Drug delivery system of therapeutic oligonucleotides

Asami, Yasushi; Yoshioka, Koshiro; Nishina, Kazutaka; Nagata, Tetsuya; Yokota, Takanori

doi:10.5582/ddt.2016.01065

Cited by 27 publications

(14 citation statements)

References 32 publications

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“…These studies demonstrate the anti -EFG1 2′OMe Candida cellular uptake without carriers or transfection agents for instance, by adsorptive endocytosis as in other microorganisms,48, 49, 50 and its ability to hybridize with the respective target with high specificity for C. albicans cells.…”

Section: Resultsmentioning

confidence: 63%

Application of 2′-OMethylRNA′ Antisense Oligomer to Control Candida albicans EFG1 Virulence Determinant

Araújo

Azevedo

Barbosa

et al. 2019

Molecular Therapy - Nucleic Acids

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Antisense oligomers and their analogs have been successfully utilized to silence gene expression for the treatment of many human diseases; however, the control of yeast's virulence determinants has never been exploited before. In this sense, this work is based on the key hypothesis that if a pathogen's genetic sequence is a determinant of virulence, it will be possible to synthesize a nucleic acid mimic based on antisense therapy (AST) that will bind to the mRNA produced, blocking its translation into protein and, consequently, reducing the pathogen virulence phenotype. EFG1 is an important determinant of virulence that is involved in the regulation of the Candida albicans switch from yeast to filamentous form. Thus, our main goal was to design and synthesize an antisense oligonucleotide (ASO) targeting the EFG1 mRNA and to validate its in vitro applicability. The results show that the anti-EFG1 2 0-OMethylRNA (2 0 OMe) oligomer was able to significantly reduce the levels of EFG1 gene expression and of Efg1p protein translation (both approximately 60%), as well as effectively prevent filamentation of C. albicans cells (by 80%). Moreover, it was verified that anti-EFG1 2 0 OMe keeps the efficacy in different simulated human body fluids. Undeniably, this work provides potentially valuable information for future research into the management of Candida infections, regarding the development of a credible and alternative method to control C. albicans infections, based on AST methodology.

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Section: Resultsmentioning

confidence: 63%

Application of 2′-OMethylRNA′ Antisense Oligomer to Control Candida albicans EFG1 Virulence Determinant

Araújo

Azevedo

Barbosa

et al. 2019

Molecular Therapy - Nucleic Acids

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“…Intracellular delivery of siRNA can be enhanced by employing nanoparticle-based delivery approaches. 4 , 5 , 6 , 7 Lipid-based delivery systems, in particular cationic lipids, have been shown to facilitate overcoming the critical obstacles to efficient siRNA delivery, which include pharmacokinetic barriers (a short circulation half-life due to susceptibility for nuclease degradation) and barriers at the cellular level (cellular uptake, intracellular trafficking, and endosomal escape to reach the cytosol). 5 However, major drawbacks of commonly applied cationic lipids for siRNA delivery, e.g., 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), and dimethyldioctadecyl-ammonium bromide (DDAB), include (1) limited electrostatic interaction with siRNA as a result of the single quaternary ammonium head group (as opposed to structures containing multiple amine functionalities; see below), (2) activation of the innate immune system leading to undesired side effects, and (3) unfavorable biodistribution because of nonspecific tissue distribution and protein binding, eventually resulting in a relatively narrow therapeutic window.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design

Groot

Thanki

Gangloff

et al. 2018

Molecular Therapy - Nucleic Acids

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Therapeutics based on small interfering RNA (siRNA) have promising potential as antiviral and anti-inflammatory agents. To deliver siRNA across cell membranes to reach the RNAi pathway in the cytosol of target cells, non-viral nanoparticulate delivery approaches are explored. Recently, we showed that encapsulation of siRNA in lipid-polymer hybrid nanoparticles (LPNs), based on poly(DL-lactic-co-glycolic acid) (PLGA) and cationic lipid-like materials (lipidoids), remarkably enhances intracellular delivery of siRNA as compared to siRNA delivery with LPNs modified with dioleoyltrimethylammoniumpropane (DOTAP) as the lipid component. However, the potential immune modulation by these cationic lipids remains unexplored. By testing lipidoids and DOTAP for innate immune-receptor-activating properties in vitro, we found that neither lipidoids nor DOTAP activate human Toll-like receptor (TLR) 2, 3, 7, and 9. However, in contrast to DOTAP, lipidoids are strong agonists for TLR4 and activate murine antigen-presenting cells in vitro. This agonistic effect was further confirmed in silico using a prediction model based on crystal structures. Also, lipidoids formulated as lipoplexes or as stable nucleic acid lipid particles, which was the reference formulation for siRNA delivery, proved to activate TLR4. However, by combining lipidoids with PLGA into LPNs, TLR4 activation was abrogated. Thus, lipidoid-mediated TLR4 activation during siRNA delivery may be modulated via optimization of the formulation design.

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“…Only a tiny fraction of the accumulated oligonucleotide spontaneously leaks from the endosomes, although this is sometimes enough to provide a pharmacological effect. There have been many efforts to increase both the cellular uptake and intracellular release of oligonucleotides including various targeting ligands and endomembrane destabilizing polymers or nanoparticles [2,8].…”

Section: Introductionmentioning

confidence: 99%

Retro-1-Oligonucleotide Conjugates. Synthesis and Biological Evaluation

et al. 2019

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Addition of small molecule Retro-1 has been described to enhance antisense and splice switching oligonucleotides. With the aim of assessing the effect of covalently linking Retro-1 to the biologically active oligonucleotide, three different derivatives of Retro-1 were prepared that incorporated a phosphoramidite group, a thiol or a 1,3-diene, respectively. Retro-1–oligonucleotide conjugates were assembled both on-resin (coupling of the phosphoramidite) and from reactions in solution (Michael-type thiol-maleimide reaction and Diels-Alder cycloaddition). Splice switching assays with the resulting conjugates showed that they were active but that they provided little advantage over the unconjugated oligonucleotide in the well-known HeLa Luc705 reporter system.

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Drug delivery system of therapeutic oligonucleotides

Cited by 27 publications

References 32 publications

Application of 2′-OMethylRNA′ Antisense Oligomer to Control Candida albicans EFG1 Virulence Determinant

Application of 2′-OMethylRNA′ Antisense Oligomer to Control Candida albicans EFG1 Virulence Determinant

Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design

Retro-1-Oligonucleotide Conjugates. Synthesis and Biological Evaluation

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