Site-specific Activation of Mitochondria-Targeting Peptide Nanomaterials for Treatment of Drug-Resistant Tumors

Multidrug resistance (MDR) is a major factor in chemotherapeutic failure and is closely associated with mitochondrial dysfunction, generating excess adenosine triphosphate (ATP) and overexpressing antiapoptotic protein (Bcl-2). Herein, a site-specific activation of mitochondria-targeting peptide nanotherapeutics is presented for addressing MDR tumor cell selectively, which shows efficient MDR tumor inhibition <i>in vivo</i>. A peptide (KLAKRGD) composed of the mitochondrial cytotoxic peptide (KLAK) and tumor-targeting peptide (RGD) is modified by reactive oxygen species (ROS)-sensitive phenylboronate to yield KLAK (PBAE) RGD, which can self-assemble into nanoparticles and induce mitochondrial cytotoxicity. The KLAK and loaded doxorubicin (DOX) in nanoparticles are selectively activated and released in tumor cells <i>via</i> the overexpression of both the α_vβ₃ integrin and ROS. ATP and antiapoptotic protein Bcl-2 are reduced as mitochondrial damage accrues, downregulating ATP-dependent drug efflux pumps and drastically enhancing DOX efficacy. The DOX-loaded KLAK (PBAE) RGD (DKPR) nanoparticles improved tumor growth control in drug-resistant tumor models, which suggests the great potential of this innovative approach to targeted chemotherapy in drug-resistant cancers.