3) when compared with free RAPTA-C. However, one has to bear in mind that the abundant presence of esterases or hydrolases in the whole biological environment 89 (not only in tumor cells) could make this general strategy less selective in vivo, and may require the addition of active targeting ligands. This is the case of a RAFT-synthesized copolymer designed to target the galectin-3 receptor (which is overexpressed in prostate cancer cells ), composed of OEGMA and The same design strategy has been applied to the anticancer drug bufalin (Buf) and two targeting ligands: (i) the octreotide peptide, to target somatostatin receptors overexpressed in breast cancer cells 126 and (ii) the arginylglycylaspartic acid peptide (RGD), to improve cancer cell penetration. In both cases, the sensitivity of esterases to β-thioester bonds and the beneficial effect of the targeting ligands were demonstrated in vitro and in vivo. Such Buf-based system has been further supplemented by an endosomal escape capability via the design of brush-type polymer prodrug nanocarriers. This was achieved by the RAFT terpolymerization of OEGMA, protected BSMA and 2-(2-bromoisobutyryloxy)ethyl methacrylate (BIEM) as a ATRP initiator, followed by synthesis of poly(N,N-diethylaminoethyl methacrylate-co-butyl methacrylate (P(DEAEMA-co-BMA)) side brushes by ATRP from pendant BIEM moieties. After deprotection of BSMA groups, the resulting P(OEGMA-co-BSTMA)-g-P(DEAEMA-co-BMA) copolymer brushes were conjugated to Buf and to the RGD peptide (Figure ) and selfassembled into nanoparticles of 148 nm. The Buf release was significant in presence of esterases at pH 7 and, to a lower extent, at pH 5 without esterases. Interestingly, the presence of esterases at pH 5 did not result in greater release of Buf than at pH 7, probably due to a reduced enzymatic activity under acidic conditions. Although the targeted nanoparticles demonstrated higher cytotoxicity against colorectal cancer cells HCT116 compared with the non-targeted nanoparticles (IC 50 = 10 and 80 nM, respectively), the beneficial effect of the RGD peptide in vivo was less marked. Nonetheless, histological and immunochemical analyses showed improved cell apoptosis, angiogenesis inhibition and anti-proliferation effect compared to the free drug.