Toward Intracellular Delivery: Aliphatic Polycarbonates with Pendant Thiol-Reactive Thiosulfonates for Reversible Postpolymerization Modification

Postpolymerization modifications are valuable techniques for creating functional polymers that are challenging to synthesize directly. This study presents aliphatic polycarbonates with pendant thiol-reactive groups for disulfide formation with mercaptans. The reductive responsive nature of this reaction allows for reversible postpolymerization modifications on biodegradable scaffolds. Six-membered cyclic carbonate monomers with pendant thiosulfonate groups were synthesized and polymerized using controlled organocatalytic ring-opening polymerization, yielding polymers with narrow molecular weight dispersities (<i>Đ</i> = 1.2) and intact reactive thiosulfonate side chains. Reversible modification with benzyl mercaptans achieved high degrees of disulfide modification. Additionally, thiol-reactive carbonate monomers were block-copolymerized onto polyethylene glycol (mPEG₁₁₃) and then converted into benzyl disulfides, while the block copolymers' hydroxyl end groups remained available for fluorescent dye labeling. The amphiphilic block copolymers self-assembled in water into micelles (∼33 nm diameter), capable of encapsulating hydrophobic molecules. These micelles successfully delivered hydrophobic dyes into macrophages, indicating the potential for intracellular drug delivery.