Abstract
Introduction of microfluidic mixing technique opens a new door for preparation of the liposomes and lipid-based nanoparticles by on-chip technologies that are applicable in a laboratory and industrial scale. This study demonstrates the role of phospholipid bilayer fragment as the key intermediate in the mechanism of liposome formation by microfluidic mixing in the channel with “herring-bone” geometry used with the instrument NanoAssemblr. The fluidity of the lipid bilayer expressed as fluorescence anisotropy of the probe N,N,N-Trimethyl-4-(6-phenyl-1,3,5-hexatrien-1-yl) was found to be the basic parameter affecting the final size of formed liposomes prepared by microfluidic mixing of an ethanol solution of lipids and water phase. Both saturated and unsaturated lipids together with various content of cholesterol were used for liposome preparation and it was demonstrated, that an increase in fluidity results in a decrease of liposome size as analyzed by DLS. Gadolinium chelating lipids were used to visualize the fine structure of liposomes and bilayer fragments by CryoTEM. Experimental data and theoretical calculations are in good accordance with the theory of lipid disc micelle vesiculation.
Highlights
Introduction of microfluidic mixing technique opens a new door for preparation of the liposomes and lipid-based nanoparticles by on-chip technologies that are applicable in a laboratory and industrial scale
Gadolinium lipid complexes represent a useful tool for visualization of lipid structures by cryoTEM as we demonstrated in this article
Because the liposome preparation by application of microfluidic mixing method is based on similar principles, such as the proliposome-liposome method or ethanol injection method, it is reasonable to assume that bilayer phospholipid fragments (BPF) in the form of disc-like bilayer micelles (DBM) is an intermediate in the process of liposome formation
Summary
Introduction of microfluidic mixing technique opens a new door for preparation of the liposomes and lipid-based nanoparticles by on-chip technologies that are applicable in a laboratory and industrial scale. The fluidity of the lipid bilayer expressed as fluorescence anisotropy of the probe N,N,N-Trimethyl-4-(6-phenyl-1,3,5-hexatrien-1-yl) was found to be the basic parameter affecting the final size of formed liposomes prepared by microfluidic mixing of an ethanol solution of lipids and water phase. Microfluidic methods have demonstrated their ability to control the process of mixing the organic and water phases, the required parameters of final liposomal products like size, polydispersity, morphology, and lamellarity are achieved in a more reproducible way. The process of microfluidic mixing can help in optimizing the method, especially for the production in industrial scale using complex on-chip technology as recently demonstrated[16,17]
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