A Study of Liposome Structure Changes with Temperature Using Non-Equilibrium Molecular Dynamics Simulations.

Liposomes, spherical bilayer lipid-containing vesicles, are promising nanocarriers used for constructing drug delivery systems (DDS). Various strategies can be employed to loosen or break the liposome and release drugs as the tumor cells-targeting DDS made of liposomes reach the targeted sites. One of the most commonly used strategies is to heat the liposomal DDS by letting the gold nanoparticles or other light-absorbing substances that partition in various portions (inner water core, lipid bilayer or outside) of the liposome absorb light irradiation. Then, which portion can lead to the largest liposome structure change due to the same temperature variation? The answer is essential to aid the design of liposomal DDS; thus, wet lab experiments were carried out. However, even though irradiation-absorbing substances in different portions were irradiated for the same time and with the same irradiation intensity, it was impossible to ensure the three portions have the same temperature increase in the experiments. Furthermore, it is impossible to learn the related micromechanism and molecular-level details of the effects of temperature changes on the liposome structure with experimental methods. The molecular dynamics (MD) method is extensively employed by researchers to obtain in-depth molecular-level insights. Most researchers tend to simulate only a planar lipid bilayer structure, but Amărandi et al. demonstrated that such simplification strategy may give wrong simulation results contrary to the experimental results. Though Jämbeck et al. and Zhu et al. established whole spherical liposome systems with a diameter of about a dozen nanometers and simulated the systems with MD simulations, they did not simulate temperature-relevant properties of the liposome. Therefore, currently there is a lack of research on simulating the structure change in a whole spherical liposome due to temperature variations. So, we established the whole spherical structure of the liposome, simulated how it changes with temperatures and obtained molecular-level research results. It is observed that the temperature increase in the lipid bilayer causes the largest increase in lipid strand sway amplitude, the largest changes in lipid positions, the largest decrease in the distribution density of lipids and water around a lipid and the largest decrease in the interactions between lipids and lipids and between lipids and water, leading to the largest change in the liposome structure. We also studied how the degree of lipid tail unsaturation affects liposome structure changes with temperatures. Due to the C3 kinks in the unsaturated lipid tails, the distribution density of unsaturated lipids is not as high as saturate ones, leading to smaller attraction interactions and consequently larger liposome structure change with temperature. The obtained results are useful for the liposomal DDS design for the purpose of improving DDS performances and delivery outcomes.