Influence of Block versus Random Monomer Distribution on the Cellular Uptake of Hydrophilic Copolymers

The use of polymers has revolutionized the field of drug delivery in the past two decades. Properties such as polymer size, charge, hydrophilicity, or branching have all been shown to play an important role in the cellular internalization of polymeric systems. In contrast, the fundamental impact of monomer distribution on the resulting biological properties of copolymers remains poorly studied and is always only investigated for biologically active self-assembling polymeric systems. Here, we explore the fundamental influence of monomer distribution on the cellular uptake of nonaggregating and biologically passive copolymers. Reversible addition-fragmentation chain-transfer (RAFT) polymerization was used to prepare precisely defined copolymers of three hydrophilic acrylamide monomers. The cellular internalization of block copolymers was compared with the uptake of a random copolymer where monomers are statistically distributed along the chain. The results demonstrate that monomer distribution in itself has a negligible impact on copolymer uptake: