1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol) (PPMP) is a potent inhibitor of glucosylceramide synthase (GCS), which can induce cell death and synergies with chemotherapeutic agents by increasing the level of ceramides in tumor cells and by overcoming cell resistance. It has been turned into a methacrylate monomer through ester bonding (MA-ester-PPMP) and polymerized from a POEGMA macro-RAFT agent to give POEGMA-b-P(MA-ester-PPMP) amphiphilic diblock copolymer prodrugs (Figure ). Due to its versatility, the GFLG peptide was also advantageously used as a proteaseresponsive linker for the design of polymer prodrugs from the "grating through" method. An efficient strategy relied on the successful functionalization of GFLG-bearing methacrylamide by a small library of anticancer drugs, such as Paclitaxel (Ptx), 177 Dox, 178 and Gem. These prodrug monomers were copolymerized with HPMA by the RAFT process to produce two different families of polymer prodrugs: (i) P(HPMA-co-MAAm-GFLG-drug) copolymer prodrugs and (ii) multiblock copolymer prodrugs in which the different P(HPMA-co-MAAm-GFLG-drug) blocks were connected through GFLG linkers via Cu(I)-catalyzed or thiol-ene click chemistry (Figure ). For instance, with the Ptx-based polymer prodrugs, 177 it was shown that the cysteine protease papain caused the molecular weight of multiblock copolymer prodrugs to decrease to half the original value due to cleavage of GFLG moieties. Cumulative releases of Ptx over time were similar for both types of copolymer prodrug, even if a slight decrease in Ptx release from the multiblock copolymer prodrugs was observed, probably linked to the formation of a more compact coil due to enhanced hydrophobic interactions. After radiolabeling of the prodrugs (Figure ), in vivo studies highlighted the long-circulating properties of the multiblock copolymer prodrugs, with an increased half-life of 27.5 h compared to 13 h for the simple copolymer prodrugs, and only 2 h for Ptx. The multiblock copolymer prodrugs also exhibited greater anticancer efficacy in A2780 human ovarian tumor-bearing mice. Similar results were obtained for the Dox-based multiblock copolymer prodrugs as they were the most efficient for tumor growth inhibition, with an optimal molecular weight of about 100 kDa to enhance the antitumor efficacy. This versatility of the PHPMA drug delivery platform has also been applied to the co-delivery of Gem and diaminocylohexane platinum (DACH Pt) and of Gem and Ptx by simple copolymerization of the respective monomer prodrugs (or the chelating ligand-bearing monomer in case of DACH Pt). 179,180