bolaamphiphile 12-bistetrahydroacridinium or with protamine. Both compounds switched particles zeta potential to positive values, showing efficient complexation with TFD and demonstrable protection from deoxyribonuclease. The effective delivery of TFD into bacteria was confirmed by confocal microscopy while SLN-bacteria interactions were studied by flow cytometry. Antibacterial efficacy was confirmed using a model TFD

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Section: Dnase I Protection Studiessupporting

confidence: 88%

Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides

González-Paredes¹,

Sitia

Ruyra

et al. 2019

European Journal of Pharmaceutics and Biopharmaceutics

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“…In order to check the efficient incorporation of LPS in GUV membranes, we employed a fluorescently labeled LPS. to what previously shown [16]. When GUVs of POPC-CL were used, LNP docked at GUV membranes and fused with them after 2 h incubation ( Figure 3a-c); in addition, part of the lipid probe originally staining the GUVs bilayer migrated into the aggregates (white arrows, Figure 3a).…”

Section: Confocal Microscopy and Microfluidicssupporting

confidence: 71%

Multifunctional nanoassemblies target bacterial lipopolysaccharides for enhanced antimicrobial DNA delivery

Montis

Joseph

Magnani

et al. 2020

Colloids and Surfaces B: Biointerfaces

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Antibacterial 12-bis-THA/TFD hybrid nanoplexes are investigated  Nanoplexes-bacteria interaction are studied using membrane models and live cells  12-bis-THA targets and sequesters LPS, delivering anti-inflammatory activity  12-bis-THA-LPS interaction facilitates the entry of antimicrobial TFD in bacteria  Versatile nanoplexes against Gram-ve bacteria are a promising therapeutic option ABSTRACT The development of new therapeutic strategies against multidrug resistant Gramnegative bacteria is a major challenge for pharmaceutical research. In this respect, it is increasingly recognized that an efficient treatment for resistant bacterial infections should combine antimicrobial and anti-inflammatory effects. Here, we explore the multifunctional therapeutic potential of nanostructured self-assemblies from a cationic bolaamphiphile, which target bacterial lipopolysaccharides (LPSs) and associates with an anti-bacterial nucleic acid to form nanoplexes with therapeutic efficacy against Gram-negative bacteria. To understand the mechanistic details of these multifunctional antimicrobial-anti-inflammatory properties, we performed a fundamental study, comparing the interaction of these nanostructured therapeutics with synthetic biomimetic bacterial membranes and live bacterial cells. Combining a wide range of experimental techniques (Confocal Microscopy, Fluorescence Correlation Spectroscopy, Microfluidics, NMR, LPS binding assays), we demonstrate that the LPS targeting capacity of the bolaamphiphile self-assemblies, comparable to that exerted by Polymixin B, is a key feature of these nanoplexes and one that permits entry of therapeutic nucleic acids in Gram-negative bacteria. These findings enable a new approach to the design of efficient multifunctional therapeutics with combined antimicrobial and anti-inflammatory effects and have therefore the potential to broadly impact fundamental and applied research on self-assembled nano-sized antibacterials for antibiotic resistant infections.

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“…1a) is characterized by a saturated hydrophobic chain of twelve carbon atoms connecting two acridinium monopositive polar headgroups. Due to hydrophobic interactions, 12-bis-THA self-assembles in water at a 0.18 mM concentration, forming nanosized entities (named empty nanoplexes, ENPs)13 with very low scattering intensity, whose hydrodynamic diameter (DLS) and zeta potential was estimated around 180 nm and +43 mV, respectively. TFD (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1a), has been described. It forms nanoplexes, which selectively target bacteria, therefore offering a potentially bacteria-selective gene-delivery system13. We propose that targeting of non-redundant transcription factors in bacterial cells is less likely to lead to resistance compared to conventional antibiotics and antimicrobial peptides1415 which can induce minor mutations and profound phenotypic shift in target bacteria16.…”

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confidence: 99%

Antimicrobial Nanoplexes meet Model Bacterial Membranes: the key role of Cardiolipin

Marín-Menéndez

Montis

Díaz-Calvo

et al. 2017

Sci Rep

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Antimicrobial resistance to traditional antibiotics is a crucial challenge of medical research. Oligonucleotide therapeutics, such as antisense or Transcription Factor Decoys (TFDs), have the potential to circumvent current resistance mechanisms by acting on novel targets. However, their full translation into clinical application requires efficient delivery strategies and fundamental comprehension of their interaction with target bacterial cells. To address these points, we employed a novel cationic bolaamphiphile that binds TFDs with high affinity to form self-assembled complexes (nanoplexes). Confocal microscopy revealed that nanoplexes efficiently transfect bacterial cells, consistently with biological efficacy on animal models. To understand the factors affecting the delivery process, liposomes with varying compositions, taken as model synthetic bilayers, were challenged with nanoplexes and investigated with Scattering and Fluorescence techniques. Thanks to the combination of results on bacteria and synthetic membrane models we demonstrate for the first time that the prokaryotic-enriched anionic lipid Cardiolipin (CL) plays a key-role in the TFDs delivery to bacteria. Moreover, we can hypothesize an overall TFD delivery mechanism, where bacterial membrane reorganization with permeability increase and release of the TFD from the nanoplexes are the main factors. These results will be of great benefit to boost the development of oligonucleotides-based antimicrobials of superior efficacy.

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

Abstract: ABSTRACT

Cited by 14 publications

References 37 publications

Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides

Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides

Multifunctional nanoassemblies target bacterial lipopolysaccharides for enhanced antimicrobial DNA delivery

Antimicrobial Nanoplexes meet Model Bacterial Membranes: the key role of Cardiolipin

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