In this context, Gem has been conjugated to the RAFT agent PABTC via an amide bond prior to the copolymerization of HEA with hydroxyethylacrylamide tetrahydropyran (HEAmTHP). Resulting Gem-amide-PHEA-b-PHEAmTHP diblock copolymer prodrugs were sensitive to three stimuli (Table ): (i) the presence of proteases due to the amide linker, (ii) the acid pH due to the acetal bond inserted between the THP moeity and HEAm and (iii) the temperature as PHEAmTHP exhibited a LCST behavior. A copolymer with a Gem-PHEA:HEAmTHP molar ratio of 1:30 led to the formation of 50 nm-nanoparticles by an all water nanoprecipitation process, which consists of solubilizing the copolymer in water at a temperature below its transition temperature (8 °C), then adding the copolymer solution to water at a temperature above its transition temperature. Only a modest release of Gem (< 5 % after 168 h) was obtained in water and in slightly acidic medium (pH 5). However, such prodrug nanoparticles exhibited significantly higher Gem release at lower pH (3.6) and in human serum, leading to a 2-fold faster release (10 % after 168 h) in both media (Figure ). Faster Gem release in human serum is likely assigned to the presence of specific enzymes able to cleave the amide bond between Gem and the copolymer. The significant difference in Gem release at pH 5 and 3.6 lies in the fact that only partial acetal hydrolysis may be achieved at pH 5 whereas it may be complete at pH 3.6 (the rate of acetal hydrolysis is indeed strongly accelerated when decreasing pH, following a first-order kinetics ). These behavioral differences were confirmed by DLS showing aggregation of nanoparticles in acidic buffers at