Liver-targeting doxorubicin-conjugated polymeric prodrug with pH-triggered drug release profile

The aim of the research presented was to develop a potential liver-targeting prolonged-circulation polymeric prodrug of doxorubicin (Dox) with a pH-triggered drug release profile. In particular, linear dendritic block copolymers composed of polyamidoamine dendrimer (PAMAM) and poly(ethylene glycol) (PEG; number-average molecular weight of 2000 g mol^-1) with or without galactose (Gal) were synthesized. Dox was coupled to the copolymers via an acid-labile hydrazone linker. These prodrugs, designated Gal-PEG-b-PAMAM-Dox_n and mPEG-b-PAMAM-Dox_m, showed accelerated Dox release as the pH decreased from 8.0 to 5.6. Cytotoxicity of the prodrugs was lower than that of free Dox due to the gradual drug release nature. Compared to mPEG-b-PAMAM-Dox_m, Gal-PEG-b-PAMAM-Dox_n showed rather high cytotoxicity against Bel-7402, suggestive of its galactose receptor-mediated enhanced tumor uptake. This galactose receptor-mediated liver-targeted profile was further confirmed by the prolonged retention time in hepatoma tissue monitored using magnetic resonance imaging. Gal-PEG-b-PAMAM-Dox_n showed better in vivo antitumor efficacy than free Dox, suggesting its great potential as a polymeric antitumor prodrug.