Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides

• Published in: European journal of pharmaceutics and biopharmaceutics 2019-01, Vol.134, p.166-177
• Main Authors: González-Paredes, Ana, Sitia, Leopoldo, Ruyra, Angels, Morris, Christopher J., Wheeler, Grant N., McArthur, Michael, Gasco, Paolo
• Format: Article
• Language: English
• Subjects: Animals; Anti-Infective Agents - administration & dosage; Antibacterial; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Cell Line, Tumor; Clostridioides difficile - drug effects; Clostridioides difficile - metabolism; Drug Carriers - chemistry; Drug Compounding - methods; Drug Resistance, Bacterial - drug effects; Embryo, Nonmammalian; Escherichia coli - drug effects; Escherichia coli - metabolism; Furans - chemistry; Gene Expression Regulation, Bacterial - drug effects; Intracellular delivery; Iron - metabolism; Lipids - chemistry; Microbial Sensitivity Tests; Nanoparticles - chemistry; Oligonucleotide; Oligonucleotides - administration & dosage; Oligonucleotides - genetics; Protamines - chemistry; Pyridones - chemistry; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - genetics; Repressor Proteins - metabolism; Sigma Factor - antagonists & inhibitors; Sigma Factor - genetics; Sigma Factor - metabolism; Solid lipid nanoparticles; Toxicity Tests - methods; Transcription factor decoy; Xenopus laevis
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2018.11.017

[Display omitted] 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-bis-tetrahydroacridinium 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 targeting the Fur iron uptake pathway in E. coli under microaerobic conditions. Biocompatibility of TFD-SLN was assessed using in vitro epithelial cell and in vivo Xenopus laevis embryo models. Taken together these results indicate that TFD-SLN complex can offer preferential accumulation of TFD in bacteria and represent a promising class of carriers for this experimental approach to tackling the worldwide AMR crisis.