Fabrication of dual responsive co-delivery system based on three-armed peptides for tumor therapy

Introducing drugs into gene delivery systems to fabricate co-delivery systems for synergy therapy has become a promising strategy for tumor therapy. In this study, a dual responsive co-delivery system RHD/p53 was fabricated to enhance the antitumor efficacy with a low dose of doxorubicin (DOX). The reducible branched cationic polypeptide (RBCP), which was cross-linked via the thiol groups of two three-armed cationic peptides (CRR)2KRRC and (CHH)2KHHC, was designated as RH. Then, DOX was immobilized on RH via pH-sensitive hydrazone bonds to obtain RHD. The positively charged RHD could compress p53 plasmid to form RHD/p53 complexes. After RHD/p53 complexes accumulated in tumor sites, the ability of cell penetrating by cationic peptide (CRR)2KRRC would facilitate the cellular internalization of complexes. Then, the complexes would be trapped in endosome, and the cleavage of hydrazone bonds in the intracellular acidic endosome could lead to pH-induced release of DOX. Additionally, the ability of protonation by (CHH)2KHHC could promote the escape of complexes from endosome to cytoplasm. Due to the cleavage of disulfide bonds triggered by the high-content GSH in cytoplasm, the complexes would be degraded and released p53 for co-therapy to improve antitumor efficacy. Both in vitro and in vivo studies indicated that dual responsive co-delivery system RHD/p53 could enhance antitumor efficacy, which provides a useful strategy for co-delivery of different therapeutic agents in tumor treatment.