In Situ Proapoptotic Peptide-Generating Rapeseed Protein-Based Nanocomplexes Synergize Chemotherapy for Cathepsin-B Overexpressing Breast Cancer.
Intracellular activation of nanomaterials within cancer cells presents a powerful means to enhance anticancer specificity and efficacy. In light of upregulated lysosomal protease cathepsin-B (CathB) in many types of invasive cancer cells, herein, we exploit CathB-catalyzed biodegradation of acetylated rapeseed protein isolate (ARPI) to design polymer-drug nanocomplexes that can produce proapoptotic peptides in situ and synergize chemotherapy. ARPI forms nanocomplexes with chitosan (CS) and anticancer drug doxorubicin (DOX) [DOX-ARPI/CS nanoparticles (NPs)] by ionic self-assembly. The dual acidic pH- and CathB-responsive properties of the nanocomplexes and CathB-catalyzed biodegradation of ARPI enable efficient lysosomal escape and nuclei trafficking of released DOX, resulting in elevated cytotoxicity in CathB-overexpressing breast cancer cells. The ARPI-derived bioactive peptides exhibit synergistic anticancer effect with DOX by regulating pro- and antiapoptotic-relevant proteins ( p53, Bax, Bcl-2, pro-caspase-3) at mitochondria. In an orthotopic breast tumor model of CathB-overexpressing breast cancer, DOX-ARPI/CS NPs remarkably inhibit tumor growth, enhance tumor cell apoptosis and prolong host survival without eliciting any systemic toxicity. These results suggest that exploitation of multifunctional biomaterials to specifically produce anticancer agents inside cancer cells and trigger drug release to the subcellular target sites is a promising strategy for designing effective synergistic nanomedicines with minimal off-target toxicity.
Wang, Z; Zhang, RX; Zhang, T; He, C; He, R; Ju, X; Wu, XY
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