(376f) Computational Study of Liposome Formation in Coaxial Turbulent Jet Flow Using CG-MD and CFD Approaches

Costa, A., UConn
Xu, X., Office of Testing and Research, U.S. Food and Drug Administration
Cruz, C. N., U.S. Food and Drug Administration
Lee, S. L., FDA
Burgess, D., UConn
Chaudhuri, B., University of Connecticut
Purpose: Liposomes are spherical structures consisting of single or multiple lipid-bilayer membranes that circumvent the central aqueous phase. They are used as a carrier for drug delivery systems including anti-cancer and anti-fungal drugs with several FDA-approved clinical applications. We have focused on the continuous process in which two liquid flows are controllably mixed using a jet in co-flow, of which the inner flow consists of a solution of lipids in ethanol and the exterior flow is an aqueous phase. Intermolecular forces between molecules cause lipid aggregation and, along with the jet flow characteristics, results in the formation of liposomes. However, the underlying mechanism as well as details of the process are only partially understood. We have carried out a multi-scale computational study of liposome formation in coaxial turbulent jet flow to probe the underlying mechanism and quantitatively predict liposome properties.

Methods: Both computational fluid dynamics (CFD), as a macro-scale simulation, and coarse-grained molecular dynamics (CG-MD), as a micro-scale investigation, have been conducted to not only reveal the detailed mechanism of liposome formation, but also implement multi-scale case studies for the process.

Results: CFD simulations were verified by comparison of flow pattern as well as formation temperature with experiments. Our CG-MD simulations indicate that MARTINI force field (FF) does not capture a realistic behavior of lipids and cholesterol in ethanol solution since the lipids aggregate which contradicts with the results of the experimentation and all-atom MD simulation. We used a versatile object-oriented toolkit for coarse-graining applications (VOTCA) to optimize MARTINI FF with reference to all-atom MD simulations. Our multi-scale simulations are in accurate agreement with experimental quantitative results and trends.

Conclusions: Discrete and continuum computational modeling of liposome formation cover micro-scale and macro-scale respectively which overlap in a short scale domain due to computational feasibility, therefore these two approaches are complementary to one another. Our CFD simulation shows that including heat of mixing in the energy equation is inevitable in order to obtain a formation temperature comparable with the experiments. Default MARTINI potential energy parameters require optimization with reference to an all-atom MD simulation for properly modeling lipids in ethanol solution.

Acknowledgements: FDA Grant# 1U01FD005773-01.

Disclaimer: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.