Lipid Conjugates Enhance Endosomal Release of Antisense Oligonucleotides Into Cells.
Nucleic Acid Ther
; 29(5): 245-255, 2019 10.
Article
in En
| MEDLINE
| ID: mdl-31158063
ABSTRACT
Antisense oligonucleotides modified with phosphorothioate linkages (PS-ASOs) can enter cells via endocytic pathways and must escape from membraned organelles to reach target RNAs. We recently found that membrane destabilization induced by different lipid species contributes to PS-ASO release from late endosomes (LEs). In this study, we characterized intracellular uptake, trafficking, and activities of PS-ASOs conjugated with different lipid species. We found that palmitic acid-, tocopherol-, and cholesterol-conjugated PS-ASOs have increased protein binding and enhanced intracellular uptake compared to unconjugated PS-ASOs. Similar to the parental PS-ASO, the lipid-conjugated PS-ASOs traffic from early to LEs without incorporation into lipid droplets. Unlike parental PS-ASOs, the lipid-conjugated PS-ASOs tend to remain associated with plasma or endosomal membranes, and this appears to influence their release from endosomes. The lipid-conjugated PS-ASOs were released more rapidly than parental PS-ASO. These results suggest that lipid conjugation enhances the interactions of PS-ASOs with proteins or membranes, in turn facilitating intracellular trafficking and endosomal release.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oligonucleotides, Antisense
/
Endocytosis
/
Phosphorothioate Oligonucleotides
/
Lipids
Limits:
Animals
/
Humans
Language:
En
Journal:
Nucleic Acid Ther
Year:
2019
Document type:
Article
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA