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We report secondary amide side-chain-bearing polyacrylates with tunable aqueous solubility and cellular interaction. Redox-initiated reversible addition-fragmentation chain transfer polymerization of methylamide ethyl acrylate (MAmEA) and ethylamide ethyl acrylate (EAmEA) yielded well-defined homopolymers. P(MAmEA) and P(EAmEA) possess high glass-transition temperatures compared to the equivalent alkylated polyacrylates. P(EAmEA) showed a degree of polymerization and concentration-dependent lower critical solution temperature (LCST) behavior, which can be fine-tuned over a biologically relevant range through copolymerization of both monomers. No cytotoxicity against NIH 3T3 and RAW 264.7 cell lines was observed. Detailed cellular interaction studies revealed cell associations for P(MAmEA) similar to poly(N-acryloylmorpholine), a well-known nonionic water-soluble polymer and colocalization of both homopolymers with lysosomes. Due to the simple access of these monomers, the aqueous solubility, cytocompatibility, and cellular interaction of the homopolymers, and the possibility to combine them with a large number of acrylates, they hold great promise to become suitable building blocks for biomedical materials.

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Cellular uptake and intracellular targeting to specific organelles are key events in the cellular processing of nanomaterials. Herein, we perform a detailed structure–property relationship study on carboxylic acid-side-chain-bearing polyacrylates to provide design criteria for the manipulation of their cellular interactions. Redox-initiated reversible addition-fragmentation chain-transfer (RRAFT) polymerization of three tert-butyl-protected N-acylated amino ester-based acrylate monomers of different substitutions and degrees of polymerization (DPs) yielded defined and pH-responsive carboxylic acid-side-chain polymers upon deprotection (N-acetyl, DP 1: P­(M1); N-propionyl, DP 1: P­(E1), DP 2: P­(E2)). Flow cytometry studies revealed time-dependent cell association with P­(E2) > P­(E1) > P­(M1) at any given time point. Importantly, the type of cyanine dye used for labeling was found to significantly influence the cellular processing of the polymers. Changing the dye from Cy5 to its sulfonated version sulfoCy5 resulted in a much lower cellular association. Moreover, Cy5-labeled polymers were targeted to mitochondria, while sulfoCy5 modification caused a significant change in the cellular fate of polymers toward lysosome trafficking. This study highlights the importance of selecting a suitable dye but also demonstrates the possibilities for the rational design of organelle-specific targeting of carboxylated polyacrylates.