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ATP Suppression by pH‐Activated Mitochondria‐Targeted Delivery of Nitric Oxide Nanoplatform for Drug Resistance Reversal and Metastasis Inhibition
Author(s) -
Deng Yongyan,
Jia Fan,
Chen Xiaohui,
Jin Qiao,
Ji Jian
Publication year - 2020
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.202001747
Subject(s) - nanocarriers , mitochondrion , cancer cell , nitric oxide , metastasis , drug delivery , chemistry , multiple drug resistance , targeted drug delivery , adenosine triphosphate , biochemistry , cancer research , microvesicles , microbiology and biotechnology , pharmacology , cancer , biology , microrna , organic chemistry , genetics , antibiotics , gene
Mitochondria, which are important mediators for cancer initiation, growth, metastasis, and drug resistance, have been considered as a major target in cancer therapy. Herein, an acid‐activated mitochondria‐targeted drug nanocarrier is constructed for precise delivery of nitric oxide (NO) as an adenosine triphosphate (ATP) suppressor to amplify the therapeutic efficacy in cancer treatments. By combining α‐cyclodextrin (α‐CD) and acid‐cleavable dimethylmaleic anhydride modified PEG conjugated mitochondria‐targeting peptide, the nanocarrier shows prolonged blood circulation time and enhanced cellular uptake together with selectively restoring mitochondria‐targeting capability under tumor extracellular pH (6.5). Such specific mitochondria‐targeted delivery of NO proves crucial in inducing mitochondria dysfunction through facilitating mitochondrial membrane permeabilization and downregulating ATP level, which can inhibit P‐glycoprotein‐related bioactivities and formation of tumor‐derived microvesicles to combat drug resistance and cancer metastasis. Therefore, this pioneering acid‐activated mitochondria‐targeted NO nanocarrier is supposed to be a malignant tumor opponent and may provide insights for diverse NO‐relevant cancer treatments.