Elevating mitochondrial reactive oxygen species by mitochondria-targeted inhibition of superoxide dismutase with a mesoporous silica nanocarrier for cancer therapy
In the intrinsic pathway of apoptosis, stresses of mitochondrial reactive oxygen species (mitoROS) might be sensed as more effective signals than those in cytosol, as mitochondria are the major sources of reactive oxygen species (ROS) and pivotal components during cell apoptosis. Mitochondrial superoxide dismutase (SOD2) takes the leading role in eliminating mitoROS, and inhibition of SOD2 might induce severe disturbances overwhelming the mitochondrial oxidative equilibrium, which would elevate the intracellular oxidative stresses and drive cells to death. Herein, we report a general strategy to kill cancer cells by targeted inhibition of SOD2 using 2-methoxyestradiol (2-ME, an inhibitor for the SOD family) via a robust mitochondria-targeted mesoporous silica nanocarrier (mtMSN), with the expected elevation of mitoROS and activation of apoptosis in HeLa cells. Fe3O4@MSN was employed in the mitochondria-targeted drug delivery and selective inhibition of mitochondrial enzymes, and was shown to be stable with good biocompatibility and high loading capacity. Due to the selective inhibition of SOD2 by 2-ME/mtMSN, enhanced elevation of mitoROS (132% of that with free 2-ME) was obtained, coupled with higher efficiency in initiating cell apoptosis (395% of that with free 2-ME in 4 h). Finally, the 2-ME/mtMSN exhibited powerful efficacy in targeted killing of HeLa cells by taking advantage of both biological recognition and magnetic guiding, causing 97.0% cell death with only 2 μg/mL 2-ME/mtMSN, hinting at its great potential in cancer therapy through manipulation of the delicate mitochondrial oxidative balance.
Keywordsmitochondria reactive oxygen species apoptosis mesoporous silica nanoparticles drug delivery
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