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.

Synthesis of Porphyrin and Bacteriochlorin Glycoconjugates through CuAAC Reaction Tuning.

Rapid and reproducible access to a series of unique porphyrin and bacteriochlorin glycoconjugates, including meso-glycosylated porphyrins and bacteriochlorins, and beta-glycosylated porphyrins, via copper catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) is reported for the first time. The work presented highlights the system-dependent reaction conditions required for glycosylation to porphyrins and bacteriochlorins based on the unique electronic properties of each ring system. Attenuated reaction conditions were used to synthesize fifteen new glycosylated porphyrin and bacteriochlorin analogs in 74 - 99% yield, and were extended to solid support to produce the first oligo(amidoamine)-based porphyrin glycoconjugate. These compounds hold significant potential as next generation water soluble catalysts and photodynamic therapy/photodynamic inactivation (PDT/PDI) agents.