The central ester group of the SMA monomer, previously used to develop pH-sensitive polymer prodrugs nanocarriers, was also found to be effective in conferring enzymatic sensitivity. For example, SMA-ester-Cpt was copolymerized with carboxy betaine methacrylate (CBM) by RAFT polymerization to yield hydrophilic, zwitterionic polymer prodrugs (Figure ). To modulate the drug release kinetics, coupling between SMA and Cpt was performed via carbodiimide chemistry, either on the hydroxyl groups of the aliphatic ester of Cpt (SMA-ester-20Cpt), or on the aromatic ester of Cpt (SMA-ester-10Cpt) (Figure ). P(CBM-co-SMA-ester-10Cpt) and P(CBM-co-SMA-ester-20Cpt) gave drug loadings of ~20 wt %. Due to the different nature of the linkers, and probably to their accessibility by enzymes, P(CBM-co-SMA-ester-10Cpt) showed faster Cpt release than P(CBM-co-SMA-ester-20Cpt) in human serum (37 and 12 % after 4 days, respectively). Such difference in drug release has been directly translated into cytotoxicity on SKOV3 cells, with an IC 50 value ~100 times higher for P(CBM-co-SMAester-10Cpt) compared to P(CBM-co-SMA-ester-20Cpt). To target the epidermal growth factor receptors overexpressed in cancer cells, these two polymer prodrugs where chain extended by copolymerization of CBM and GE11 peptide-functionalized methacrylamide (GE11-MAAm) (Figure ). Flow cytometry studies showed a 2-fold increase in binding for the targeted polymer prodrug relative to the untargeted counterparts. The synthesis of enzyme-sensitive polymer prodrug nanocarriers based on the anticancer drug methotrexate (Mtx) has also been attempted by the "grafting through" approach. It was carried out by esterification of HPMA with Mtx (HPMA-ester-Mtx) under DCC/DMAP coupling conditions, followed by its RAFT polymerization from a PHPMA macro-RAFT agent in presence of EGDMA, resulting in core-crosslinked star polymer prodrugs of 20 nm with a Mtx loading of 20 wt %. Whereas porcine liver esterase achieved a significant release of Mtx from HPMA-Mtx (30 % after 96 h), no release was observed from the core-crosslinked star polymer prodrugs, probably due to poor enzymatic access to the ester bond. This study highlighted the key role of polymer architecture and linker environment in its cleavage and drug release efficiency.