(267f) Molecular Simulations of Mechanical Properties of Liposomes: Effects of Hydrophobic Small Drug Molecules, Lipid Molecular Structure and Composition.

Liposomes are spherical vesicles formed by a lipid bilayer encapsulating an aqueous core, which are used to protect and carry active ingredients in applications in the pharmaceutical, nutraceutical, cosmetic, food, and textile industries. Recent experimental studies¹ suggest that elastic, softer liposomes exhibit enhanced cellular uptake by cancer cells in vitro and greater tumor accumulation in vivo compared to more rigid liposomes. Through molecular dynamics simulations with all-atom and coarse-grained models, in combination with experiments, we seek to fundamentally understand how the mechanical properties of liposomes are influenced by factors such as the molecular structure of the lipids, liposome composition, and presence of cargo molecules. We first examined how the mechanical properties of DOPC liposomes are affected by the presence of the small drug molecules Panobinostat, Ki16425, or Vorinostat, which can be used in breast cancer treatment but have elevated hydrophobicity. Our results indicate that adding Panobinostat or Ki16425 resulted in softer liposomes, with smaller area compressibility modulus and larger lipid diffusivities compared to blank (pure DOPC) or Vorinostat-containing liposomes. Softer liposomes were observed to have weaker lipid-lipid, drug-lipid, and drug-drug interactions compared to stiffer systems. Building on our previous work,^2,3 we also studied binary mixtures of DOPC with lipids having different headgroups and/or different tail structures. The observed liposome stiffness is rationalized in terms of properties such as lipid tail disorder and headgroup polarity.

REFERENCES

(1) Guo, P.; Liu, D.; Subramanyam, K.; Wang, B.; Yang, J.; Huang, J.; Auguste, D. T.; Moses, M. A. Nanoparticle Elasticity Directs Tumor Uptake. Nat. Commun. 2018, 9 (1), 130. https://doi.org/10.1038/s41467-017-02588-9.

(2) Xu, J.; Karra, V.; Large, D. E.; Auguste, D. T.; Hung, F. R. Understanding the Mechanical Properties of Ultradeformable Liposomes Using Molecular Dynamics Simulations. J. Phys. Chem. B 2023, 127 (44), 9496–9512. https://doi.org/10.1021/acs.jpcb.3c04386.

(3) Xu, J.; Adepoju, S.; Pandey, S.; Pérez Tetuán, J.; Williams, M.; Abdelmessih, R. G.; Auguste, D. T.; Hung, F. R. Effects of Lipid Headgroups on the Mechanical Properties and In Vitro Cellular Internalization of Liposomes. Langmuir 2025, 41 (4), 2600–2618. https://doi.org/10.1021/acs.langmuir.4c04363.