Targeting inhibitors of apoptosis
proteins (IAPs) family comprising high level expression in many
cancer cells, could sensitize
tumor cells to conventional
chemotherapies. In the present study, we designed both
doxorubicin and SmacN6 (an antagonist of the IAPs) encapsulated polymeric nanoparticles (NPs) and investigated their synergistic effect of combination
therapy in vitro and in vivo. According to the results, NPs-SmacN6 significantly enhanced the cytotoxicity effect of NPs-DOX and reduced its IC50 in MCF-7, 4T1 and C26
cancer cells. Western blot analysis confirmed mechanism of cell apoptosis via
caspase activation through intrinsic and also extrinsic pathways. Moreover,
5TR1 aptamer-modified NPs could effectively deliver DOXor SmacN6 to C26
cancer cells (MUC1 positive) in comparison with the non-targeted one (p < 0.001). However, they could not be efficiently internalized into CHO cells (MUC1 negative), showing less cytotoxicity in this cell line. In vivo experiments in BALB/c mice bearing C26
tumor indicated that
Apt-NPs-DOX in combination with Apt-NPs-SmacN6 had significant
tumor growth inhibition in comparison with mice receiving either free DOX or
Apt-NPs-DOX with p < 0.0001 and p < 0.05, respectively. Our results revealed that combination
therapy of DOX and SmacN6 via
Apt-modified nanoparticles can lead to improvement of therapeutic index of DOX in MUC1 positive
cancer cells.