Design, postpolymerization conjugation and self-assembly of di-block copolymer-based prodrug for intracellular acid-triggered DOX release
Novel di-block copolymer-based prodrug was designed by atom transfer radical polymerization (ATRP) of glycidyl methacrylate (GMA) with a polyethylene glycol-based initiator (PEG-Br), postpolymerization aldehyde-modification, and doxorubicin (DOX) conjugation via an acid-labile imine bond. The polymer prodrug could self-assemble into the core-shell structure nanoparticles with the PEG block as the hydrophilic shell and DOX-containing block as the hydrophobic core. The longer hydrophobic block length resulted into higher drug content but bigger particle size, although all the four polyprodrug nanoparticles showed excellent fast pH-triggered DOX release owing to the auto-acceleration mechanism because of the transformation from hydrophobic to semi-hydrophobic block during DOX release, with cumulative release of 79% at the simulated tumor microenvironment within 12 h while a premature drug leakage of < 14%. So the PEG-P(GMA-CBA)51-DOX polyprodrug with a middle hydrophobic block length was optimized as promising drug delivery system (DDS), with hydrodynamic diameter around 250 nm and high DOX content of 30.35%. The in vitro cellular experiments indicated that the PEG-P(GMA-CBA)51-DOX polyprodrug nanoparticles could efficiently delivery DOX into the cell nuclei and possessed an enhanced anti-tumor efficacy on the HepG2 cells than the free DOX.