Interaction of cisplatin and two potential antitumoral platinum(ii) complexes with a model lipid membrane: a combined NMR and MD study

Abstract

In this study, the interaction of cisplatin (1) and two potential antitumoral Pt(II) complexes (2 and 3) with a model DMPC bilayer was investigated by multinuclear NMR spectroscopy and MD simulations in order to understand its implication for the different antitumoral properties shown by the three complexes. In particular, (31)P, (13)C and (2)H solid state NMR experiments were performed to obtain information on the phase structure, phase transitions and structural and dynamic changes in the phospholipid bilayer upon interaction with the platinum complexes. On the other hand, MD calculations yielded free energy profiles for the different complexes across the bilayer; the results were analysed to obtain MD predictions on complex distribution with respect to the bilayer, as well as to establish their effects on the conformational equilibrium of the DMPC acyl chains. The combination of NMR and MD approaches highlighted that, whereas the more hydrophilic cisplatin tends to remain in the polar head group region causing a decrease in flexibility of the bilayer, the two new complexes enter into the bilayer. In particular, complex 2 is preferentially located relatively close to the surface, only slightly affecting the bilayer structure and mobility, while complex 3 penetrates more deeply, strongly perturbing the bilayer and giving rise to lateral phase separation.

Permeation of cisplatin through the membranes of normal and cancer cells: a molecular dynamics study

“…The only computational work which is directly comparable with the present study is the paper of Nierwzicki et al (99) where the permeability of cisplatin in a pure DMPC bilayer was reported as 6.67 10 −7 • −1 . This value is of the same order of magnitude as our result for pure DOPC bilayer.…”

“…There is a high energy barrier in the center of the membrane, which is expected for such hydrophilic compound as cisplatin. The height of the barrier is the smallest for pure DOPC membrane (~40 kJ/mol) which is comparable to previous results obtained in a pure 1,2-dimyristoyl-sn-glycero-3phosphocholine (DMPC) membrane (~50 kJ/mol) (99). For normal membrane with 0% cholesterol it is much higher (~62 kJ/mol) and increases even more with the increase of CHL content (up to 70 kJ/mol).…”

Biophysics in cancer: The relevance of drug-membrane interaction studies

“…Notwithstanding, it causes severe side effects such as neurotoxicity and cellular resistance that are thought to be related to the interplay of cisplatin with biological membranes. Over the years, considerable studies regarding cisplatin interaction with model membranes have been performed [56,[78][79][80][81][82][83]. Particular attention has been paid to anionic phospholipids, such as PS -as they play crucial roles in several cell functions [84]-and their influence in cisplatin-lipid interaction.…”

Cisplatin‐induced alteration on membrane composition of A549 cells revealed by ToF‐SIMS

“…Results indicated that phospholipids such as phosphatidylcholine (PC) make the model cellular membrane more fluidly and would facilitate the passing through of cisplatin for effective intracellular accumulation . In most recent research of the design of Pt(II)‐based drugs, ligands with suitable properties such as polarity and hydrophilicity, which may regulate passive diffusion, are being the focus . Nuclear magnetic resonance (NMR) spectroscopy has been applied to study the interaction of cisplatin as well as potential antitumor complexes with a lipid bilayer, which showed that the structures of the complexes determined different effects on the bilayer structure and mobility and further the depth of their penetration into the bilayer .…”

“…10 Nuclear magnetic resonance (NMR) spectroscopy has been applied to study the interaction of cisplatin as well as potential antitumor complexes with a lipid bilayer, which showed that the structures of the complexes determined different effects on the bilayer structure and mobility and further the depth of their penetration into the bilayer. 10 Such kind of investigations contribute significantly to the understanding of complex-lipid interactions and provide fundamental insights into structural design of new drug candidates. However, due to the difficulty in data acquirement or complexity in interpretation of IR and NMR spectra from real biological membranes, only simple model systems of lipid bilayers were investigated, which might not uncover the real situation in complex cellular membrane systems.…”