Abstract
Cisplatin and its analogues are a cornerstone of cancer chemotherapy; however, their therapeutic potential is limited by severe side effects and the development of drug resistance. To address these issues, nanocarriers and/or platinum prodrugs are being evaluated. Previous in vitro studies showed that ultra-small (< 5 nm) iron oxide nanoparticles coated with tartaric and adipic acids (FeAT-NPs) are an efficient delivery system for the cisplatin prodrug cis-diamminetetrachloroplatinum(IV) (cisplatin(IV)). In this study, the in vivo behavior of cisplatin (IV) conjugated with the FeAT-NPs (FeAT-NPs-Pt(IV)) was evaluated using Drosophila melanogaster as a preliminary non-mammalian animal model. The resulting FeAT-NPs-Pt(IV) nanoconjugate was compared to free cisplatin and cisplatin(IV) regarding platinum incorporation into DNA, measured using inductively coupled plasma mass spectrometry (ICP-MS), as well as toxicity and genotoxicity, which were assessed using the alkaline comet and the w/w[+] eye-spot SMART assays. Results revealed that the nanoconjugate achieved over eightfold higher DNA platination than free cisplatin, which is consistent with efficient cellular uptake and the subsequent intracellular release and activation of the prodrug. Despite this high platination, the nanoconjugate induced DNA strand-break levels similar to cisplatin and lower mutation and recombination frequencies than both cisplatin and cisplatin(IV), in both nucleotide excision repair (NER) efficient and deficient conditions. No significant toxicity was detected at the tested concentrations. These findings suggest that, in vivo, FeAT-NPs-Pt(IV) acts as an effective delivery system, potentially enabling the slow intracellular formation of active cisplatin. This would increase bioavailability to its target (DNA), while maintaining a significantly lower genotoxic stress profile compared to free cisplatin. Nonetheless, additional studies in tumor mammalian models are required to further explore these observations.
