Phosphonium-containing diblock copolymers for enhanced colloidal stability and efficient nucleic acid delivery

Area of Science:

• Polymer Chemistry
• Biomaterials Science
• Gene Delivery

Background:

• Nonviral gene delivery systems are crucial for therapeutic applications.
• Developing stable and efficient gene delivery vectors remains a challenge.
• Phosphonium-based polymers offer potential for nucleic acid complexation.

Purpose of the Study:

• To synthesize phosphonium-based AB diblock copolymers for nonviral gene delivery.
• To evaluate the DNA binding, polyplex stability, and transfection efficiency of these copolymers.
• To assess the cytotoxicity of the developed gene delivery vehicles.

Main Methods:

• Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization was employed for controlled copolymer synthesis.
• Diblock copolymers were synthesized with stabilizing blocks (oligo(ethylene glycol) methyl ether methacrylate or 2-(methacryloxy)ethyl phosphorylcholine) and cationic phosphonium blocks.
• DNA binding, polyplex formation, colloidal stability, cellular uptake, transfection efficiency, and cytotoxicity were evaluated in vitro.

Main Results:

• Well-defined diblock copolymers with varying phosphonium block lengths were synthesized.
• Efficient DNA binding and polyplex formation (100-200 nm hydrodynamic diameter) were observed.
• Polyplexes demonstrated excellent colloidal stability under physiological conditions and low cytotoxicity (>80% cell viability).
• Successful in vitro transfection was achieved in HepaRG cells, comparable to commercial Jet-PEI, despite low uptake in COS-7 and HeLa cells.

Conclusions:

• Phosphonium-based AB diblock copolymers synthesized via RAFT polymerization are effective nonviral gene delivery vehicles.
• The developed copolymers exhibit favorable DNA complexation, polyplex stability, and low cytotoxicity.
• Promising in vitro transfection results warrant further investigation for in vivo applications.