Guanidine-Containing Methacrylamide (Co)polymers via <i>a</i>RAFT: Toward a Cell-Penetrating Peptide Mimic

We report the synthesis and controlled radical homopolymerization and block copolymerization of 3-guanidinopropyl methacrylamide (GPMA) utilizing aqueous reversible addition–fragmentation chain transfer (<i>a</i>RAFT) polymerization. The resulting homopolymer and block copolymer with <i>N</i>-(2-hydroxypropyl) methacrylamide (HPMA) were prepared to mimic the behavior of cell-penetrating peptides (CPPs) and poly­(arginine) (>6 units), which have been shown to cross cell membranes. The homopolymerization mediated by 4-cyano-4-(ethylsulfanylthiocarbonylsulfanyl)­pentanoic acid (CEP) in aqueous buffer exhibited pseudo-first-order kinetics and linear growth of molecular weight with conversion. Retention of the “living” thiocarbonylthio ω-end group was demonstrated through successful chain extension of the GPMA macroCTA yielding GPMA₃₇-<i>b</i>-GPMA₆₁ (<i>M</i>_w/<i>M</i>_n = 1.05). Block copolymers of GPMA with the nonimmunogenic, biocompatible HPMA were synthesized yielding HPMA₂₇₁-<i>b</i>-GPMA₁₃ (<i>M</i>_w/<i>M</i>_n = 1.15). Notably, intracellular uptake was confirmed by fluorescence microscopy, confocal laser scanning microscopy, and flow cytometry experiments after incubation for 2.5 h with KB cells at 4 °C and at 37 °C utilizing FITC-labeled, GPMA-containing copolymers. The observed facility of cellular uptake and the structural control afforded by <i>a</i>RAFT polymerization suggest significant potential for these synthetic (co)­polymers as drug delivery vehicles in targeted therapies