Design, postpolymerization conjugation and self-assembly of a di-block copolymer-based prodrug for tumor intracellular acid-triggered DOX release.

A 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 polyprodrug could self-assemble into core-shell structured nanoparticles with the PEG block as the hydrophilic shell and the DOX-containing block as the hydrophobic core. The longer hydrophobic block resulted in a higher drug content but a 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 the hydrophobic to semi-hydrophobic block during DOX release, with a cumulative release of >79% in the simulated tumor microenvironment within 12 h and a premature drug leakage of <14%. So the PEG-P(GMA-CBA)51-DOX polyprodrug with a middle hydrophobic block length was optimized as a promising drug delivery system (DDS), with a hydrodynamic diameter around 250 nm and a high DOX content of 30.35%. The in vitro cellular experiments indicated that the PEG-P(GMA-CBA)51-DOX polyprodrug nanoparticles could efficiently deliver DOX into the cell nuclei and show an enhanced anti-tumor efficacy on the HepG2 cells compared to the free DOX.