title: Controlled nucleation of lipid nanoparticles.
abstract: OBJECTIVE
  We describe a nucleation-based method which allows for the generation of monodisperse lipid nanoparticles over a range of diameters. Using a set of novel zwitterionic lipids and inverse phosphocholine lipids with pKas ranging from 2 to 5, we showed how the hydrodynamic diameter of lipid nanoparticles can be systematically manipulated over a 60 nm to 500 nm size range.
  
  
  METHODS
  Lipid nanoparticles were prepared by adding an anti-solvent, such as water, to the organic phase containing the lipid components. This led to super-saturation and the spontaneous formation of particles.
  
  
  RESULTS
  The growth and final particle size was controlled by the ratio of the components in the ternary system: lipid, organic solvent and aqueous phase. Particles with diameter below 125 nm were formed under conditions where the super-saturation coefficient was between 2.3 and 20. PEG-lipid served as an efficient growth inhibitor except at very high and low lipid concentrations. Encapsulation efficiency of siRNA into lipid nanoparticles was shown to be pH-dependent and requires the protonation of the anionic carboxylate groups of the zwitterionic lipids, emphasizing the importance of electrostatic forces.
  
  
  CONCLUSIONS
  This process enables high encapsulation efficiency of nucleic acids and allows the size of lipid nanoparticles to be controlled.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Nguyen
authors.forename: Colin L
authors.initials: CL
authors.lastname: Walsh
authors.forename: J P Michael
authors.initials: JP
authors.lastname: Motion
authors.forename: Emily K
authors.initials: EK
authors.lastname: Perttu
authors.forename: Francis
authors.initials: F
authors.lastname: Szoka
mesh_terms: D057446:Hydrodynamics; D008055:Lipids / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology; D010316:Particle Size; D010767:Phosphorylcholine / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011522:Protons; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D012997:Solvents
chemical_list: D008055:Lipids; D011522:Protons; D034741:RNA, Small Interfering; D012997:Solvents; D010767:Phosphorylcholine; D011092:Polyethylene Glycols