Figure 3.

Mitochondrial enzymes triggered in situ lipid peroxidation of synergistic MMC-DHA combination and their sequential targeting capability using MMC-DHA-PLN. (A) Reaction schemes showing the cascade of lipid peroxidation produced by MMC-DHA combination that elevates intracellular oxidative stress. Activation of MMC through one-electron bio-reduction by mitochondrial enzymes generates the free radical, superoxide (O₂^˙-), which in turn is converted to the hydroxyl radical (HO^˙) to attack the methylene bridge between C=C double bonds of DHA, leading to a chain of lipid peroxidation. (B) MMC-DHA-PLN targeted mitochondrial lipid peroxidation and induced irreversible ultra-structural damages to mitochondria in MDR EMT6/AR1 murine breast cancer cells with high expression of P-gp and rigid cell membrane. (i) Laser confocal microscope images of lipid peroxidation localization (green fluorescence) in mitochondria (red fluorescence) of cells treated with 5% dextrose and MMC-DHA-PLN; (ii) The level of MDA before and after various free MMC and/or DHA formulations, blank PLN or MMC-DHA-PLN for 4 h or 24 h; (iii) Transmission electron microscopy images of drug-resistant cells treated with 5% dextrose and MMC-DHA-PLN for 4 h and 24 h. All data are means±SEM (n=3–4) with ^*P<0.05, ^**P<0.01, and ^***P<0.001. The figures are adapted and reproduced from Zhang et al⁷⁸ with permission.