Gene Delivery Mediated by Backbone-Degradable RAFT Copolymers

Cationic polymers present an attractive platform for
gene delivery.
However, these highly charged macromolecules can also lead to cytotoxicity.
Therefore, there is a strong unmet need to develop efficacious polymeric
gene delivery vehicles with high biocompatibility. Here, we leverage
recent advances in polymer chemistry to develop backbone-degradable
cationic copolymers and evaluate their potential as gene delivery
vehicles. Specifically, polycations were prepared via copolymerization
with macrocyclic allylic sulfides, which can participate in PET-RAFT
polymerization via radical ring-opening cascade copolymerization to
install degradable backbone segments. A polymer library with varying
degradabilities was prepared and evaluated using a model GFP plasmid
to transfect U-2 OS cells. Incorporation of degradable groups into
the copolymer backbone improved transfection efficiency 10-fold at
low amine/phosphate (N/P) ratios without increasing cytotoxicity,
thereby enhancing their value as gene delivery carriers. We hypothesize
that degradability may enhance the complex’s disassembly kinetics
in the cytosol, enabling more efficient payload release.