Mitochondria-Targeted Mesoporous Organic Silica Nanoplatforms for Overcoming Cisplatin Resistance by Disturbing Mitochondrial Redox Homeostasis

Abstract

Cisplatin (also known as DDP) resistance is one of the biggest challenges in the treatment of ovarian cancer. Recent studies have found that mitochondrion, as a potential target of DDP, participates in drug-related apoptosis and resistance. Overexpressed glutathione (GSH) in resistant cells is involved in protecting mitochondria from DDP or DDP-induced ROS. In this work, triphenylphosphonium (TPP) modified disulfide bond-rich (S-S) mesoporous organic silica nanoplatforms (DMON) were developed to deliver DDP (TPP-DMON@DDP) to mitochondria for overcoming DDP resistance. TPP supported the migration of nanoplatforms to the mitochondria, with consequent depletion of mitochondrial GSH by the S-S bond of DMON, leading to mitochondria in redox dyshomeostasis. These treated cells seemed more susceptible to the DDP released from the nanoplatforms. Significantly increased ROS production, mitochondrial damage, and apoptosis were observed in TPP-DMON@DDP-treated cells. Overall, interference of mitochondrial redox homeostasis provides a new opportunity for improving DDP cytotoxicity against resistant cells.

α-Synuclein Attenuates Maneb Neurotoxicity through the Modulation of Redox-Sensitive Transcription Factors

“…This data was calculated in 60 cells in three independent experiments. To analyze MitoTracker Red diffusion as a marker of defects of mitochondrial membrane potential, profile plots were created with ImageJ software [ 27 ].…”

Drug-induced oxidative stress in cancer treatments: Angel or devil?

“…Triphenylphosphine is a lipophilic compound with mitochondrial targeting effect, that can easily pass through the biomembrane structure and bind to the mitochondrial membrane, precisely delivering drugs to mitochondria. For example, the chemical linking of mitochondria-targeting to transport DOX to mitochondria has successfully achieved the accurate induction of OS and apoptosis through the mitochondrial pathway in tumor cells [ [232] , [233] , [234] ]. Other approaches to target the mitochondrial compartment have focused on the protein channel (BAK), which is a pro-apoptotic effector protein at the outer mitochondrial membrane.…”