Folate-decorated hydrophilic three-arm star-block terpolymer as a novel nanovehicle for targeted co-delivery of doxorubicin and Bcl-2 siRNA in breast cancer therapy

To minimize the side effects and enhance the efficiency of chemotherapy, a novel folate-decorated hydrophilic cationic star-block terpolymer , [poly( l -glutamic acid γ-hydrazide)- b -poly(N,N-dimethylaminopropyl methacrylamide)] 3 - g -poly(ethylene glycol) ((PGAH- b -PDMAPMA) 3 - g -PEG), with disulfide linkages between the PEG and PDMAPMA blocks, was developed for targeted co-delivery of doxorubicin and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The terpolymer was synthesized by a combination of ring-opening polymerization, reversible addition–fragmentation chain transfer polymerization, PEGylation and hydrazinolysis. The chemical structures of the polymers were confirmed by 1 H-NMR analysis. The terpolymer could conjugate doxorubicin via an acid-labile hydrazone linkage and simultaneously efficiently complex siRNA through electrostatic interaction at N/P ratios of ⩾4:1 to form “two-in-one” nanomicelleplexes, which displayed a spherical shape and had an average size of 101.3   nm. The doxorubicin loading efficiency and content were 61.0 and 13.23%, respectively. The cytotoxicity, drug release profile, targeting ability, cellular uptake and intracellular distribution of the nanomicelleplexes were evaluated in vitro. We found that the release behaviors of doxorubicin and siRNA had a pH/reduction dual dependency. They were released faster under reductive acidic conditions (pH 5.0, glutathione : 10   mM) than under physiological conditions (pH 7.4). The folate-decorated nanomicelleplexes could deliver doxorubicin and Bcl-2 siRNA more efficiently into the same MCF-7 cell and exhibited a higher cytotoxicity than non-targeted nanomicelleplexes. These results indicate that the terpolymer could act as an efficient vehicle for targeted intracellular co-delivery of doxorubicin and therapeutic siRNA in cancer therapy.