Therapeutic effect of multifunctional celastrol nanoparticles with mitochondrial alkaline drug release in breast cancer
Materials Today Advances(2023)
摘要
Mitochondria have been shown to play a variety of roles in tumorigenesis and progression, and thus present an attractive therapeutic target for cancer treatment. Herein, we developed multifunctional celastrol (cela) nanoparticles with mitochondrial alkaline drug release and feature a positive core and a negative outer layer. First, the mitochondria-targeting material, triphenyl phosphonium-tocopherol polyethylene glycol succinate (TPP-TPGS, TT), was synthesised, and TT/PLGA@cela nanoparticles (NPs) were prepared. Then, the positive charge on the surface was neutralised using tumor-targeting, pH-sensitive chondroitin sulfate-folic acid (CS-FA) to generate CS-FA/TT/PLGA@cela NPs. Characterisation revealed these NPs to be globular particles with smooth surfaces and an average diameter of 100 nm - characteristics that could enhance their uptake by 4T1 murine breast cancer cells. After CS-FA/TT/PLGA@cela NPs entered 4T1 cells, CS-FA was degraded and the positively charged TT/PLGA@cela NPs were exposed and able to target the mitochondria after performing lysosomal escape. Celastrol is released upon exposure of TT/PLGA@cela NPs to the alkaline mitochondrial environment, and assessment of mitochondrial respiration and membrane potential revealed celastrol to induce mitochondrial injury and damage. Exposure of 4T1 cells to these nanoparticles significantly upregulated proapoptotic protein expression in vitro, and generated robust anticancer effects in vivo. Together, these results indicate that CS-FA/TT/PLGA@cela NPs with mitochondrial alkaline drug release represent a promising advancement in breast cancer treatment.
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关键词
Mitochondria targeting,Alkaline pH-responsive release,Enhance antitumor effects,Celastrol,Breast cancer
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