Oligonucleotide Delivery across the Caco-2 Monolayer: The Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS)

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.

Comparison of Cellular Monolayers and an Artificial Membrane as Absorptive Membranes in the in vitro Lipolysis-permeation Assay

“…Based on the current and previous studies, the Caco-2 cells seem more suitable than the MDCK monolayers for (dissolution-)permeation systems that evaluate the performance of enabling formulations and LBFs in particular. 17,30,43,44 A strategy to protect the MDCK cells from potentially detrimental effects of the digestion medium could be a mucus layer on top of the membrane, as has been done with Caco-2 cells. 25 Falavigna et al applied biosimilar mucus to an artificial PVPA barrier with the aim of simulating the intestinal mucosa.…”

Therapeutic Peptides and Proteins: Stabilization Challenges and Biomedical Applications by Means of Nanodelivery Systems

“…Self-emulsifying drug delivery systems (SEDDS) are systems that are easy to produce, the reason why they are preferred by the pharmaceutical industry (Kubackova et al 2021). SEDDS are defined as mixtures of oils, surfactants, solvents and optionally co-solvents/surfactants that form nano-scaled oil-in-water (o/w) emulsions when they come into contact with an aqueous medium (Leonaviciute and Bernkop-Schnürch 2015).…”

Sorafenib Repurposing for Ophthalmic Delivery by Lipid Nanoparticles: A Preliminary Study

“…These results highlighted a different ability of the two cationic lipids to interact with mucin, with DDAB having greater mucoadhesive properties compared to DOTAP. This effect could be related to their different chemical structure, also affecting their physical state at room temperature (DDAB exists as gel while DOTAP as liquid crystalline): both aliphatic chains of DDAB are saturated, unlike DOTAP, whose chains present a double bond in the C9 position [43]. The mucoadhesive properties are correlated with the ionic interaction between the monovalent cationic lipid and the negatively charged sialic acid groups of eye mucin, with subsequent formation of non-covalent bonds [42].…”