Codelivery of Cell Apoptosis AVPIAQ Peptide and Doxorubicin for Synergistic Cancer Therapy

Conventional combination chemotherapy, which utilizes noncovalent bonding for self-assembly and encapsulation for drug loading and delivery, faces challenges in clinical application. The development of combination chemotherapy systems that enable multiple drugs to be contained within a single molecule to achieve synergistic therapy is an innovative concept for cancer treatment. In this study, a polymeric micelle named mPEG-GFLGAVPIAQDEVD-DOX&DOX was constructed through the covalent linkage of two chemotherapy drugs of doxorubicin (DOX) and the pro-apoptotic peptide SMAC (AVPIAQ) and then using the thin-film hydration method. The micelle can be specifically recognized by cathepsin B within cancer cells, leading to the cleavage of the peptide GFLG. This action facilitates the shedding of mPEG, thereby enhancing the efficiency of micelle uptake by cells. Upon internalization, the micelles release the encapsulated DOX, thereby promoting apoptosis and activating Caspase-3, which in turn cleaves the peptide DEVD. This process accelerates the release of DOX, thereby enhancing the efficacy of tumor cell killing. Subsequently, the pro-apoptotic peptide SMAC was exposed, which bonded to inhibitors of apoptosis proteins (IAPs) and inhibited their antiapoptotic activity, thereby accelerating tumor cell apoptosis. SMAC plays a key role in apoptosis by alleviating the inhibitory effect of IAPs on Caspase-3, allowing DOX and SMAC to act synergistically on tumor cells as cocktail therapy, achieving a double-killing effect, thereby improving therapeutic efficacy against tumors. These results indicated that the dual-drug polymer micelles prepared can significantly enhance antitumor therapeutic efficacy and reduce their side effects.