Abstract
Ultrasmall iron oxide nanoparticles (<10 nm) were loaded with cis-diamminetetrachloroplatinum (IV), a cisplatin (II) prodrug, and used as an efficient nanodelivery system in cell models. To gain further insight into their behavior in ovarian cancer cells, the level of cellular incorporation as well as the platination of mitochondrial and nuclear DNA were measured using inductively coupled plasma mass spectrometry (ICP-MS) strategies. Quantitative Pt results revealed that after 24 h exposure to 20 µM Pt in the form of the Pt(IV)-loaded nanoparticles, approximately 10% of the incorporated Pt was associated with nuclear DNA. This concentration increased up to 60% when cells were left to stand in drug-free media for 3 h. These results indicated that the intracellular reducing conditions permitted the slow release of cisplatin (II) from the cisplatin (IV)-loaded nanoparticles. Similar results were obtained for the platination of mitochondrial DNA, which reached levels up to 17,400 ± 75 ng Pt/ mg DNA when cells were left in drug-free media for 3 h, proving that this organelle was also a target for the action of the released cisplatin (II). The time-dependent formation of Pt-DNA adducts could be correlated with the time-dependent decrease in cell viability. Such a decrease in cell viability was correlated with the induction of apoptosis as the main route of cell death. The formation of autophagosomes, although observed upon exposure in treated cells, does not seem to have played an important role as a means for cells to overcome nanoparticles’ toxicity. Thus, the designed nanosystem demonstrated high cellular penetration and the “in situ” production of the intracellularly active cisplatin (II), which is able to induce cell death, in a sustained manner.
Highlights
The use of cisplatin as an effective anticancer drug for treating various malignancies has been well-established over the years [1]
Its antineoplastic effects were initially ascribed to its ability to generate unrepairable nuclear DNA lesions, increasing evidence associates its mode of action with the alteration of both nuclear and cytoplasmic signaling pathways [2]
Several mechanisms have been suggested to participate in conferring platinum-resistant properties to a tumor cell, such as genetic alterations in genes involved in drug uptake, DNA repair, autophagy [4], apoptosis, and cell cycle control pathways [5]
Summary
The use of cisplatin as an effective anticancer drug for treating various malignancies has been well-established over the years [1]. Recent studies have indicated that acute cisplatin treatment activates an autophagic response that serves as a survival factor to counteract cisplatin-induced cell death, increasing cell drug resistance [19] To minimize all these routes of resistance, various alternatives have been proposed regarding drug design. The loading of these nanoparticles with Pt(IV)- prodrugs was expected to facilitate drug penetration into cells by using endocytic routes and the slow release of the drug locally inside the intracellular targets (nDNA and mtDNA). These effects altogether were expected to induce a more efficient apoptotic pathway when using the Pt(IV)-loaded nanoparticles than when using cisplatin directly. Evaluation of the drug uptake in different cell lines of ovarian cancer, the access to molecular targets (nDNA and mtDNA) and toxicity pathways in terms of cell viability, the level of apoptotic and autophagic cells, and cell cycle arrest are studied
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