TY - JOUR

T1 - Oligonucleotide Delivery across the Caco-2 Monolayer

T2 - The Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS)

AU - Kubackova, Jana

AU - Holas, Ondrej

AU - Zbytovska, Jarmila

AU - Vranikova, Barbora

AU - Zeng, Guanghong

AU - Pavek, Petr

AU - Mullertz, Anette

PY - 2021/4

Y1 - 2021/4

N2 - 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 x 10(-7) cm/s, unlike neutral SEDDS, which displayed an increasing permeability reaching up to 7 x 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.

AB - 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 x 10(-7) cm/s, unlike neutral SEDDS, which displayed an increasing permeability reaching up to 7 x 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.

KW - oligonucleotide

KW - self-emulsifying drug delivery systems

KW - hydrophobic ion pairing

KW - intestinal permeation enhancers

KW - Caco-2 monolayer

U2 - 10.3390/pharmaceutics13040459

DO - 10.3390/pharmaceutics13040459

M3 - Journal article

C2 - 33800701

VL - 13

JO - Pharmaceutics

JF - Pharmaceutics

SN - 1999-4923

IS - 4

M1 - 459

ER -