Journal
MOLECULAR PHARMACEUTICS
Volume 20, Issue 2, Pages 918-928Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.2c00321
Keywords
cisplatin; aquated cisplatin; membrane fluidity and permeability; gel phase; fluorescence spectroscopy
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Increasing evidence suggests that lipids play a critical role in the toxicity and resistance mechanisms of platinum(II) complexes. This study investigated the ability of cisplatin and its cationic species to induce phase changes in model membranes with different lipid compositions. The results showed that the effect of platinum(II) complexes on membrane fluidity depends on the lipid composition and properties, and that high concentrations of these complexes can alter the permeability of lipid membranes without inducing collapse or aggregation.
Increasing evidence suggests a critical role of lipids in both the mechanisms of toxicity and resistance of cells to platinum(II) complexes. In particular, cisplatin and other analogues were reported to interact with lipids and transiently promote lipid phase changes both in the bulk membranes and in specific membrane domains. However, these processes are complex and not fully understood. In this work, cisplatin and its cationic species formed at pH 7.4 in low chloride concentrations were tested for their ability to induce phase changes in model membranes with different lipid compositions. Fluorescent probes that partition to different lipid phases were used to report on the fluidity of the membrane, and a leakage assay was performed to evaluate the effect of cisplatin in the permeability of these vesicles. The results showed that platinum(II) complex effects on membrane fluidity depend on membrane lipid composition and properties, promoting a stronger decrease in the fluidity of membranes containing gel phase. Moreover, at high concentration, these complexes were prone to alter the permeability of lipid membranes without inducing their collapse or aggregation.
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