Cell-penetrating apoptotic peptide/p53 DNA nanocomplex as adjuvant therapy for drug-resistant breast cancer.

Drug resistance becomes a formidable challenge against effective cancer therapy. Defective apoptosis in cancer cells is a key factor responsible for chemoresistance or radioresistance. Promoting apoptosis is an important method to sensitize the resistant cells, thereby achieving successful treatment for MDR cancer. We present a strategy of codelivery of apoptotic AVPI peptide and p53 DNA as apoptosis-induction adjuvant therapy for combating the resistant breast cancer. AVPI tetrapeptide is poorly cell-permeable, thereby with very limited value for therapeutic use. Cell-penetrating chimeric AVPI derivative was developed by modification with an octa-arginine sequence (R8). The AVPIR8 is able to not only efficiently penetrate into tumor cells but also work as a vector for gene delivery by forming nanocomplexes based on its cationic R8 moiety. The combination of AVPIR8/p53 DNA was selected for targeting apoptotic pathways, thereby sensitizing the cancer cells to chemotherapeutics. The anti-MDR effect was demonstrated both in vitro and in vivo. The synergistic use of AVPIR8/p53 significantly increased the sensitivity of the resistant tumor cells to the cytotoxic agent doxorubicin by inducing apoptosis, as demonstrated in the cellular studies. Importantly, the treatment improvement was also observed in the animal studies with resistant breast tumor model. Coadministration of AVPIR8/p53 enabled a full arrest of tumor growth combined with a reduced DOX dose, yielding a productive and safe cancer treatment.