Abstract
Oligonucleotides (OND) represent a promising therapeutic approach. However, their instability and low intestinal permeability hamper oral bioavailability. Well-established for oral delivery, self-emulsifying drug delivery systems (SEDDS) can overcome the weakness of other delivery systems such as long-term instability of nanoparticles or complicated formulation processes. Therefore, the present study aims to prepare SEDDS for delivery of a nonspecific fluorescently labeled OND across the intestinal Caco-2 monolayer. The hydrophobic ion pairing of an OND and a cationic lipid served as an effective hydrophobization method using either dimethyldioctadecylammonium bromide (DDAB) or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). This strategy allowed a successful loading of OND-cationic lipid complexes into both negatively charged and neutral SEDDS. Subjecting both complex-loaded SEDDS to a nuclease, the negatively charged SEDDS protected about 16% of the complexed OND in contrast to 58% protected by its neutral counterpart. Furthermore, both SEDDS containing permeation-enhancing excipients facilitated delivery of OND across the intestinal Caco-2 cell monolayer. The negatively charged SEDDS showed a more stable permeability profile over 120 min, with a permeability of about 2 × 10−7 cm/s, unlike neutral SEDDS, which displayed an increasing permeability reaching up to 7 × 10−7 cm/s. In conclusion, these novel SEDDS-based formulations provide a promising tool for OND protection and delivery across the Caco-2 cell monolayer.
Highlights
This article is an open access articleGene therapy offers highly specific therapeutics without significant side effects
If OND becomes cleaved by a nuclease, short OND fragments are detected in the supernatant that do not precipitate into pellets
The OND solution was confirmed to be nontoxic. For both the Citrem and Standard self-emulsifying drug delivery systems (SEDDS), there were no significant differences between the applied SEDDS formulations, which suggests that the main contribution to the cytotoxicity is from the surfactants in SEDDS and not the cationic lipids or the complexes
Summary
Gene therapy offers highly specific therapeutics without significant side effects. It covers a wide variety of approaches, ranging from the replacement of malfunctioning genetic information, often in the form of a large nonviral plasmid DNA (pDNA), to the currently more investigated oligonucleotide (OND)-based therapy acting on the level of mRNA destabilization or translation [1,2]. The hydrophobic ion pairing of nucleic acids is a method based on replacing the counterions associated with negatively charged phosphate groups with surfactants carrying the positive charge This method leads to a lipophilicity increase of the resulting ion-paired complexes [20]. Mahmood et al improved the transfection efficiency of pDNA-cetrimide in an of alogical SEDDS by the incorporation of a cell-penetrating peptide and confirmed an internalization of 50-nm nanoemulsions in Caco-2 cells [32] Both studies focused on the delivery of large pDNA into cells. SEDDS by delivery the incorporation of a cell-penetrating peptide and confirmed interstudy focuses on the of short OND sequences as emerging, highly potentantheranalization of. In this study hydrophobized beled 20-mer OND were thoroughly described and subsequently loaded into SEDDS
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