The amide bond is suitable for enzymatic cleavage (e.g., proteases), but also for nonenzymatic cleavage following either direct hydrolysis or intramolecular aminolysis (Figure ). A typical example is the coupling of Gem through its amine group to: (i) the NMP alkoxyamine initiator 2-(N-tert-butyl-N-(1-diethoxyphosphoryl-2,2-dimethylpropyl)aminoxy)propionic acid) (AMA-SG1) using PyBOP as a coupling agent prior to the polymerization of isoprene (I) to produce Gem-amide-PI polymer prodrugs (Figure ) 191 or (ii) S-1-dodecyl-S'-(α,α'-dimethylα''-acetic acid)trithiocarbonate as a RAFT agent prior to the polymerization of the methyl methacrylate (MMA) to achieve Gem-amide-PMMA polymer prodrugs. In both cases, Gemamide-PI and Gem-amide-PMMA polymer prodrugs exhibited high drug loadings (the lower the M n , the higher the drug loading) in the 10-30 wt % range and ability to self-assemble into 120-160 nm nanoparticles by nanoprecipitation without the use of a surfactant. Enhanced Gem release at pH 5.5 from Gem-amide-PMMA has been observed after 72 h reaching ~47 % compared to only 10 % at physiological pH. Interestingly, further enhancement of the Gem release by a factor 1.5 (reaching ~72 %) was observed at pH 5.5 in presence of cathepsin B.