Patients treated with the cisplatin often develop strong resistance to the drug after prolonged treatments, ultimately resulting in limited clinical efficacy. One of the possible mechanisms is that the internalized compound may be inactivated before getting access to the nucleus where cisplatin forms a complex with the genomic DNA and triggers a cell death program. However, the nature and intracellular fate of inactivated cisplatin is poorly illustrated. In the present study, we reported for the first time the presence of platinum nanoparticles(Pt-NPs) in the cytoplasm of cells treated with cisplatin. Further analysis also evidenced a correlation of the increased intracellular PtNPs formation with cisplatin resistance, and confirmed the process was glutathione S-transferase relevant. Our data suggest that tumor cells may develop cisplatin resistance by converting the drug into less toxic intracellular Pt-NPs, thereby impeding the drug from targeting its substrates.
The interactions with the pulmonary surfactant,the initial biological barrier of respiratory pathway,determine the potential therapeutic applications and toxicological effects of inhaled nanoparticles(NPs). Although much attention has been paid to optimize the physicochemical properties of NPs for improved delivery and targeting,shape effects of the inhaled NPs on their interactions with the pulmonary surfactant are still far from clear. Here,we studied the shape effects of NPs on their penetration abilities and structural disruptions to the dipalmitoylphosphatidylcholine(DPPC) monolayer(being model pulmonary surfactant film) using coarse-grained molecular dynamics simulations. It is found that during the inspiration process(i.e.,surfactant film expansion),shape effects are negligible. However,during the expiration process(i.e.,surfactant film compression),NPs of different shapes show various penetration abilities and degrees of structural disruptions to the DPPC monolayer. We found that rod-like NPs showed the highest degree of penetration and the smallest side-effects to the DPPC monolayer. Our results may provide a useful insight into the design of NPs for respiratory therapeutics.
Engineered iron oxide magnetic nanoparticles(MNPs) are one of the most promising tools in nanomedicine-based diagnostics and therapy. However, increasing evidence suggests that their specific delivery efficiency and potential long-term cytotoxicity remain a great concern. In this study, using 12 nm γ-Fe2O3 MNPs, we investigated three types of uptake pathways for MNPs into Hep G2 cells:(1) a conventional incubation endocytic pathway;(2) MNPs co-administrated with microbubbles under ultrasound exposure; and(3) ultrasound delivery of MNPs covalently coated on the surface of microbubbles. The delivery efficiency and intracellular distribution of MNPs were evaluated, and the cytotoxicity induced by reactive oxygen species(ROS) was studied in detail. The results show that MNPs can be delivered into the lysosomes via classical incubation endocytic internalization; however, microbubbles and ultrasound allow the MNPs to pass through the cell membrane and enter the cytosol via a non-internalizing uptake route much more evenly and efficiently. Further, these different delivery routes result in different ROS levels and antioxidant capacities, as well as intracellular glutathione peroxidase activity for Hep G2 cells. Our data indicate that the microbubble–ultrasound treatment method can serve as an efficient cytosolic delivery strategy to minimize long-term cytotoxicity of MNPs.
