J Control Release. 2021 Jul 15:S0168-3659(21)00366-7. doi: 10.1016/j.jconrel.2021.07.023. Online ahead of print.
Inducing mitochondrial malfunction is an appealing strategy to overcome tumor multidrug resistance (MDR). Reported here a versatile mitochondrial-damaging molecule, vitamin E succinate (VES), is creatively utilized to assist MDR reversal of doxorubicin hydrochloride (DOX·HCl) via a nanovesicle platform self-assembled from amphiphilic polyphosphazenes containing pH-sensitive 1H-benzo-[d]imidazol-2-yl) methanamine (BIMA) groups. Driven by multiple non-covalent interactions, VES is fully introduced into the hydrophobic membrane of DOX·HCl-loaded nanovesicles with loading content of 23.5%. The incorporated VES also offers robust anti-leakage property toward DOX·HCl under normal physiological conditions. More importantly, upon release within acidic tumor cells, VES can target mitochondria and result in various dysfunctions including excessive generation of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) loss, and inhibited adenosine triphosphate (ATP) synthesis, which contribute to cell apoptosis and insufficient energy supply for drug efflux pumps. Consequently, the killing-effect of DOX·HCl is significantly enhanced toward drug resistant cancer cells at the optimal mass ratio of DOX·HCl to VES. Further in vivo antitumor investigation on nude mice bearing xenograft drug-resistant human chronic myelogenous leukemia K562/ADR tumors verifies the extremely enhanced anti-tumor efficacy of the dual drug-loaded nanovesicle with the tumor inhibition rate (TIR) of 82.38%. Collectively, this study provides a s safe, facile and promising strategy for both precise drug delivery and MDR eradication to improve cancer therapy.