Guanidine-Containing Methacrylamide (Co)polymers via aRAFT: Toward a Cell-Penetrating Peptide Mimic

Nicolas J. Treat, University of Southern Mississippi
DeeDee Smith, University of Southern Mississippi
Joel D. Flores, University of Southern Mississippi
Brooks A. Abel, University of Southern Mississippi


We report the synthesis and controlled radical homopolymerization and block copolymerization of 3-guanidinopropyl methacrylamide (GPMA) utilizing aqueous reversible addition-fragmentation chain transfer (aRAFT) polymerization. The resulting homopolymer and block copolymer with N-(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-cyano4-(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 omega-end group was demonstrated through successful chain extension of the GPMA macroCTA yielding GPMA(37)-b-GPMA(61) (M-w/M-n = 1.05). Block copolymers of GPMA with the nonimmunogenic, biocompatible HPMA were synthesized yielding, HPMA(271)-b-GPMA(13) (M-w/M-n = 1.15). Notably, intracellular uptake as confirmed by fluorescence microscopy, confocal laser scanning microscopy, and flow cytometry experiments after incubation for 2.5 h with KB cells at 4 degrees C and at 37 degrees C utilizing FITC-labeled, GPMA-containing copolymers. The observed facility of cellular uptake and the structural control afforded by aRAFT polymerization suggest significant potential for these synthetic (co)polymers as drug delivery vehicles in targeted therapies.