Self-assembling doxorubicin prodrug forming nanoparticles for cancer chemotherapy: synthesis and anticancer study in vitroand in vivo

The clinical utility of doxorubicin (DOX) is restricted by its severe side effects. Continuous efforts are aimed at developing efficacious DOX-delivery systems that may overcome the drawbacks of existing ones. Herein, we report a self-assembling prodrug forming high drug loading nanoparticles for DOX delivery. A low molecular weight polyethylene glycol (PEG) chain as the hydrophilic part was anchored to hydrophobic DOX viaan acid-cleavable hydrazone bond to form the amphiphilic prodrug PEG–DOX. In aqueous solution, PEG–DOX formed nanoparticles with a diameter of ∼125 nm and extremely high drug loading (∼46 wt%). These nanoparticles were stable in PBS but released DOX in an acidic pH-triggered manner. Interestingly, taken up by cells viaendocytosis, PEG–DOX bypassed the P-glycoprotein (P-gp)-mediated efflux of DOX, leading to drug accumulation in DOX-resistant human breast cancer cells (MCF-7/ADR). More importantly, PEG–DOX exhibited potent antitumor activity in vitroand in vivo, and showed significantly increased in vivosafety than free DOX. These encouraging data merit further preclinical and clinical development on PEG–DOX.