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

Multidrugresistance (MDR) is a major factor in chemotherapeuticfailure and is closely associated with mitochondrial dysfunction,generating excess adenosine triphosphate (ATP) and overexpressingantiapoptotic protein (Bcl-2). Herein, a site-specific activationof mitochondria-targeting peptide nanotherapeutics is presented foraddressing MDR tumor cell selectively, which shows efficient MDR tumorinhibition in vivo. A peptide (KLAKRGD) composedof the mitochondrial cytotoxic peptide (KLAK) and tumor-targetingpeptide (RGD) is modified by reactive oxygen species (ROS)-sensitivephenylboronate to yield KLAK (PBAE) RGD, which can self-assemble intonanoparticles and induce mitochondrial cytotoxicity. The KLAK andloaded doxorubicin (DOX) in nanoparticles are selectively activatedand released in tumor cells via the overexpressionof both the & alpha;(v)& beta;(3) integrin and ROS.ATP and antiapoptotic protein Bcl-2 are reduced as mitochondrial damageaccrues, downregulating ATP-dependent drug efflux pumps and drasticallyenhancing DOX efficacy. The DOX-loaded KLAK (PBAE) RGD (DKPR) nanoparticlesimproved tumor growth control in drug-resistant tumor models, whichsuggests the great potential of this innovative approach to targetedchemotherapy in drug-resistant cancers.

Automated summary

In this study, a mitochondria-targeting peptide nanotherapeutic was developed to selectively target MDR tumor cells and inhibit their growth. The nanotherapeutic showed great potential for targeted chemotherapy in drug-resistant cancers.