A novel pH-sensitive polymeric prodrug was prepared by SPAAC click chemistry for intracellular delivery of doxorubicin and evaluation of its anti-cancer activity in vitro

A novel cytocompatible and pH-sensitive amphiphilic polymeric prodrug named as mPEG- b -norbornene functional PLA-graft-Doxorubicin (mPEG- b -PLA- g -DOX) was synthesized by ROP (ring-opening polymerization), then condensation and followed by click reaction. The polymeric carriers were grafted with triazo group. Doxorubicin (DOX) was modified by the cyclooctyne via condensation reaction and conjugated to the polymeric carriers through the SPAAC (Strain-Promoted Alkyne-Azide Cycloaddition) click reaction. There was a Schiff base between the DOX and cyclooctyne which could result in the pH stimuli-responsiveness for controlled release of anti-cancer drug. The resultant mPEG- b -PLA- g -DOX prodrug was characterized by the 1 H NMR, GPC and HPLC. The content of DOX in prodrug reached 17.4% as measured by the UV spectrum. The amphiphilic polymeric prodrug could self-assemble into micelle which was characterized by the dynamic light scattering (DLS) and scanning electron microscope (SEM). The profile of in vitro drug release exhibited enhanced drug release at acidic pH (pH = 5.3) compared with neutral pH (pH = 7.4). The results of MTT assay showed that the amount of DOX required for MCF-7 cells was reduced after DOX molecules were prepared into polymer prodrug, which was conducive to reducing side effects under the premise of ensuring inhibitory effect.