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 in vivo. 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 via the overexpression of both the αvβ3 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.