3 research outputs found
GalNAc- or Mannose-PEG-Functionalized Polyplexes Enable Effective Lectin-Mediated DNA Delivery
A cationic,
dendrimer-like oligo(aminoamide) carrier with four-arm
topology based on succinoyl tetraethylene pentamine and histidines,
cysteines, and N-terminal azido-lysines was screened
for plasmid DNA delivery on various cell lines. The incorporated azides
allow modification with various shielding agents of different polyethylene
glycol (PEG) lengths and/or different ligands by copper-free click
reaction, either before or after polyplex formation. Prefunctionalization
was found to be advantageous over postfunctionalization in terms of
nanoparticle formation, stability, and efficacy. A length of 24 ethylene
oxide repetition units and prefunctionalization of ≥50% of
azides per carrier promoted optimal polyplex shielding. PEG shielding
resulted in drastically reduced DNA transfer, which could be successfully
restored by active lectin targeting via novel GalNAc or mannose ligands,
enabling enhanced receptor-mediated endocytosis of the carrier system.
The involvement of the asialoglycoprotein receptor (ASGPR) in the
uptake of GalNAc-functionalized polyplexes was confirmed in the ASGPR-positive
hepatocarcinoma cell lines HepG2 and Huh7. Mannose-modified polyplexes
showed superior cellular uptake and transfection efficacy compared
to unmodified and shielded polyplexes in mannose-receptor-expressing
dendritic cell-like DC2.4 cells