摘要
Malignant tumors are one of the most dangerous types of diseases seriously threatening global health, and how to better treat them is a difficult issue for the medical community. Podophyllotoxin and its derivatives were known to have good antitumor efficacy. But their poor water solubility, toxicity to normal tissues, susceptibility to drug resistance, and low absorption by cancer cells have limited their clinical application. A striking feature of cancer cells compared to normal cells is the existence of intracellular overproduction of reactive oxygen species (ROS), frequently used as stimuli for drug release from nanocarriers. In this study, we developed a ROS responsive twin prodrug PPT-S-PPT, in which two podophyllotoxins (PPTs) were coupled by 3,3′-thiodipropionic acid via a thioether bond. PPT-S-PPT can form spherical nanoparticles with a mean diameter of about 200 nm in water. These self-assembled nanoparticles maintained good storage stability for up to 3 weeks. In vitro release study showed that H 2 O 2 can accelerate the drug release of PPT-S-PPT NPs in PBS. Both HPLC assay and fluorescence study showed that the intracellular uptake of PPT-S-PPT NPs was significantly higher than free drug or free fluorescence probe. The PPT-S-PPT NPs were up-taken by Hela cells via multiple endocytic pathways, and lipid rafts may play a greater role in the endocytosis of PPT-S-PPT NPs. In addition, the PPT-S-PPT NPs showed higher inhibitory effect (almost 14-fold) than free PPT against Hela cells after 24h treatment. The potent cellular inhibition effect of NPs might be due to the increased cellular uptake as well as the enhanced intracellular drug release resulting from the ROS responsiveness. Moreover, PPT-S-PPT NPs revealed favorable cytocompatibility and good hemocompatiblity. This carrier-free ROS-sensitive twin drug nanoassebly provides possibilities for the development of ROS-responsive prodrugs or dimer nanoparticles for efficient cancer therapy.
危险品化学品经营许可证（带存储）