Journal
JOURNAL OF CONTROLLED RELEASE
Volume 337, Issue -, Pages 117-131Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2021.07.023
Keywords
Mitochondrial targeting; Vitamin E succinate; Multidrug resistance; pH-sensitive nanovesicle; Doxorubicin
Funding
- National Natural Science Foundation of China [81673384, 81872825]
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The study demonstrated a successful strategy of utilizing vitamin E succinate within nanovesicles to target mitochondria and induce dysfunction, resulting in enhanced killing-effect of doxorubicin hydrochloride towards drug resistant cancer cells. This approach provides a safe and promising method for precise drug delivery and MDR eradication in cancer therapy.
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 center dot 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 center dot HCl-loaded nanovesicles with loading content of 23.5%. The incorporated VES also offers robust antileakage property toward DOX center dot 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 (Delta Psi(m)) 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 center dot HCl is significantly enhanced toward drug resistant cancer cells at the optimal mass ratio of DOX center dot 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.
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