Elucidating the cellular response of silver nanoparticles as a potential combinatorial agent for cisplatin chemotherapy

Abstract

Background: Combination chemotherapy uses drugs that target different cancer hallmarks, resulting in synergistic or additive toxicity. This strategy enhances therapeutic efficacy as well as minimizes drug resistance and side effects. In this study, we investigated whether silver nanoparticles act as a combinatorial partner to cisplatin. In so doing, we compared post-exposure biological endpoints, intracellular drug accumulation, and changes in the proteome profile of tumoral and normal cell lines. Results: Combinatorial exposure corresponded to cytotoxicity and oxidative stress in both cell lines, yet was substantially more effective against tumoral cells. Proteome analysis revealed that proteins related to energy metabolism pathways were upregulated in both cell lines, suggesting that combinatorial exposure corresponded to energetic modulation. However, proteins and upstream regulators involved in the cell cycle were downregulated, indicating reduced cell proliferation. The response to oxidative stress was markedly different in both cell lines; downregulation of antioxidant proteins in tumoral cells, yet upregulation of the antioxidant defense system in normal cells. These outcomes may have avoided higher cell death rates in normal cells. Conclusions: Taken together, our results indicate that combining silver nanoparticles with cisplatin increases the biological activity of the latter, and the combination warrants further exploration for future therapies.

Using design of experiments (DoE) to optimize performance and stability of biomimetic cell membrane-coated nanostructures for cancer therapy

“…Alkylation was performed using 300 mM iodoacetamide (IAA) for 30 min in the dark, following digestion with trypsin (1:100 w/w trypsin: protein) overnight, at room temperature. Finally, the peptides were acidified using 1% v/v formic acid to stop the trypsin digestion and lyophilized before desalting (Rank Miranda et al, 2020). Samples were resuspended in 0.1% v/v trifluoroacetic acid (TFA) and desalted using ZipTipC18 Pipette Tip with C18 Resin (Sigma Aldrich, Brazil) following the manufacturer's instructions.…”